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.

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.

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.

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.

Effects of medication on neuroimaging findings in bipolar disorder: an updated review.

OBJECTIVE: Neuroimaging is an important tool for better understanding the neurobiological underpinnings of bipolar disorder (BD). However, potential study participants are often receiving psychotropic medications which can possibly confound imaging data. To better interpret the results of neuroimaging studies in BD, it is important to understand the impact of medications on structural magnetic resonance imaging (sMRI), functional MRI (fMRI), and diffusion tensor imaging (DTI). METHODS: To better understand the impact of medications on imaging data, we conducted a literature review and searched MEDLINE for papers that included the key words bipolar disorder and fMRI, sMRI, or DTI. The search was limited to papers that assessed medication effects and had not been included in a previous review by Phillips et al. (Medication effects in neuroimaging studies of bipolar disorder. Am J Psychiatry 2008; 165: 313-320). This search yielded 74 sMRI studies, 46 fMRI studies, and 15 DTI studies. RESULTS: Medication appeared to influence many sMRI studies, but had limited impact on fMRI and DTI findings. From the structural studies, the most robust finding (20/45 studies) was that lithium was associated with increased volumes in areas important for mood regulation, while antipsychotic agents and anticonvulsants were generally not. Regarding secondary analysis of the medication effects of fMRI and DTI studies, few showed significant effects of medication, although rigorous analyses were typically not possible when the majority of subjects were medicated. Medication effects were more frequently observed in longitudinal studies designed to assess the impact of particular medications on the blood oxygen level-dependent (BOLD) signal. With a few exceptions, the observed effects were normalizing, meaning that the medicated individuals with BD were more similar than their unmedicated counterparts to healthy subjects. CONCLUSIONS: The effects of psychotropic medications, when present, are predominantly normalizing and thus do not seem to provide an alternative explanation for differences in volume, white matter tracts, or BOLD signal between BD participants and healthy subjects. However, the normalizing effects of medication could obfuscate differences between BD and healthy subjects, and thus might lead to type II errors.

Brain activation to facial expressions in youth with PTSD symptoms.

OBJECTIVE: This study examined activation to facial expressions in youth with a history of interpersonal trauma and current posttraumatic stress symptoms (PTSS) compared to healthy controls (HC). DESIGN AND ANALYSIS: Twenty-three medication-naive youth with PTSS and 23 age- and gender-matched HC underwent functional magnetic resonance imaging (fMRI) while viewing fearful, angry, sad, happy, and neutral faces. Data were analyzed for group differences in location of activation, as well as timing of activation during the early versus late phase of the block. Using SPM5, significant activation (P < .05 FWE [Family-Wise Error] corrected, extent = 10 voxels) associated with the main effect of group was identified. Activation from selected clusters was extracted to SPSS software for further analysis of specific facial expressions and temporal patterns of activation. RESULTS: The PTSS group showed significantly greater activation than controls in several regions, including the amygdala/hippocampus, medial prefrontal cortex, insula, and ventrolateral prefrontal cortex, and less activation than controls in the dorsolateral prefrontal cortex (DLPFC). These group differences in activation were greatest during angry, happy, and neutral faces, and predominantly during the early phase of the block. Post hoc analyses showed significant Group × Phase interactions in the right amygdala and left hippocampus. CONCLUSIONS: Traumatic stress may impact development of brain regions important for emotion processing. Timing of activation may be altered in youth with PTSS.

Aberrant Neural Response to Social Exclusion Without Significantly Greater Distress in Youth With Bipolar Disorder: Preliminary Findings.

Background: Little is known about the effects of social exclusion on youth with bipolar disorder (BD). Understanding these effects and the functional neural correlates of social exclusion in youth with BD may establish differences from healthy youth and help identify areas of intervention. Methods: We investigated brain function in 19 youth with BD and 14 age and gender matched healthy control (HC) participants while performing Cyberball, an fMRI social exclusion task. Whole brain activation, region-of-interest, and functional connectivity were compared between groups and examined with behavioral measures. Results: Compared with the HC group, youth with BD exhibited greater activation in the left fusiform gyrus (FFG) during social exclusion. Functional connectivity between the left FFG and the posterior cingulate/precuneus was significantly greater in the HC compared with the BD group. For the HC group only, age and subjective distress during Cyberball significantly predicted mean FFG activation. No significant differences in distress during social exclusion were found between groups. Conclusion: Although preliminary due to small sample size, these data suggest that youth with BD process social exclusion in a manner that focuses on basic visual information while healthy youth make use of past experiences to interpret current social encounters. This difference may account for the social cognitive issues experienced by youth with BD, which can lead to more severe anxiety and mood symptoms.

Work-loop contractions reveal that the afterload-dependent time course of cardiac Ca2+ transients is modulated by preload.

