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Mild traumatic brain injury (mTBI) and posttraumatic stress are prevalent in military service members and share objective and subjective cognitive symptoms, complicating recovery. We investigated the effects of remote mTBI characteristics and current posttraumatic stress symptoms on neuropsychological performance in 152 veterans with a history of remote mTBI and current cognitive concerns. Participants completed clinical neuropsychological evaluations within a Veterans Affairs Level-II TBI/Polytrauma outpatient clinic (i.e. tertiary trauma care center for US military veterans outside of a research or teaching hospital setting). Archival data analysis of mTBI injury characteristics, clinical diagnoses, scores on the Posttraumatic Stress Disorder Checklist-Military Version (PCL-M) and performance on tests of processing speed, attention and executive function was conducted. Hierarchical linear regression demonstrated that elevated PCL-M scores were associated with slower performance on trail making test (TMT) Parts A and B (p < .016). PCL-M symptoms moderated the effect of alteration of consciousness (AOC) on TMT performance, with endorsement of AOC associated with better performance, but only when PCL-M scores were high (p < .005). Follow-up mediation analyses demonstrated that PCL-M score fully mediated the relationship between AOC and TMT-A performance and partially mediated the relationship between AOC and TMT-B performance. Post-hoc analyses meant to separate the impact of processing speed on TMT-B were all non-significant. Remote mTBI characteristics, specifically AOC, were not associated with decrements in cognitive performance. Posttraumatic symptoms were associated with worse processing speed, suggesting that psychological distress and psychopathology are contributing factors in understanding and treating persistent cognitive distress following remote mTBI., (© 2024 The British Psychological Society.)

Background: Deep-learning (DL) methods are rapidly changing the way researchers classify neurological disorders. For example, combining functional magnetic resonance imaging (fMRI) and DL has helped researchers identify functional biomarkers of neurological disorders (e.g., brain activation and connectivity) and pilot innovative diagnostic models. However, the knowledge required to perform DL analyses is often domain-specific and is not widely taught in the brain sciences (e.g., psychology, neuroscience, and cognitive science). Conversely, neurological diagnoses and neuroimaging training (e.g., fMRI) are largely restricted to the brain and medical sciences. In turn, these disciplinary knowledge barriers and distinct specializations can act as hurdles that prevent the combination of fMRI and DL pipelines. The complexity of fMRI and DL methods also hinders their clinical adoption and generalization to real-world diagnoses. For example, most current models are not designed for clinical settings or use by nonspecialized populations such as students, clinicians, and healthcare workers. Accordingly, there is a growing area of assistive tools (e.g., software and programming packages) that aim to streamline and increase the accessibility of fMRI and DL pipelines for the diagnoses of neurological disorders., Objectives and Methods: In this study, we present an introductory guide to some popular DL and fMRI assistive tools. We also create an example autism spectrum disorder (ASD) classification model using assistive tools (e.g., Optuna, GIFT, and the ABIDE preprocessed repository), fMRI, and a convolutional neural network., Results: In turn, we provide researchers with a guide to assistive tools and give an example of a streamlined fMRI and DL pipeline., Conclusions: We are confident that this study can help more researchers enter the field and create accessible fMRI and deep-learning diagnostic models for neurological disorders., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

This study explores the neural underpinnings of cognitive control deficits in ADHD, focusing on overlooked aspects of trial-level variability of neural coding. We employed a novel computational approach to neural decoding on a single-trial basis alongside a cued stop-signal task which allowed us to distinctly probe both proactive and reactive cognitive control. Typically developing (TD) children exhibited stable neural response patterns for efficient proactive and reactive dual control mechanisms. However, neural coding was compromised in children with ADHD. Children with ADHD showed increased temporal variability and diminished spatial stability in neural responses in salience and frontal-parietal network regions, indicating disrupted neural coding during both proactive and reactive control. Moreover, this variability correlated with fluctuating task performance and with more severe symptoms of ADHD. These findings underscore the significance of modeling single-trial variability and representational similarity in understanding distinct components of cognitive control in ADHD, highlighting new perspectives on neurocognitive dysfunction in psychiatric disorders., Competing Interests: Competing financial interests The authors declare no competing financial interests.

Psychopathology in youth is highly prevalent and associated with psychopathology in adulthood. However, the developmental trajectories of psychopathology symptoms, including potential gender differences, are markedly underspecified. The present study employed a directed network approach to investigate longitudinal relationships and gender differences among eight transdiagnostic symptom domains across three years, in a homogenous age sample of youth participants (n = 6,414; mean baseline age = 10.0 years; 78.6% White; Adolescent Brain Cognitive Development study). Anxious/depressed problems and aggressive behaviors were central symptoms and most predictive of increases in other symptom clusters at later timepoints. Rule-breaking behaviors, aggressive behaviors, and withdrawn/depressed problems emerged as bridge symptoms between externalizing and internalizing problems. Results supported cascade models in which externalizing problems predicted future internalizing problems, but internalizing problems also significantly predicted future externalizing problems, which is contrary to cascade models. Network structure, symptom centrality, and patterns of bridge symptoms differed between female and male participants, suggesting gender differences in the developmental trajectories of youth psychopathology. Results provide new insights into symptom trajectories and associated gender differences that may provide promising pathways for understanding disorder (dis)continuity and co-occurrence. The central and bridge symptoms identified here may have important implications for screening and early intervention for youth psychopathology., (© 2023. The Author(s).)

Many current statistical and machine learning methods have been used to explore Alzheimer's disease (AD) and its associated patterns that contribute to the disease. However, there has been limited success in understanding the relationship between cognitive tests, biomarker data, and patient AD category progressions. In this work, we perform exploratory data analysis of AD health record data by analyzing various learned lower dimensional manifolds to separate early-stage AD categories further. Specifically, we used Spectral embedding, Multidimensional scaling, Isomap, t-Distributed Stochastic Neighbour Embedding, Uniform Manifold Approximation and Projection, and sparse denoising autoencoder based manifolds on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. We then determine the clustering potential of the learned embeddings and then determine if category sub-groupings or sub-categories can be found. We then used a Kruskal-sWallis H test to determine the statistical significance of the discovered AD subcategories. Our results show that the existing AD categories do exhibit sub-groupings, especially in mild cognitive impairment transitions in many of the tested manifolds, showing there may be a need for further subcategories to describe AD progression., (© 2023. The Author(s).)

