Myocardial Elasticity Imaging Correlates with Histopathology in a Model of Anthracycline-Induced Cardiotoxicity.

Background: There is considerable focus on developing strategies for identifying subclinical cardiac decline prior to cardiac failure. Myocardial tissue elasticity changes may precede irreversible cardiac damage, providing promise for an early biomarker for cardiac decline. Biomarker strategies are of particular interest in cardio-oncology due to cardiotoxic effects of anti-neoplastic therapies, particularly anthracycline-based chemotherapeutics. Current clinical methods for diagnosing cardiotoxicity are too coarse to identify cardiac decline early enough for meaningful therapeutic intervention, or too cumbersome for clinical implementation. Methods: Utilizing changes in myocardial elasticity as a biomarker for subclinical cardiac decline, we developed a biomechanical model-based elasticity imaging methodology (BEIM) to estimate spatial maps of left ventricle (LV) myocardial elasticity. In this study, we employ this methodology to assess changes in LV elasticity in a non-human primate model of doxorubicin-induced cardiotoxicity. Cardiac magnetic resonance imaging of five African Green monkeys was acquired at baseline prior to doxorubicin administration, 6-weeks, and 15-weeks after final doxorubicin dose and histopathological samples of the LV were taken at 15-weeks after final doxorubicin dose. Spatial elasticity maps of the mid-short axis plane of the LV were estimated at each image acquisition. Global and regional LV elasticity were calculated and changes between imaging time points was assessed. LV elasticity at baseline and final time point were compared to cardiomyocyte size and collagen volume fraction measurements calculated from histopathological staining of archived tissue bank samples and study endpoint tissue samples utilizing Pearson's correlation coefficients. Results: We identify significant changes in LV elasticity between each imaging time point both globally and regionally. We also demonstrate strong correlation between LV elasticity and cardiomyocyte size and collagen volume fraction measurements. Results indicate that LV elasticity estimates calculated using BEIM correlate with histopathological changes that occur due to doxorubicin administration, validating LV elasticity solutions and providing significant promise for use of BEIM to non-invasively elucidate cardiac injury. Conclusions: This methodology can show progressive changes in LV elasticity and has potential to be a more sensitive indicator of elasticity changes than current clinical measures of cardiotoxicity. LV elasticity may provide a valuable biomarker for cardiotoxic effects of anthracycline-based chemotherapeutics and cardiac disease detection.

Quantifying social skill deficits and strengths profiles in autistic youth.

While social difficulties in autism are well-established, questions remain regarding whether these represent challenges in acquiring or performing such skills, reduced social strengths, or a unique distribution across these domains (i.e., social profile). This study empirically derived social profiles of 211 autistic and non-autistic youth (Mage  = 13.50; Autistic N = 150; Male N = 151; 85.3% White). Assessments occurred between 2016 and 2020. Results showed that autistic youth exhibit significantly more social acquisition and performance deficits and fewer strengths than nonautistic youth (ds = -.44 to .65). Performance deficits were most-and acquisition deficits least-prominent within autistic profiles, potentially implicating longstanding theoretical models of social difficulties in autism, and supporting new, idiographic approaches for conceptualizing, assessing, and treating social challenges.

Reproducibility assessment of a biomechanical model-based elasticity imaging method for identifying changes in left ventricular mechanical stiffness.