Preload and afterload dictate the dynamics of the cyclical work-loop contraction that the heart undergoes in vivo. Cellular Ca2+ dynamics drive contraction, but the effects of afterload alone on the Ca2+ transient are inconclusive. To our knowledge, no study has investigated whether the putative afterload dependence of the Ca2+ transient is preload dependent. This study is designed to provide the first insight into the Ca2+ handling of cardiac trabeculae undergoing work-loop contractions, with the aim to examine whether the conflicting afterload dependency of the Ca2+ transient can be accounted for by considering preload under isometric and physiological work-loop contractions. Thus, we subjected ex vivo rat right-ventricular trabeculae, loaded with the fluorescent dye Fura-2, to work-loop contractions over a wide range of afterloads at two preloads while measuring stress, length changes, and Ca2+ transients. Work-loop control was implemented with a real-time Windkessel model to mimic the contraction patterns of the heart in vivo. We extracted a range of metrics from the measured steady-state twitch stress and Ca2+ transients, including the amplitudes, time courses, rates of rise, and integrals. Results show that parameters of stress were afterload and preload dependent. In contrast, the parameters associated with Ca2+ transients displayed a mixed dependence on afterload and preload. Most notably, its time course was afterload dependent, an effect augmented at the greater preload. This study reveals that the afterload dependence of cardiac Ca2+ transients is modulated by preload, which brings the study of Ca2+ transients during isometric contractions into question when aiming to understand physiological Ca2+ handling.NEW & NOTEWORTHY This study is the first examination of Ca2+ handling in trabeculae undergoing work-loop contractions. These data reveal that reducing preload diminishes the influence of afterload on the decay phase of the cardiac Ca2+ transient. This is significant as it reconciles inconsistencies in the literature regarding the influence of external loads on cardiac Ca2+ handling. Furthermore, these findings highlight discrepancies between Ca2+ handling during isometric and work-loop contractions in cardiac trabeculae operating at their optimal length.

Modeling and experimental approaches for elucidating multi-scale uterine smooth muscle electro- and mechano-physiology: A review.

The uterus provides protection and nourishment (via its blood supply) to a developing fetus, and contracts to deliver the baby at an appropriate time, thereby having a critical contribution to the life of every human. However, despite this vital role, it is an under-investigated organ, and gaps remain in our understanding of how contractions are initiated or coordinated. The uterus is a smooth muscle organ that undergoes variations in its contractile function in response to hormonal fluctuations, the extreme instance of this being during pregnancy and labor. Researchers typically use various approaches to studying this organ, such as experiments on uterine muscle cells, tissue samples, or the intact organ, or the employment of mathematical models to simulate the electrical, mechanical and ionic activity. The complexity exhibited in the coordinated contractions of the uterus remains a challenge to understand, requiring coordinated solutions from different research fields. This review investigates differences in the underlying physiology between human and common animal models utilized in experiments, and the experimental interventions and computational models used to assess uterine function. We look to a future of hybrid experimental interventions and modeling techniques that could be employed to improve the understanding of the mechanisms enabling the healthy function of the uterus.

In vivo multi-channel measurement of electrical activity of the non-pregnant rat uterus.

In the uterus, the characteristics of smooth muscle contraction and the electrical activity that drives this contraction depends on hormonal cycles, and pregnancy status. Smooth muscle contraction is initiated by a change in membrane electrical potential, due to the flux of ions in and out of the intracellular space. Chains of action potentials throughout a section of muscle can result in coordinated contraction events. In this study, flexible printed circuit electrode arrays were applied to measure the bioelectric signals on the surface of a rat uterus in vivo. Variations in the electrical activity were quantified, including intermittent periods of activity and inactivity, which contain both slow-wave type activity (0.039 Hz ±0.017 Hz) and faster, spike-like activity (3.26 Hz ±0.27 Hz). The spike activity initiated at the ovarian end of the uterine horn, spreading towards the cervical end with a propagation velocity of 5.34 ± 2.32 mm [Formula: see text]. In conclusion, this pilot study outlines a new method of in vivo measurement of uterine electrical activity in rats. Clinical Relevance- Measurement of bioelectrical data using in vivo techniques provides insight into the electromechanical function of uterine smooth muscle, which could provide insights into what drives coordinated contraction in the uterus.

Metabolic syndrome predictors of brain gray matter volume in an age-stratified community sample of 776 Mexican- American adults: Results from the genetics of brain structure image archive.

Introduction: This project aimed to investigate the association between biometric components of metabolic syndrome (MetS) with gray matter volume (GMV) obtained with magnetic resonance imaging (MRI) from a large cohort of community-based adults (n = 776) subdivided by age and sex and employing brain regions of interest defined previously as the "Neural Signature of MetS" (NS-MetS). Methods: Lipid profiles, biometrics, and regional brain GMV were obtained from the Genetics of Brain Structure (GOBS) image archive. Participants underwent T1-weighted MR imaging. MetS components (waist circumference, fasting plasma glucose, triglycerides, HDL cholesterol, and blood pressure) were defined using the National Cholesterol Education Program Adult Treatment Panel III. Subjects were grouped by age: early adult (18-25 years), young adult (26-45 years), and middle-aged adult (46-65 years). Linear regression modeling was used to investigate associations between MetS components and GMV in five brain regions comprising the NS-MetS: cerebellum, brainstem, orbitofrontal cortex, right insular/limbic cluster and caudate. Results: In both men and women of each age group, waist circumference was the single component most strongly correlated with decreased GMV across all NS-MetS regions. The brain region most strongly correlated to all MetS components was the posterior cerebellum. Conclusion: The posterior cerebellum emerged as the region most significantly associated with MetS individual components, as the only region to show decreased GMV in young adults, and the region with the greatest variance between men and women. We propose that future studies investigating neurological effects of MetS and its comorbidities-namely diabetes and obesity-should consider the NS-MetS and the differential effects of age and sex.