Cognitive control deficits are a hallmark of attention deficit hyperactivity disorder (ADHD) in children. Theoretical models posit that cognitive control involves reactive and proactive control processes but their distinct roles and inter-relations in ADHD are not known, and the contributions of proactive control remain vastly understudied. Here, we investigate the dynamic dual cognitive control mechanisms associated with both proactive and reactive control in 50 children with ADHD (16F/34M) and 30 typically developing (TD) children (14F/16M) aged 9-12 years across two different cognitive controls tasks using a within-subject design. We found that while TD children were capable of proactively adapting their response strategies, children with ADHD demonstrated significant deficits in implementing proactive control strategies associated with error monitoring and trial history. Children with ADHD also showed weaker reactive control than TD children, and this finding was replicated across tasks. Furthermore, while proactive and reactive control functions were correlated in TD children, such coordination between the cognitive control mechanisms was not present in children with ADHD. Finally, both reactive and proactive control functions were associated with behavioral problems in ADHD, and multi-dimensional features derived from the dynamic dual cognitive control framework predicted inattention and hyperactivity/impulsivity clinical symptoms. Our findings demonstrate that ADHD in children is characterized by deficits in both proactive and reactive control, and suggest that multi-componential cognitive control measures can serve as robust predictors of clinical symptoms., (© 2023. The Author(s).)

The Alzheimer's disease (AD) continuum is a unique spectrum of cognitive impairment that typically involves the stages of subjective memory complaints (SMC), mild cognitive impairment (MCI), and AD dementia. Neuropsychiatric symptoms (NPS), such as apathy, anxiety, stress, and depression, are highly common throughout the AD continuum. However, there is a dearth of research on how these NPS vary across the AD continuum, especially SMC. There is also disagreement on the effects of specific NPS on each stage of the AD continuum due to their collinearity with other NPS, cognitive decline, and environmental factors (e.g., stress). In this article, we conduct a novel perspective review of the scientific literature to understand the presence of NPS across the AD continuum. Specifically, we review the effects of apathy, depression, anxiety, and stress in AD, MCI, and SMC. We then build on this knowledge by proposing two theories of NPS' occurrence across the AD continuum. Consequently, we highlight the current landscape, limitations (e.g., differing operationalization), and contentions surrounding the NPS literature. We also outline theories that could clear up contention and inspire future NPS research., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) is currently diagnosed using a mixture of psychological tests and clinical observations. However, these diagnoses are not perfect, and additional diagnostic tools (e.g., MRI) can help improve our understanding of AD as well as our ability to detect the disease. Accordingly, a large amount of research has been invested into innovative diagnostic methods for AD. Functional MRI (fMRI) is a form of neuroimaging technology that has been used to diagnose AD; however, fMRI is incredibly noisy, complex, and thus lacks clinical use. Nonetheless, recent innovations in deep learning technology could enable the simplified and streamlined analysis of fMRI. Deep learning is a form of artificial intelligence that uses computer algorithms based on human neural networks to solve complex problems. For example, in fMRI research, deep learning models can automatically denoise images and classify AD by detecting patterns in participants' brain scans. In this systematic review, we investigate how fMRI (specifically resting-state fMRI) and deep learning methods are used to diagnose AD. In turn, we outline the common deep neural network, preprocessing, and classification methods used in the literature. We also discuss the accuracy, strengths, limitations, and future direction of fMRI deep learning methods. In turn, we aim to summarize the current field for new researchers, suggest specific areas for future research, and highlight the potential of fMRI to aid AD diagnoses., (© 2022 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Objective: To investigate whether the BDNF Val66Met polymorphism influences the associations of hypertension, executive functioning and processing speed in older adults diagnosed with amnestic Mild Cognitive Impairment (aMCI)., Design: Secondary data analysis using moderation modeling., Setting: Veterans Affairs Hospital, Palo Alto, CA., Participants: Sample included 108 community-dwelling volunteers (mean age 71.3 ± 9.2 years) diagnosed with aMCI., Measurements: Cognitive performance was evaluated from multiple baseline assessments (Trail Making Test; Stroop Color-Word Test; Symbol Digit Modality Test) and grouped into standardized composite scores representing executive function and processing speed domains. BDNF genotypes were determined from whole blood samples. Hypertension was assessed from resting blood pressures or by self-report., Results: Controlling for age, BDNF Val66Met moderated the effects of hypertension on executive functioning, but added no significant variance to processing speed scores. Specifically, hypertensive carriers of the BDNF Met allele performed significantly below the sample mean on tasks of executive functioning, and evidenced significantly lower scores when compared to Val-Val homozygotes and normotensive participants., Conclusions: Results posit that the executive functioning of non-demented older adults may be susceptible to interactions between BDNF genotype and hypertension, and Val-Val homozygotes and normotensive older adults may be more resilient to these effects of cognitive change. Further research is needed to understand the underlying processes and to implement strategies that target modifiable risk factors and promote cognitive resilience., Competing Interests: DISCLOSURES The authors report no conflicts with any product mentioned or concept discussed in this article. No disclosures to report., (Published by Elsevier Inc.)

The Penn State Worry Questionnaire (PSWQ) is a widely used assessment of excessive worry. American undergraduate samples have predominately been used to evaluate its factor structure, which may not generalize to other developmental, cultural, and psychopathology populations. The present study tested the PSWQ's factor structure across three diverse samples: American undergraduate students ( n = 3,243), Dutch high school students ( n = 3,906), and American adults with psychopathology ( n = 384). Exploratory, confirmatory, and multigroup confirmatory factor analyses were conducted. Measurement invariance and concurrent validity were also tested. Method-factor and two-factor models were largely equivalent and superior to a one-factor model. Invariance tests supported configural and metric invariance but only partial scalar invariance. Positively worded items but not negatively worded items demonstrated concurrent validity with anxiety and depression symptom measures and diagnoses. Overall, the PSWQ appears to measure a unitary construct. Present results warrant further testing of the PSWQ across diverse samples.

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are highly prevalent, co-occurring disorders with significant symptom overlap, posing challenges in accurately distinguishing and diagnosing these disorders. The tripartite model proposes that anxious arousal is specific to anxiety and anhedonia is specific to depression, though anxious apprehension may play a greater role in GAD than anxious arousal. The present study tested the efficacy of the Mood and Anxiety Symptom Questionnaire anhedonic depression (MASQ-AD) and anxious arousal (MASQ-AA) scales and the Penn State Worry Questionnaire (PSWQ) in identifying lifetime or current MDD, current major depressive episode (MDE), and GAD using binary support vector machine learning algorithms in an adult sample (n = 150). The PSWQ and MASQ-AD demonstrated predictive utility in screening for and identification of GAD and current MDE respectively, with the MASQ-AD eight-item subscale outperforming the MASQ-AD 14-item subscale. The MASQ-AA did not predict MDD, current MDE, or GAD, and the MASQ-AD did not predict current or lifetime MDD. The PSWQ and MASQ-AD are efficient and accurate screening tools for GAD and current MDE. Results support the tripartite model in that anhedonia is unique to depression, but inclusion of anxious apprehension as a separate dimension of anxiety is warranted., (Copyright © 2022. Published by Elsevier B.V.)