Purpose: Cardiotoxicity of antineoplastic therapies is increasingly a risk to cancer patients treated with curative intent with years of life to protect. Studies highlight the importance of identifying early cardiac decline in cancer patients undergoing cardiotoxic therapies. Accurate tools to study this are a critical clinical need. Current and emerging methods for assessing cardiotoxicity are too coarse for identifying preclinical cardiac degradation or too cumbersome for clinical implementation. Approach: In the previous work, we developed a noninvasive biomechanical model-based elasticity imaging methodology (BEIM) to assess mechanical stiffness changes of the left ventricle (LV) based on routine cine cardiac magnetic resonance (CMR) images. We examine this methodology to assess methodological reproducibility. We assessed a cohort of 10 participants that underwent test/retest short-axis CMR imaging at baseline and follow-up sessions as part of a previous publicly available study. We compare test images to retest images acquired within the same session to assess within-session reproducibility. We also compare test and retest images acquired at the baseline imaging session to test and retest images acquired at the follow-up imaging session to assess between-session reproducibility. Results: We establish the within-session and between-session reproducibility of our method, with global elasticity demonstrating repeatability within a range previously demonstrated in cardiac strain imaging studies. We demonstrate increased repeatability of global elasticity compared to segmental elasticity for both within-session and between-session. Within-subject coefficients of variation for within-session test/retest images globally for all modulus directions and a mechanical fractional mechanical stiffness anisotropy metric ranged from 11% to 28%. Conclusions: Results suggest that our methodology can reproducibly generate estimates of relative mechanical elasticity of the LV and provides a threshold for distinguishing true changes in myocardial mechanical stiffness from experimental variation. BEIM has applications in identifying preclinical cardiotoxicity in breast cancer patients undergoing antineoplastic therapies.

Are There Resilient Children with ADHD?

OBJECTIVE: The adverse outcomes associated with ADHD are well known, but less is known about the minority of children with ADHD who may be flourishing despite this neurodevelopmental risk. The present multi-informant study is an initial step in this direction with the basic but unanswered question: Are there resilient children with ADHD? METHOD: Reliable change analysis of the BASC-3 Resiliency subscale for a clinically evaluated sample of 206 children with and without ADHD (ages 8-13; 81 girls; 66.5% White/Non-Hispanic). RESULTS: Most children with ADHD are perceived by their parents and teachers as resilient (52.8%-59.2%), with rates that did not differ from the comorbidity-matched Non-ADHD sample. CONCLUSION: Exploratory analyses highlighted the importance of identifying factors that promote resilience for children with ADHD specifically, such that some child characteristics were promotive (associated with resilience for both groups), some were protective (associated with resilience only for children with ADHD), and some were beneficial only for children without ADHD.

Developing a biomechanical model-based elasticity imaging method for assessing hormone receptor positive breast cancer treatment-related myocardial stiffness changes.

Purpose: Assessing cardiotoxicity as a result of breast cancer therapeutics is increasingly important as breast cancer diagnoses are trending younger and overall survival is increasing. With evidence showing that prevention of cardiotoxicity plays a significant role in increasing overall survival, there is an unmet need for accurate non-invasive methods to assess cardiac injury due to cancer therapies. Current clinical methods are too coarse and emerging research methods have not yet achieved clinical implementation. Approach: As a proof of concept, we examine myocardial elasticity imaging in the setting of premenopausal women diagnosed with hormone receptor positive (HR-positive) breast cancer undergoing severe estrogen depletion, as cardiovascular injury from early estrogen depletion is well-established. We evaluate the ability of our model-based cardiac elasticity imaging analysis method to indicate subclinical cancer therapy-related cardiac decline by examining differences in the change in cardiac elasticity over time in two cohorts of premenopausal women either undergoing severe estrogen depletion for HR-positive breast cancer or triple negative breast cancer patients as comparators. Results: Our method was capable of producing functional mechanical elasticity maps of the left ventricle (LV). Using these elasticity maps, we show significant differences in cardiac mechanical elasticity in the HR-positive breast cancer cohort compared to the comparator cohort. Conclusions: We present our methodology to assess the mechanical stiffness of the LV by interrogating cardiac magnetic resonance images within a computational biomechanical model. Our preliminary study suggests the potential of this method for examining cardiac tissue mechanical stiffness properties as an early indicator of cardiac decline.

Clinical assessment of a biophysical model for distinguishing tumor progression from radiation necrosis.