Objective: There is a growing recognition that the use of conventional norms (e.g., age, sex, years of education, race) as proxies to capture a broad range of sociocultural variability on cognitive performance is suboptimal, limiting sample representativeness. The present study evaluated the incremental utility of family income, family conflict, and acculturation beyond the established associations of age, gender,maternal years of education, and race on cognitive performance., Method: Hierarchical linear regressions evaluated the incremental utility of sociocultural factors on National Institutes of Health Toolbox in a nationally representative sample of pre-adolescent children (n = 11,878; Mage = 10.0 years; Adolescent Brain Cognitive Development Study). A regression-based norming procedure was implemented for significant models. Paired sample t-tests were used to compare original and newly created demographically corrected T-scores., Results: Nearly all regression models predicted performance on the NIH-TB subtests and composite scores (p < .005). Greater family income and lower family conflict predicted better performance, although the effect sizes were small by traditional standards. Acculturation scores did not explain additional variance in cognitive performance. Lastly, there were no significant differences between the original and newly created demographically corrected T-scores (Mdiff < 0.50)., Conclusions: The present study highlights that, although family income, family conflict, and acculturation have been shown to routinely influence cognitive performance in preadolescent children, the NIH-TB appears to be highly robust to individual differences in sociocultural factors in children between ages 9 and 10. Contextual and temporal implications of the present results are discussed., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Anhedonia is a prominent characteristic of depression and related pathology that is associated with a prolonged course of mood disturbance and treatment resistance. However, the neurobiological mechanisms of anhedonia are poorly understood as few studies have disentangled the specific effects of anhedonia from other co-occurring symptoms. Here, we take a transdiagnostic, dimensional approach to distinguish anhedonia alterations from other internalizing symptoms on intrinsic functional brain circuits. 53 adults with varying degrees of anxiety and/or depression completed resting-state fMRI. Neural networks were identified through independent components analysis. Dual regression was used to characterize within-network functional connectivity alterations associated with individual differences in anhedonia. Modulation of between-network functional connectivity by anhedonia was tested using region-of-interest to region-of-interest correlational analyses. Anhedonia was associated with visual network hyperconnectivity and expansion of the visual, dorsal attention, and default networks. Additionally, anhedonia was associated with decreased between-network connectivity among default, salience, dorsal attention, somatomotor, and visual networks. Findings suggest that anhedonia is associated with aberrant connectivity and structural alterations in resting-state networks that contribute to impairments in reward learning, low motivation, and negativity bias characteristic of depression. Results reveal dissociable effects of anhedonia on resting-state network dynamics, characterizing possible neurocircuit mechanisms for intervention., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A rapid increase in the number of patients with Alzheimer's disease (AD) is expected over the next decades. Accordingly, there is a critical need for early-stage AD detection methods that can enable effective treatment strategies. In this study, we consider the ability of episodic-memory measures to predict mild cognitive impairment (MCI) to AD conversion and thus, detect early-stage AD. For our analysis, we studied 307 participants with MCI across four years using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using a binary logistic regression, we compared episodic-memory tests to each other and to prominent neuroimaging methods in MCI converter (MCI participants who developed AD) and MCI non-converter groups (MCI participants who did not develop AD). We also combined variables to test the accuracy of mixed-predictor models. Our results indicated that the best predictors of MCI to AD conversion were the following: a combined episodic-memory and neuroimaging model in year one (59.8%), the Rey Auditory Verbal Learning Test in year two (71.7%), a mixed episodic-memory predictor model in year three (77.7%) and the Logical Memory Test in year four (77.2%) of ADNI. Overall, we found that individual episodic-memory measure and mixed models performed similarly when predicting MCI to AD conversion. Comparatively, individual neuroimaging measures predicted MCI conversion worse than chance. Accordingly, our results indicate that episodic-memory tests could be instrumental in detecting early-stage AD and enabling effective treatment., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Children with Attention Deficit Hyperactivity Disorder (ADHD) have prominent deficits in sustained attention that manifest as elevated intra-individual response variability and poor decision-making. Influential neurocognitive models have linked attentional fluctuations to aberrant brain dynamics, but these models have not been tested with computationally rigorous procedures. Here we use a Research Domain Criteria approach, drift-diffusion modeling of behavior, and a novel Bayesian Switching Dynamic System unsupervised learning algorithm, with ultrafast temporal resolution (490 ms) whole-brain task-fMRI data, to investigate latent brain state dynamics of salience, frontoparietal, and default mode networks and their relation to response variability, latent decision-making processes, and inattention. Our analyses revealed that occurrence of a task-optimal latent brain state predicted decreased intra-individual response variability and increased evidence accumulation related to decision-making. In contrast, occurrence and dwell time of a non-optimal latent brain state predicted inattention symptoms and furthermore, in a categorical analysis, distinguished children with ADHD from controls. Importantly, functional connectivity between salience and frontoparietal networks predicted rate of evidence accumulation to a decision threshold, whereas functional connectivity between salience and default mode networks predicted inattention. Taken together, our computational modeling reveals dissociable latent brain state features underlying response variability, impaired decision-making, and inattentional symptoms common to ADHD. Our findings provide novel insights into the neurobiology of attention deficits in children., (© 2021. The Author(s).)

Purpose: The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported., Methods: Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety., Results: Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label., Conclusion: Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options., Competing Interests: Ajjai S. AlvaConsulting or Advisory Role: AstraZeneca, Merck, Pfizer, Bristol Myers SquibbResearch Funding: Genentech, Bristol-Myers Squibb, Merck Sharp & Dohme, Prometheus, Mirati Therapeutics, AstraZeneca, Roche, Bayer, Progenics, Astellas Pharma, Arcus Biosciences, Harpoon Therapeutics, Progenics, Celgene, JanssenTravel, Accommodations, Expenses: Merck, Bristol Myers Squibb Elizabeth Garrett-MayerConsulting or Advisory Role: Deciphera, TYME Susan HalabiEmployment: ASCOConsulting or Advisory Role: Eisai, Ferring Pharmaceuticals Damien HansraEmployment: Cancer Treament Centers of America, Hansra Health Corporation Eugene R. AhnEmployment: Cancer Treament Centers of AmericaLeadership: Cancer Treament Centers of America Timothy L. CannonConsulting or Advisory Role: Loxo, NavicanOther Relationship: Navican/Intermountain Healthcare Pamela CrilleyEmployment: Cancer Treament Centers of AmericaLeadership: Cancer Treament Centers of AmericaTravel, Accommodations, Expenses: Cancer Treament Centers of America Richard L. SchilskyResearch Funding: AstraZeneca, Bayer, Bristol-Myers Squibb, Genentech/Roche, Lilly, Merck, Pfizer, Boehringer IngelheimOpen Payments Link: https://openpaymentsdata.cms.gov/physician/1138818/summaryNo other potential conflicts of interest were reported.

Background: Although research has demonstrated that depression and anxiety are associated with problematic executive function (EF), results are often inconsistent and underspecified. Delineating specific EF impairments in depression and anxiety has the potential to provide a mechanistic account of symptom presentation and course in these highly co-occurring disorders. The present study evaluated associations between components of EF and symptom dimensions of depression (depressed mood) and anxiety (anxious apprehension, anxious arousal) using factor analyses and structural equation modeling., Methods: Undergraduates (N = 1,123) completed self-report measures of EF in everyday life and of psychopathology. Based on a three-factor model (Miyake et al., 2000), item-level exploratory (n = 561) and confirmatory (n = 562) factor analyses were conducted on inhibition, shifting, and working memory scales chosen from the EF measure. Structural equation modeling tested the relationship of EF factors to dimensions of psychopathology using the total sample., Results: A three-factor model of EF best fit the data and was replicated via confirmatory factor analysis. Depressed mood and anxious arousal evidenced broad deficits across all EF domains, whereas anxious apprehension evidenced shifting disruptions., Limitations: Perceived EF may not index the same constructs as performance-based EF tests. Further, the present study was restricted to college students, warranting replication in other samples., Conclusions: Findings suggest that depressed mood and anxious arousal are characterized by a general disruption in the ability to maintain task goals, whereas anxious apprehension is characterized by cognitive inflexibility. EF impairments are likely contributory factors in the maintenance of affective disorders., (Copyright © 2020. Published by Elsevier B.V.)

Background: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets., Objective: With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations., Patients and Methods: Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/m 2 over 60 min). A Simon two-stage design, requiring ten patients in stage I, was employed per each disease-specific cohort. The primary endpoint was disease control (objective response or stable disease for at least 16 weeks). If two or more patients in stage I achieved disease control, the cohort would enroll 18 more patients in stage II. Power and alpha of the design are 85% and 10%, respectively. Secondary endpoints included progression-free survival, overall survival, and safety., Results: Patients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab., Conclusions: Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations., Clinical Trial Registration: NCT02693535 (26 February, 2016).

Background: Anxiety and stress reactivity are risk factors for the development of affective disorders. However, the behavioral and neurocircuit mechanisms that potentiate maladaptive emotion regulation are poorly understood. Neuroimaging studies have implicated the amygdala and dorsolateral prefrontal cortex (DLPFC) in emotion regulation, but how anxiety and stress alter their context-specific causal circuit interactions is not known. Here, we use computational modeling to inform affective pathophysiology, etiology, and neurocircuit targets for early intervention., Methods: Forty-five children (10-11 years of age; 25 boys) reappraised aversive stimuli during functional magnetic resonance imaging scanning. Clinical measures of anxiety and stress were acquired for each child. Drift-diffusion modeling of behavioral data and causal circuit analysis of functional magnetic resonance imaging data, with a National Institute of Mental Health Research Domain Criteria approach, were used to characterize latent behavioral and neurocircuit decision-making dynamics driving emotion regulation., Results: Children successfully reappraised negative responses to aversive stimuli. Drift-diffusion modeling revealed that emotion regulation was characterized by increased initial bias toward positive reactivity during viewing of aversive stimuli and increased drift rate, which captured evidence accumulation during emotion evaluation. Crucially, anxiety and stress reactivity impaired latent behavioral dynamics associated with reappraisal and decision making. Anxiety and stress increased dynamic casual influences from the right amygdala to DLPFC. In contrast, DLPFC, but not amygdala, reactivity was correlated with evidence accumulation and decision making during emotion reappraisal., Conclusions: Our findings provide new insights into how anxiety and stress in children impact decision making and amygdala-DLPFC signaling during emotion regulation, and uncover latent behavioral and neurocircuit mechanisms of early risk for psychopathology., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To test embedded symptom validity scales of the Neurobehavioral Symptom Inventory (NSI) as predictors of performance validity., Setting: A Veterans Affairs Level II TBI/Polytrauma outpatient care unit in the Midwestern United States., Participants: Veterans with a history of mild traumatic brain injury undergoing neuropsychological assessment as part of their routine care within the TBI/Polytrauma clinic., Design: Retrospective analysis of the existing clinical data., Main Measures: The NSI, the b Test, Test of Memory Malingering, Reliable Digit Span, California Verbal Learning Test-II Forced Choice., Results: Embedded NSI validity scales were positively correlated with number of performance validity test failures. Participants identified as invalid responders scored higher on embedded NSI validity scales than participants identified as valid responders. Using receiver operating characteristic analysis, the embedded NSI validity scales showed poor sensitivity and specificity for invalid responding using previously published cutoff scores. Only 1 scale differentiated valid from invalid responders better than chance., Conclusion: The embedded NSI validity scales' usefulness in predicting invalid neuropsychological performance validity was limited in this sample. Continued measurement of both symptom and performance validity in clinical settings involving traumatic brain injury treatment is recommended, as the present results support the existing research suggesting symptom validity tests and performance validity tests tap into related but ultimately distinct constructs.