PURPOSE: The efficacy of an imaging-driven mechanistic biophysical model of tumor growth for distinguishing radiation necrosis from tumor progression in patients with enhancing lesions following stereotactic radiosurgery (SRS) for brain metastasis is validated. METHODS: We retrospectively assessed the model using 73 patients with 78 lesions and histologically confirmed radiation necrosis or tumor progression. Postcontrast T1-weighted MRI images were used to extract parameters for a mechanistic reaction-diffusion logistic growth model mechanically coupled to the surrounding tissue. The resulting model was then used to estimate mechanical stress fields, which were then compared with edema visualized on FLAIR imaging using DICE similarity coefficients. DICE, model, and standard radiographic morphometric analysis parameters were evaluated using a receiver operating characteristic (ROC) curve for prediction of radiation necrosis or tumor progression. Multivariate logistic regression models were then constructed using mechanistic model parameters or advanced radiomic features. An independent validation was performed to evaluate predictive performance. RESULTS: Tumor cell proliferation rate resulted in ROC AUC = 0.86, 95% CI: 0.76-0.95, P < 0.0001, 74% sensitivity and 95% specificity) and DICE similarity coefficient associated with high stresses demonstrated an ROC AUC = 0.93, 95% CI: 0.86-0.99, P < 0.0001, 81% sensitivity and 95% specificity. In a multivariate logistic regression model using an independent validation dataset, mechanistic modeling parameters had an ROC AUC of 0.95, with 94% sensitivity and 96% specificity. CONCLUSIONS: Imaging-driven biophysical modeling of tumor growth represents a novel method for accurately predicting clinically significant tumor behavior.

Activities of daily living and working memory in pediatric attention-deficit/hyperactivity disorder (ADHD).

Most children with ADHD have impaired working memory abilities. These working memory deficits predict impairments in activities of daily living (ADLs) for adults with ADHD. However, our understanding of the relation between pediatric ADHD and ADLs is limited. Thus, this study aimed to examine (1) the extent to which pediatric ADHD is associated with ADL difficulties; and if so (2) the extent to which these difficulties are related to their well-documented working memory difficulties and/or core ADHD inattentive and hyperactive/impulsive symptom domains. A well-characterized, clinically evaluated sample of 141 children ages 8-13 years (M = 10.36, SD = 1.46; 51 girls; 70% White/non-Hispanic) were administered a battery of well-validated working memory tests and assessed for ADHD symptoms (teacher-ratings) and ADL difficulties (parent-ratings); cross-informant reports were used to control for mono-informant bias. Children with ADHD exhibited medium magnitude difficulties with ADLs (d = 0.61, p < .005, 38% impaired). Results of the bias-corrected, bootstrapped conditional effects model indicated that lower working memory predicted reduced performance of age-expected ADLs (ß =0.28) and greater ADHD inattentive (ß = -0.40) and hyperactive/impulsive symptoms (ß = -0.16). Greater inattentive, but not hyperactive/impulsive, symptoms predicted greater ADL difficulties (ß = -0.36) even after controlling for working memory. Interestingly, working memory exerted a significant indirect effect on ADLs via inattentive (indirect effect: ß = 0.15, effect ratio = .54) but not hyperactive/impulsive symptoms. These findings implicate ADHD inattentive symptoms as a potential mechanism underlying ADL difficulties for children with ADHD, both independently and via working memory's role in regulating attention.

Evidence against emotion inference deficits in children with ADHD.