Background: We compared characteristics and outcomes of palpable versus nonpalpable, hormone-sensitive, early-stage breast cancers., Methods: Patients from the North American Fareston vs. Tamoxifen Adjuvant (NAFTA) trial were divided into palpable (n = 513) and nonpalpable (n = 1063) tumor groups. Differences in pathological features, loco-regional therapy, disease-free survival (DFS) and overall survival (OS) were analyzed., Results: Patients with palpable tumors were older, had larger tumors, and higher rates of lymph-node involvement. The tumors were more likely to be poorly differentiated, of high nuclear grade, and display lymphovascular invasion. After mean followup of 59 months, DFS and OS were significantly lower for palpable than nonpalpable tumors (DFS 93.5% vs. 98.4%, p < 0.001, OS 88.5% vs. 95.6%, p < 0.001). Controlling for age, size and nodal status, palpability was an independent factor for DFS (OR = 2.56; 95%CI, 1.37-4.79, p = 0.003) and OS (OR = 2.12; 95%CI, 1.38-3.28, p < 0.001)., Conclusions: In a group of hormone-sensitive, mostly postmenopausal early-stage breast cancer patients, palpable tumors were more likely to have more aggressive features and metastatic potential, which translated in to a higher incidence of breast cancer-related events and worse overall survival., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Although there has been extensive research showing that depression is associated with executive function (EF) deficits, the nature of these deficits is not clearly delineated. Specifically, previous reviews on this topic have yielded different conclusions about the particular domains of EF that are disrupted in depressed individuals. Further, research on whether these deficits persist after depressed mood has remitted is less prevalent and not consistent., Methods: In two independent samples of college students, we examined associations between clinical ratings of current and past symptoms of a Major Depressive Episode (MDE) and difficulties in two domains of EF: inhibition and shifting. In Study 1 (n=162), EF was measured using behavioral tasks shown to index these two domains. In Study 2 (n=95), EF was measured using a self-report questionnaire believed to capture EF difficulties experienced in daily life., Results: In both studies, past MDE symptoms were associated with worse shifting. In contrast, current MDE symptoms were associated with worse inhibition, though only on the behavioral measure (in Study 1)., Limitations: Both studies used college samples and retrospective assessments of past symptoms. Further, only two domains of EF were examined, and the EF measures employed in each study have their own unique methodological limitations., Conclusions: Findings suggest that inhibition deficits vary as a function of current symptoms and thus may be a by-product of distress rather than a causal contributor. In contrast, shifting deficits associated with depression appear to be more enduring, suggesting that they could contribute to risk for depression., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Few studies have investigated how attentional control is affected by transient affective states while taking individual differences in affective traits into consideration. In this study, participants completed a color-word Stroop task immediately after undergoing a positive, neutral or negative affective context manipulation (ACM). Behavioral performance was unaffected by any ACM considered in isolation. For individuals high in trait negative affect (NA), performance was impaired by the negative but not the positive or neutral ACM. Neuroimaging results indicate that activity in primarily top-down control regions of the brain (inferior frontal gyrus and dorsal anterior cingulate cortex) was suppressed in the presence of emotional arousal (both negative and positive ACMs). This effect appears to have been exacerbated or offset by co-occurring activity in other top-down control regions (parietal) and emotion processing regions (orbitofrontal cortex, amygdala and nucleus accumbens) as a function of the valence of state affect (positive or negative) and trait affect (trait NA or trait PA). Neuroimaging results are consistent with behavioral findings. In combination, they indicate both additive and interactive influences of trait and state affect on top-down control of attention., (© The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Previous studies have shown that depressed individuals have difficulty directing attention away from negative distractors, a phenomenon known as affective interference. However, findings are mixed regarding the neural mechanisms and network dynamics of affective interference. The present study addressed these issues by comparing neural activation during emotion-word and color-word Stroop tasks in participants with varying levels of (primarily subclinical) depression. Depressive symptoms predicted increased activation to negative distractors in areas of dorsal anterior cingulate cortex (dACC) and posterior cingulate cortex (PCC), regions implicated in cognitive control and internally directed attention, respectively. Increased dACC activity was also observed in the group-average response to incongruent distractors, suggesting that dACC activity during affective interference is related to overtaxed cognitive control. In contrast, regions of PCC were deactivated across the group in response to incongruent distractors, suggesting that PCC activity during affective interference represents task-independent processing. A psychophysiological interaction emerged in which higher depression predicted more positively correlated activity between dACC and PCC during affective interference, i.e. greater connectivity between cognitive control and internal-attention systems. These findings suggest that, when individuals high in depression are confronted by negative material, increased attention to internal thoughts and difficulty shifting resources to the external world interfere with goal-directed behavior., (© The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Obsessive-compulsive disorder (OCD) is a serious and often chronically disabling condition. The current dominant model of OCD focuses on abnormalities in prefrontal-striatal circuits that support executive function (EF). While there is growing evidence for EF impairments associated with OCD, results have been inconsistent, making the nature and magnitude of these impairments controversial. The current meta-analysis uses random-effects models to synthesize 110 previous studies that compared participants with OCD to healthy control participants on at least one neuropsychological measure of EF. The results indicate that individuals with OCD are impaired on tasks measuring most aspects of EF, consistent with broad impairment in EF. EF deficits were not explained by general motor slowness or depression. Effect sizes were largely stable across variation in demographic and clinical characteristics of samples, although medication use, age, and gender moderated some effects.

Executive function (EF) deficits are associated with depression. Given that few prospective studies have been conducted, it is unclear whether deficits contribute to depression or result from it. The present study examined whether self-reported EF prospectively predicted worsening of depression symptoms. Time 1 (T1) shifting, inhibition, and working memory (WM) were assessed in relation to T1 and time 2 (T2) depressive symptoms in participants pre-selected to range in risk for depression. Analyses indicated that poorer EF at T1 predicted increases in depressive symptoms and furthermore that this relationship was specific to WM. In contrast, a bidirectional relationship was not evident, as depressive symptoms did not prospectively predict changes in EF. Finally, T1 EF accounted for T2 depressive symptoms beyond two well established predictors of depression: depressive symptoms at T1 and rumination at T2. These findings suggest that EF deficits play an active role in depression onset, maintenance, and/or recurrence., Competing Interests: Conflict of Interest Allison M. Letkiewicz, Gregory A. Miller, Laura D. Crocker, Stacie L. Warren, Zachary P. Infantolino, Katherine J. Mimnaugh, Wendy Heller declare that they have no conflict of interest.

Given the complexity of the brain, characterizing relations among distributed brain regions is likely essential to describing the neural instantiation of posttraumatic stress symptoms. This study examined patterns of functional connectivity among key brain regions implicated in the pathophysiology of posttraumatic stress disorder (PTSD) in 35 trauma-exposed adults using an emotion-word Stroop task. PTSD symptom severity (particularly hyperarousal symptoms) moderated amygdala-mPFC coupling during the processing of unpleasant words, and this moderation correlated positively with reported real-world impairment and amygdala reactivity. Reexperiencing severity moderated hippocampus-insula coupling during pleasant and unpleasant words. Results provide evidence that PTSD symptoms differentially moderate functional coupling during emotional interference and underscore the importance of examining network connectivity in research on PTSD. They suggest that hyperarousal is associated with negative mPFC-amygdala coupling and that reexperiencing is associated with altered insula-hippocampus function, patterns of connectivity that may represent separable indicators of dysfunctional inhibitory control during affective processing.

Background: Advancing research on the etiology, prevention, and treatment of psychopathology requires the field to move beyond modular conceptualizations of neural dysfunction toward understanding disturbance in key brain networks. Although some studies of anxiety and depression have begun doing so, they typically suffer from several drawbacks, including: (1) a categorical approach ignoring transdiagnostic processes, (2) failure to account for substantial anxiety and depression comorbidity, (3) examination of networks at rest, which overlooks disruption manifesting only when networks are challenged. Accordingly, the present study examined relationships between transdiagnostic dimensions of anxiety/depression and patterns of functional connectivity while goal maintenance was challenged., Methods: Participants (n = 179, unselected community members and undergraduates selected to be high/low on anxiety/depression) performed a task in which goal maintenance was challenged (color-word Stroop) while fMRI data were collected. Analyses examined moderation by anxiety/depression of condition-dependent coupling between regions of dorsolateral prefrontal cortex (dlPFC) previously associated with approach and avoidance motivation and amygdala/orbitofrontal cortex (OFC)., Results: Anxious arousal was positively associated with amygdala↔right dlPFC coupling. Depression was positively associated with OFC↔right dlPFC coupling and negatively associated with OFC↔left dlPFC coupling., Conclusions: Findings advance the field toward an integrative model of the neural instantiation of anxiety/depression by identifying specific, distinct dysfunctions associated with anxiety and depression in networks important for maintaining approach and avoidance goals. Specifically, findings shed light on potential neural mechanisms involved in attentional biases in anxiety and valuation biases in depression and underscore the importance of examining transdiagnostic dimensions of anxiety/depression while networks are challenged., (© 2014 Wiley Periodicals, Inc.)

Background: Prior brain imaging and autopsy studies have suggested that structural abnormalities of the basal ganglia (BG) nuclei may be present in Tourette Syndrome (TS). These studies have focused mainly on the volume differences of the BG structures and not their anatomical shapes.  Shape differences of various brain structures have been demonstrated in other neuropsychiatric disorders using large-deformation, high dimensional brain mapping (HDBM-LD).  A previous study of a small sample of adult TS patients demonstrated the validity of the method, but did not find significant differences compared to controls. Since TS usually begins in childhood and adult studies may show structure differences due to adaptations, we hypothesized that differences in BG and thalamus structure geometry and volume due to etiological changes in TS might be better characterized in children., Objective: Pilot the HDBM-LD method in children and estimate effect sizes., Methods: In this pilot study, T1-weighted MRIs were collected in 13 children with TS and 16 healthy, tic-free, control children. The groups were well matched for age.  The primary outcome measures were the first 10 eigenvectors which are derived using HDBM-LD methods and represent the majority of the geometric shape of each structure, and the volumes of each structure adjusted for whole brain volume. We also compared hemispheric right/left asymmetry and estimated effect sizes for both volume and shape differences between groups., Results: We found no statistically significant differences between the TS subjects and controls in volume, shape, or right/left asymmetry.  Effect sizes were greater for shape analysis than for volume., Conclusion: This study represents one of the first efforts to study the shape as opposed to the volume of the BG in TS, but power was limited by sample size. Shape analysis by the HDBM-LD method may prove more sensitive to group differences.

Background Habituation of the fear response, critical for the treatment of anxiety, is inconsistently observed during exposure to threatening stimuli. One potential explanation for this inconsistency is differential attentional engagement with negatively valenced stimuli as a function of anxiety type. Methods The present study tested this hypothesis by examining patterns of neural habituation associated with anxious arousal, characterized by panic symptoms and immediate engagement with negatively valenced stimuli, versus anxious apprehension, characterized by engagement in worry to distract from negatively valenced stimuli. Results As predicted, the two anxiety types evidenced distinct patterns of attentional engagement. Anxious arousal was associated with immediate activation in attention-related brain regions that habituated over time, whereas anxious apprehension was associated with delayed activation in attention-related brain regions that occurred only after habituation in a worry-related brain region. Conclusions Results further elucidate mechanisms involved in attention to negatively valenced stimuli and indicate that anxiety is a heterogeneous construct with regard to attention to such stimuli.

Individual differences in inhibition-related functions have been implicated as risk factors for a broad range of psychopathology, including anxiety and depression. Delineating neural mechanisms of distinct inhibition-related functions may clarify their role in the development and maintenance of psychopathology. The present study tested the hypothesis that activity in common and distinct brain regions would be associated with an ecologically sensitive, self-report measure of inhibition and a laboratory performance measure of prepotent response inhibition. Results indicated that sub-regions of DLPFC distinguished measures of inhibition, whereas left inferior frontal gyrus and bilateral inferior parietal cortex were associated with both types of inhibition. Additionally, co-occurring anxiety and depression modulated neural activity in select brain regions associated with response inhibition. Results imply that specific combinations of anxiety and depression dimensions are associated with failure to implement top-down attentional control as reflected in inefficient recruitment of posterior DLPFC and increased activation in regions associated with threat (MTG) and worry (BA10). Present findings elucidate possible neural mechanisms of interference that could help explain executive control deficits in psychopathology.

Emotion-cognition and motivation-cognition relationships and related brain mechanisms are receiving increasing attention in the clinical research literature as a means of understanding diverse types of psychopathology and improving biological and psychological treatments. This paper reviews and integrates some of the growing evidence for cognitive biases and deficits in depression and anxiety, how these disruptions interact with emotional and motivational processes, and what brain mechanisms appear to be involved. This integration sets the stage for understanding the role of neuroplasticity in implementing change in cognitive, emotional, and motivational processes in psychopathology as a function of intervention.

Dimensions of psychopathy are theorized to be associated with distinct cognitive and emotional abnormalities that may represent unique neurobiological risk factors for the disorder. This hypothesis was investigated by examining whether the psychopathic personality dimensions of fearless-dominance and impulsive-antisociality moderated neural activity and behavioral responses associated with selective attention and emotional processing during an emotion-word Stroop task in 49 adults. As predicted, the dimensions evidenced divergent selective-attention deficits and sensitivity to emotional distraction. Fearless-dominance was associated with disrupted attentional control to positive words, and activation in right superior frontal gyrus mediated the relationship between fearless-dominance and errors to positive words. In contrast, impulsive-antisociality evidenced increased behavioral interference to both positive and negative words and correlated positively with recruitment of regions associated with motivational salience (amygdala, orbitofrontal cortex, insula), emotion regulation (temporal cortex, superior frontal gyrus) and attentional control (dorsal anterior cingulate cortex). Individuals high on both dimensions had increased recruitment of regions related to attentional control (temporal cortex, rostral anterior cingulate cortex), response preparation (pre-/post-central gyri) and motivational value (orbitofrontal cortex) in response to negative words. These findings provide evidence that the psychopathy dimensions represent dual sets of risk factors characterized by divergent dysfunction in cognitive and affective processes.

Research indicates that dorsolateral prefrontal cortex (DLPFC) is important for pursuing goals, and areas of DLPFC are differentially involved in approach and avoidance motivation. Given the complexity of the processes involved in goal pursuit, DLPFC is likely part of a network that includes orbitofrontal cortex (OFC), cingulate, amygdala, and basal ganglia. This hypothesis was tested with regard to one component of goal pursuit, the maintenance of goals in the face of distraction. Examination of connectivity with motivation-related areas of DLPFC supported the network hypothesis. Differential patterns of connectivity suggest a distinct role for DLPFC areas, with one involved in selecting approach goals, one in selecting avoidance goals, and one in selecting goal pursuit strategies. Finally, differences in trait motivation moderated connectivity between DLPFC and OFC, suggesting that this connectivity is important for instantiating motivation., (Copyright © 2012 Society for Psychophysiological Research.)

The present research examined the hypothesis that cognitive processes are modulated differentially by trait and state negative affect (NA). Brain activation associated with trait and state NA was measured by fMRI during an attentional control task, the emotion-word Stroop. Performance on the task was disrupted only by state NA. Trait NA was associated with reduced activity in several regions, including a prefrontal area that has been shown to be involved in top-down, goal-directed attentional control. In contrast, state NA was associated with increased activity in several regions, including a prefrontal region that has been shown to be involved in stimulus-driven aspects of attentional control. Results suggest that NA has a significant impact on cognition, and that state and trait NA disrupt attentional control in distinct ways.