Inconsistent evidence suggests that pediatric attention deficit/hyperactivity disorder (ADHD) may be associated with impairments in the ability to use context clues to infer the emotion states of others. However, the evidence base for these impairments is comprised of data from laboratory-based tests of emotion inference that may be confounded by demands on nonaffective cognitive processes that have been linked with ADHD. The current study builds on our previous study of facial affect recognition to address this limitation and investigate a potential mechanism underlying children's ability to infer emotion state from context clues. To do so, we used a fully crossed, counterbalanced experimental design that systematically manipulated emotion inference and working memory demands in 77 carefully phenotyped children ages 8-13 (Mage = 10.46, SD = 1.54; 66% Caucasian/Non-Hispanic; 42% female) with ADHD (n = 42) and without ADHD (n = 35). Results of Bayesian mixed-model ANOVAs indicated that using context clues to infer the emotion state of others competed for neurocognitive resources with the processes involved in rehearsing/maintaining information within working memory (BF10 = 1.57 × 10¹9, d = 0.72). Importantly, there was significant evidence against the critical Group × Condition interaction for response times (BF01 = 4.93), and no significant evidence for this interaction for accuracy (BF01 = 2.40). In other words, children with ADHD do not infer emotions more slowly than children without ADHD (d = 0.13), and their small magnitude impairment in accuracy (d = 0.30) was attributable to their generally less accurate performance on choice-response tasks (i.e., across both emotion and control conditions). Taken together, the evidence indicates that emotion inference abilities are likely unimpaired in pediatric ADHD and that working memory is implicated in the ability to infer emotion from context for all children-not just children with ADHD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A randomized controlled trial of central executive training (CET) versus inhibitory control training (ICT) for ADHD.

OBJECTIVE: Executive function deficits are well-established in ADHD. Unfortunately, replicated evidence indicates that executive function training for ADHD has been largely unsuccessful. We hypothesized that this may reflect insufficient targeting, such that extant protocols do not sufficiently and specifically target the neurocognitive systems associated with phenotypic ADHD behaviors/impairments. METHOD: Children with ADHD ages 8-12 (M = 10.41, SD = 1.46; 12 girls; 74% Caucasian/Non-Hispanic) were randomized with allocation concealment to either central executive training (CET; n = 25) or newly developed inhibitory control training (ICT; n = 29). Detailed data analytic plans were preregistered. RESULTS: Both treatments were feasible/acceptable based on training duration, child-reported ease of use, and parent-reported high satisfaction. CET was superior to ICT for improving its primary intervention targets: phonological and visuospatial working memory (d = 0.70-0.84). CET was also superior to ICT for improving go/no-go (d = 0.84) but not stop-signal inhibition. Mechanisms of change analyses indicated that CET-related working memory improvements produced significant reductions in the primary clinical endpoints (objectively assessed hyperactivity) during working memory and inhibition testing (indirect effects: ß ≥ -.11; 95% CIs exclude 0.0). CET was also superior to ICT on 3 of 4 secondary clinical endpoints (blinded teacher-rated ADHD symptoms; d = 0.46-0.70 vs. 0.16-0.42) and 2 of 4 feasibility/acceptability clinical endpoints (parent-reported ADHD symptoms; d = 0.96-1.42 vs. 0.45-0.65). CET-related gains were maintained at 2-4 month follow-up; ICT-related gains were maintained for attention problems but not hyperactivity/impulsivity per parent report. CONCLUSIONS: Results support the use of CET for treating executive function deficits and targeting ADHD behavioral symptoms in children with ADHD. Findings for ICT were mixed at best and indicate the need for continued development/study. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Executive functioning rating scales: Ecologically valid or construct invalid?