Research has indicated that regions of left and right dorsolateral prefrontal cortex (DLPFC) are involved in integrating the motivational and executive function processes related to, respectively, approach and avoidance goals. Given that sensitivity to pleasant and unpleasant stimuli is an important feature of conceptualizations of approach and avoidance motivation, it is possible that these regions of DLPFC are preferentially activated by valenced stimuli. The present study tested this hypothesis by using a task in which goal pursuit was threatened by distraction from valenced stimuli while functional magnetic resonance imaging data were collected. The analyses examined whether the impact of trait approach and avoidance motivation on the neural processes associated with executive function differed depending on the valence or arousal level of the distractor stimuli. The present findings support the hypothesis that the regions of DLPFC under investigation are involved in integrating motivational and executive function processes, and they also indicate the involvement of a number of other brain areas in maintaining goal pursuit. However, DLPFC did not display differential sensitivity to valence.

Background: The current standard repair for anorectal malformations in children is a posterior sagittal anorectoplasty. Recently, laparoscopic-assisted anorectoplasty (LAARP) was performed at the Red Cross Children's Hospital., Methods: A detailed case note review was conducted. Patient outcome was prospectively evaluated by colorectal nurse specialists using the Krickenbeck standardized questionnaire. Comparison among patients undergoing posterior sagittal anorectoplasty was performed., Results: Between September 2005 and June 2009, 24 children underwent LAARP. Sixteen had associated anomalies, including 7 children with renal and 4 children with cardiac abnormalities. Median age at surgery was 7.5 months (range, 2.6-15.0 months). Subtypes of anorectal malformation were as follows: vestibular, 2; bulbar, 9; prostatic, 7; vesical, 3; and with no fistula, 3. There was a 16% early complication rate. Redo-anoplasty was required in 9 patients. Eleven children had difficulties with follow-up. Thirteen children had regular follow-up and were analyzed further. Toilet training had been completed in 7 children (median age, 4.3 years; range, 3.5-6 years). Six children developed voluntary bowel motions. Six children are awaiting toilet training or are unable to train because of incontinence., Conclusions: Anal stenosis was the most common complication post-LAARP. Etiology appeared to be multifactorial, but poor compliance with dilatations was a leading cause., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Using data from 34 participants who completed an emotion-word Stroop task during functional magnetic resonance imaging, we examined the effects of adult attachment on neural activity associated with top-down cognitive control in the presence of emotional distractors. Individuals with lower levels of secure-base-script knowledge--reflected in an adult's inability to generate narratives in which attachment-related threats are recognized, competent help is provided, and the problem is resolved--demonstrated more activity in prefrontal cortical regions associated with emotion regulation (e.g., right orbitofrontal cortex) and with top-down cognitive control (left dorsolateral prefrontal cortex, anterior cingulate cortex, and superior frontal gyrus). Less efficient performance and related increases in brain activity suggest that insecure attachment involves a vulnerability to distraction by attachment-relevant emotional information and that greater cognitive control is required to attend to task-relevant, nonemotional information. These results contribute to the understanding of mechanisms through which attachment-related experiences may influence developmental adaptation.

Brain activation associated with anhedonic depression and co-occurring anxious arousal and anxious apprehension was measured by fMRI during performance of an emotion word Stroop task. Consistent with EEG findings, depression was associated with rightward frontal lateralization in the dorsolateral prefrontal cortex (DLPFC), but only when anxious arousal was elevated and anxious apprehension was low. Activity in the right inferior frontal gyrus (IFG) was also reduced for depression under the same conditions. In contrast, depression was associated with more activity in the anterior cingulate cortex (dorsal ACC and rostral ACC) and the bilateral amygdala. Results imply that depression, particularly when accompanied by anxious arousal, may result in a failure to implement top-down processing by appropriate brain regions (left DLPFC, right IFG) due to increased activation in regions associated with responding to emotionally salient information (right DLPFC, amygdala).

In mammals, the functional significance of the presence of evolutionarily conserved, multiple non-allelic H1 variants remains unclear. We used a unique overproduction approach coupled with cell cycle synchronization and early time point assays to assess differential effects of H1 variants, H1c and H1(0), on global gene expression in the absence of compensatory events that may mask variant-specific effects. We found that H1c and H1(0) act primarily as specific rather than global regulators of gene expression. Many of the genes affected were uniquely targeted by either H1c or H1(0), affirming that H1 variants have some unique roles. We also identified genes that were affected by both variants, in which cases the expression of these genes was, for the most part, affected similarly by both the variants. This observation suggests that as well as having specific functions, the H1 variants share common roles in the organization of chromatin. We further noted that H1(0) repressed more genes than did H1c, which may underlie the prevailing notion that H1(0) is a stronger repressor of transcription.

Objective: Despite the general consensus that youth with type 1 diabetes mellitus (T1DM) can experience modest cognitive impairment, debate continues over the role of severe hypoglycemia (Hypo) and/or hyperglycemia (Hyper) in producing such impairment. Our aim was to determine how Hypo and Hyper experienced during brain development predict patterns of subsequent cognitive performance in youth with T1DM., Methods: We tested youth aged 5-16 yr (T1DM, n = 117; non-diabetic sibling controls, n = 58) on cognitive tasks (verbal and spatial intelligence, verbal and spatial memory, and processing speed). T1DM participants were categorized as having experienced 0, 1-2, or 3 or more (3+) Hypo episodes, as having their first Hypo episode before or after 5 yr of age and as having early (before age 5) or late (after age 5) diabetes onset. Hyper exposure was estimated with median hemoglobin A1c, adjusted for diabetes duration for each subject., Results: The group with T1DM had lower estimated verbal intelligence than sibling controls. Within the T1DM group, verbal intelligence was reduced with increased exposure to Hyper, not to Hypo. In contrast, spatial intelligence and delayed recall were reduced only with repeated Hypo, particularly when Hypo episodes occurred before the age of 5 yr. Age of onset did not explain these results., Conclusions: Hypo and Hyper have qualitatively different effects on cognitive function in T1DM that depend in part on the timing of exposure during development, independent of onset age. This information extends the known benefits of avoiding both Hypo and chronic Hyper during childhood to include preservation of specific cognitive skills.

Objective: Despite interest in the effects of type 1 diabetes on the developing brain, structural brain volumes in youth with this disease have not previously been examined. This study is the first to quantify regional brain volume differences in a large sample of youth with diabetes., Research Design and Methods: Magnetic resonance images (MRIs) were acquired from youth with diabetes (n = 108) and healthy sibling control subjects (n = 51) aged 7-17 years. History of severe hypoglycemia was assessed by parent interview and included seizure, loss of consciousness, or requiring assistance to treat. A1C values since diagnosis were obtained from medical records; median A1C was weighted by duration of disease. Voxel-based morphometry was used to determine the relationships of prior hypo- and hyperglycemia to regional grey and white matter volumes across the whole brain., Results: No significant differences were found between diabetic and healthy control groups in grey or white matter. However, within the diabetic group, a history of severe hypoglycemia was associated with smaller grey matter volume in the left superior temporal region. Greater exposure to hyperglycemia was associated with smaller grey matter volume in the right cuneus and precuneus, smaller white matter volume in a right posterior parietal region, and larger grey matter volume in a right prefrontal region., Conclusions: Qualitatively different relationships were found between hypo- and hyperglycemia and regional brain volumes in youth with type 1 diabetes. Future studies should investigate whether these differences relate to cognitive function and how these regions are affected by further exposure.

Functional differentiation of dorsal (dACC) and rostral (rACC) anterior cingulate cortex for cognitive and emotional function has received considerable indirect support. Using fMRI, parallel tasks, and within-subject analysis, the present study directly tested the proposed specialization of ACC subdivisions. A Task x Region interaction confirmed more dACC activation during color-word distractors and more rACC activation during emotion-word distractors. Activity in ACC subdivisions differentially predicted behavioral performance. Connectivity with prefrontal and limbic regions also supported distinct dACC and rACC roles. Findings provide direct evidence for differential engagement of ACC subdivisions in cognitive and emotional processing and for differential functional connectivity in the implementation of cognitive control and emotion regulation. Results point to an anatomical and functional continuum rather than segregated operations.

The aim of the research was to test hypotheses concerning the associations between maternal depressive symptoms and child sleep using longitudinal data to examine possible predictive pathways. Data from the National Institute of Child Health and Human Development Study of Early Child Care with 1222 children studied from 1 to 36 months of age were analyzed to examine: effects on trajectories over time, and phase-specific effects over three defined age periods (6 to 15, 15 to 24, and 24 to 36 months). Child sleep was found to influence maternal depressive symptoms only for the 15- to 24-month age period, where, contrary to expectation, longer duration of child awakenings predicted decreased maternal depressive symptoms. Maternal depressive symptoms were found to predict an increased frequency of child awakenings across the 15- to 24-month age period only. In contrast, maternal depressive symptoms were found to significantly predict increased duration of child awakenings both for the 3-year trajectory and across the 15- to 24- and 24- to 36-month age periods. Additional research is needed to clarify the mechanisms by which maternal depressive symptoms predict increased duration of child awakenings.

Objective: This research examined the validity of criteria for diagnosing social phobia (SOC) and generalized anxiety disorder (GAD), where the DSM-IV criteria were modified to better identify toddlers who could have these disorders., Method: Diagnoses were made with a semistructured clinical interview that included child observations. Parents and caregivers completed child behavior, temperament, and socioemotional functioning questionnaires to test convergent and discriminant validity., Results: Of 72 children, 18 months to 5 years old, 19 met modified SOC criteria (8 met DSM-IV criteria SOC also), 29 met modified GAD criteria (5 met DSM-IV criteria GAD also), and 35 met no anxiety disorder criteria. Children with modified SOC were more likely than nonanxious children to display higher levels of anxiety symptoms and shyness/inhibition and to have anxious parents. Modified SOC did not relate to the nonanxiety constructs (cuddling, imaginary play, fine motor). Children with modified GAD did not consistently demonstrate higher levels of anxiety symptoms, did not have more anxious parents than nonanxious children, and did not have higher mean scores on the nonanxiety constructs., Conclusions: This research provides initial evidence supporting convergent and discriminant validity for the modified SOC criteria but not the modified GAD criteria.

The aim of this pilot research was to investigate whether infants of mothers with panic disorder (PD) would be at higher risk for prematurity and low birth weight (corrected for gestational age) than controls. Medical records were reviewed for 25 mothers with PD and 33 mothers without a lifetime history of anxiety disorders or other major psychopathology as determined by diagnostic interview. Mothers also completed questionnaires concerning demographic information and life stresses. Compared to controls, infants with PD mothers were not significantly more likely to be born prematurely or earlier than controls but did show smaller birth weight corrected for gestational age, even after accounting for possible confounding influences. Additional research is needed to confirm these preliminary findings. Studying PD mothers during pregnancy could provide insight concerning mechanisms for the development of low birth weight and psychopathology.

Objective: Repeated severe hypoglycemia has been reported to reduce long-term spatial memory in children with type 1 diabetes. Early exposure to hypoglycemia may be more damaging to cognitive function than later exposure. Our goal was to determine whether the age at which severe hypoglycemia occurs modulates the impact of severe hypoglycemia frequency on long-term spatial memory., Research Design and Methods: We combined data from three independent studies to obtain a sample of children aged 6-18 years with type 1 diabetes (n = 103) and nondiabetic control subjects (n = 60). Each study evaluated previous severe hypoglycemia and tested short (5 s)- and long (60 s)-delay spatial memory with the spatial delayed response task. Type 1 diabetic participants were categorized as having zero, one to two, or three or more severe hypoglycemic episodes and as having their first severe hypoglycemic episode before or after 5 years of age. Information on chronic hyperglycemia (HbA1c values) was also collected., Results: We found that repeated severe hypoglycemia (more than three episodes) reduced long-delay spatial delayed response performance, particularly when severe hypoglycemic episodes began before the age of 5 years. Age of type 1 diabetes onset and estimates of chronic hyperglycemia did not influence performance., Conclusions: High frequency of and early exposure to severe hypoglycemia during development negatively affects spatial long-term memory performance.

This research examines whether maternal sensitivity in early childhood reduces later anxiety/depressive symptoms for children with more temperamental vulnerability, and whether these effects are different for boys and girls. Data from the National Institute of Child Health and Human Development Early Child Care study with 1,226 subjects (631 boys, 595 girls) were analyzed. Mothers and other caregivers rated children's difficult temperament at 1 and 6 months. Trained observers scored maternal sensitivity when children were 6 and 15 months. Child anxiety/depressive symptoms were rated by mothers and other caregivers when children were 2 and 3 years of age. Maternal sensitivity in early childhood significantly predicted decreased 2- and 3-year-old anxiety/depressive symptoms. Children with more difficult temperament were significantly more likely to show decreased anxiety/depressive symptoms at 2 years of age if their mothers had been more sensitive. Maternal sensitivity also was a significant predictor of decreased anxiety/depressive symptoms for more temperamentally difficult boys, and temperamentally difficult boys with more sensitive mothers were found to be significantly more likely than girls to show decreased anxiety/depressive symptoms at 3 years of age. The findings of this pilot research suggest that facilitating and supporting increased sensitivity for mothers with more temperamentally difficult children could be beneficial. ©2005 Michigan Association for Infant Mental Health., (Copyright © 2005 Michigan Association for Infant Mental Health.)