OBJECTIVE: Executive functions are commonly measured using rating scales and performance tests. However, replicated evidence indicates weak/nonsignificant cross-method associations that suggest divergent rather than convergent validity. The current study is the first to investigate the relative concurrent and predictive validities of executive function tests and ratings using (a) multiple gold-standard performance tests, (b) multiple standardized rating scales completed by multiple informants, and (c) both performance-based and ratings-based assessment of academic achievement-a key functional outcome with strong theoretical links to executive function. METHOD: A well-characterized sample of 136 children oversampled for ADHD and other forms of child psychopathology associated with executive dysfunction (ages 8-13; 68% Caucasian/non-Hispanic) completed a counterbalanced series of executive function and academic tests. Parents/teachers completed executive function ratings; teachers also rated children's academic performance. RESULTS: The executive function tests/ratings association was modest (r = .30) and significantly lower than the academic tests/ratings association (r = .63). Relative to ratings, executive function tests showed significantly higher cross-method predictive validity and significantly better within-method prediction; executive function ratings failed to demonstrate improved within-method prediction. Both methods uniquely predicted academic tests and ratings. CONCLUSION: These findings replicate prior evidence that executive function tests and ratings cannot be used interchangeably as executive function measures in research and clinical applications, while suggesting that executive function tests may have superior validity for predicting academic behavior/achievement. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Rethinking hyperactivity in pediatric ADHD: Preliminary evidence for a reconceptualization of hyperactivity/impulsivity from the perspective of informant perceptual processes.

Hyperactivity is a core ADHD symptom that has been both positively and negatively associated with cognition and functional outcomes. The reason for these conflicting findings is unclear but may relate to subjective assessments that conflate excess physical movement (hyperactivity) with verbally intrusive/impulsive behaviors. The current study adopted a model-driven, rational-empirical approach to distinguish excess physical movement symptoms from other, auditorily perceived behaviors assessed under the "hyperactivity/impulsivity" umbrella. We then tested this alternative conceptualization's fit, reliability, replicability, convergent/divergent validity via actigraphy, and generalizability across informants (parents, teachers) in a well-characterized, clinically evaluated sample of 132 children ages 8-13 years (M = 10.34, SD = 1.51; 47 girls; 67% White/non-Hispanic). The current DSM hyperactivity/impulsivity item pool can be reliably reclassified by knowledgeable judges into items reflecting excess physical movement (visual hyperactivity) and auditory interruptions (verbal intrusion). This bifactor structure showed evidence for multidimensionality and superior model fit relative to traditional hyperactivity/impulsivity models. The resultant visual hyperactivity factor was reliable, replicable, and showed strong convergent validity evidence via associations with objectively assessed hyperactivity. The verbal intrusion factor also showed evidence for reliability and explained a substantive portion of reliable variance, but demonstrated lower estimated replicability. These findings provide preliminary support for conceptualizing ADHD symptoms from the perspective of their cognitive-perceptual impact on others, as well as differentiating excess physical movement (hyperactivity) from other behaviors assessed under the hyperactivity/impulsivity umbrella. "Verbal intrusion" appears to provide a better explanation than "impulsivity" for the reliable, non-hyperactivity variance assessed by these items, but the current item set appears insufficient for replicable measurement of this construct. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Working memory and short-term memory deficits in ADHD: A bifactor modeling approach.

Objective: Attention-deficit/hyperactivity disorder (ADHD) has been associated with large magnitude impairments in working memory, whereas short-term memory deficits, when detected, tend to be less pronounced. However, confidence in these findings is limited due to task impurity combined with methodological and statistical limitations of the current evidence base. Method: A well-characterized, clinically evaluated sample of 172 children ages 8-13 years (M = 10.30, SD = 1.42; 72 girls; 64% White/non-Hispanic) were administered multiple, counterbalanced working memory tests. Bifactor-(s-1) modeling was used to characterize the presence and magnitude of central executive working memory, phonological short-term memory, and visuospatial short-term memory deficits in pediatric ADHD. Results: ADHD status was associated with very large magnitude impairments in central executive working memory that are present in most pediatric cases (d = 1.63-2.03; 75%-81% impaired), and these deficits covaried with ADHD inattentive and hyperactive/impulsive symptom severity based on both parent and teacher report. There was also evidence for a unique, albeit significantly smaller, impairment in visuospatial short-term memory (d = 0.60; 38% impaired); however, visuospatial short-term memory abilities did not covary with ADHD symptom severity. There was no evidence linking ADHD with phonological short-term memory deficits across either the dimensional or categorical analyses. Conclusion: These findings provide strong evidence that ADHD is associated with marked central executive working memory deficits that covary with their behavioral symptom presentation across settings. In contrast, visuospatial short-term memory deficits, when present, are likely epiphenomenal, and the most parsimonious conclusion appears to be that phonological short-term memory is intact in pediatric ADHD. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

What cognitive processes are "sluggish" in sluggish cognitive tempo?

OBJECTIVE: Sluggish cognitive tempo refers to a constellation of symptoms that include slowed behavior/thinking, reduced alertness, and getting lost in one's thoughts. Despite the moniker "sluggish cognitive tempo," the evidence is mixed regarding the extent to which it is associated globally with slowed (sluggish) mental (cognitive) information processing speed (tempo). METHOD: A well-characterized clinical sample of 132 children ages 8-13 years (M = 10.34, SD = 1.51; 47 girls; 67% White/non-Hispanic) were administered multiple, counterbalanced neurocognitive tests and assessed for sluggish cognitive tempo symptoms via multiple-informant reports. RESULTS: Bayesian linear regressions revealed significant evidence against associations between sluggish cognitive tempo and computationally modeled processing speed (BF01 > 3.70), and significant evidence for associations with slower working memory manipulation speed. These findings were consistent across parent and teacher models, with and without control for attention-deficit/hyperactivity disorder inattentive symptoms and IQ. There was also significant evidence linking faster inhibition speed with higher parent-reported sluggish cognitive tempo symptoms. CONCLUSIONS: These findings provide strong evidence against characterizing children with sluggish cognitive tempo symptoms as possessing a globally sluggish cognitive tempo. Instead, these symptoms appear to be related, to a significant extent, to executive dysfunction characterized by working memory systems that are too slow and inhibition systems that are too fast. Behaviorally, these findings suggest that requiring extra time to rearrange the active contents of working memory delays responding, whereas an overactive inhibition system likely terminates thoughts too quickly and therefore prevents intended behaviors from starting or completing, thereby giving the appearance that children are absent-minded or failing to act when expected. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Who is likely to benefit from phase II cardiac rehabilitation?

PURPOSE: To ascertain which patients are most likely to benefit from a phase II cardiac rehabilitation (CR) program. METHODS: A retrospective chart review was conducted on 425 patients who completed a 6-minute walk test (6MWT), body weight (BW), and the Medical Outcomes Short Form Health Survey physical (PCS) and mental (MCS) component scores before and after CR. These variables were compared between patients who attended 24 or less and 25 or more sessions and between tertiles on the basis of initial 6MWT and the relative change in 6MWT. RESULTS: The entire cohort of patients improved their 6MWT 20.1 +/- 16.3% with CR (P < .001). On average, patients experienced a modest reduction in BW (P = .03) and had higher PCS and MCS scores (P < .001 for both) after CR. The improvement in 6MWT was inversely related to initial walk distance (r = -0.465, P < .001). Patients in the lowest initial 6MWT tertile exhibited greater improvement in the 6MWT than those in the highest tertile (28 +/- 20 vs 13 +/- 10%, P < .001). Patients who attended 25 or more sessions demonstrated greater 6MWT (20 +/- 18 vs 18 +/- 14%, P = .012) and reductions in BW (-1.3 +/- 2.8 vs -0.5 +/- 2.5 kg, P = .003) than those attending 24 or fewer sessions. Patients exhibiting greater than 23% improvement in 6MWT lost more BW (-1.4 +/- 2.9 vs -0.6 +/- 2.5 kg, P = .006) and exhibited greater PCS (10.2 +/- 9.8 vs 6.3 +/- 9.4, P = .004) than those exhibiting <12% improvement. CONCLUSIONS: Most patients benefit physically and mentally from CR. Patients with lower initial functional ability and who attend 25 or more sessions enjoy the greatest improvements in walking ability and perception of physical health and function.