Faculty Bibliography

Children's development is largely dependent on caregiving; when caregiving is disrupted, children are at increased risk for numerous poor outcomes, in particular psychopathology. Therefore, determining how caregivers regulate children's affective neurobiology is essential for understanding psychopathology etiology and prevention. Much of the research on affective functioning uses fear learning to map maturation trajectories, with both rodent and human studies contributing knowledge. Nonetheless, as no standard framework exists through which to interpret developmental effects across species, research often remains siloed, thus contributing to the current therapeutic impasse. Here, we propose a developmental ecology framework that attempts to understand fear in the ecological context of the child: their relationship with their parent. By referring to developmental goals that are shared across species (to attach to, then, ultimately, separate from the parent), this framework provides a common grounding from which fear systems and their dysfunction can be understood, thus advancing research on psychopathologies and their treatment. Expected final online publication date for the Annual Review of Clinical Psychology Volume 15 is May 7, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) often emerges during the preschool years and remains impairing throughout the life span. Early identification and intervention may yield lasting benefits that alter the often-adverse trajectory of the disorder. METHODS:This Practitioner Review provides up-to-date information regarding the evaluation and treatment of ADHD in preschool children. The clinical presentation of ADHD in preschool children, its persistence into later childhood, the applicability of DSM-5 criteria for preschoolers with ADHD, and early predictors of long-term trajectories are addressed, as well as current findings from randomized controlled trials of both nonpharmacological and pharmacological interventions. RESULTS:Symptoms of hyperactivity/impulsivity extend down to age 3, but several inattention symptoms, as defined by DSM-V, less accurately differentiate preschoolers with and without ADHD. Most preschool youth with ADHD symptoms continue to manifest symptoms and impairment into school-age and adolescence. However, few predictors of persistence beyond early severity have been identified. Behavioral interventions constitute a first-line treatment for preschool ADHD symptoms, with telepsychiatry increasing in prominence to help to mitigate financial, geographic, and/or logistical barriers to care. Pharmacological interventions, particularly psychostimulants, also confer demonstrable benefits, yet efficacy and safety profiles are less desirable relative to findings in school-age youth. CONCLUSIONS:Acute treatments have demonstrable efficacy, but do not appear to fundamentally alter underlying mechanisms or long-term trajectories.

PURPOSE/OBJECTIVE:Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T cell infiltration of tumors include vaccines targeting established oncogenic drivers like the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). EXPERIMENTAL DESIGN/METHODS:In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were evaluated. We tested VRP-HER2 in a Phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of three doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. RESULTS:Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was one partial response and two patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n=4) and 32.7 months in cohort 2 (n=18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. CONCLUSIONS:VRP-HER2 increased HER2-specific memory CD8 T cells and had anti-tumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T cell activity by combining with anti-PD-1.

Human olfactory function requires the identification of everyday odors. A characteristic feature of olfaction is that most people find it hard to identify and name common odors, and when odors are presented simultaneously in mixtures, performance is even further compromised. Few studies have systematically assessed how training might enhance identification of single odors and mixtures. This study compared how odor identification training with either single odors or binary mixtures affected identification performance, as well as transfer effects to untrained tasks and odors. Twenty-seven healthy participants (22 F; 28.0 ± 4.7 years old) completed identification training of 8 odors using a list of 16 veridical names. The study included 8 training sessions, as well as pre-test and post-test evaluations. Results suggest notable effects of learning, as well as transfer to novel tasks and odors. Overall, training with single odors led to slightly better results than the binary mixture condition, suggesting that in novices, odor identification may be facilitated via consolidation of single odor objects, before learning to dissociate binary mixtures. Overall, odor identification may be trained to generate transfer of learning, although transfer effects were observed in both training methods. Our work suggests that odor identification abilities, while often limited, are highly trainable.

AIM/OBJECTIVE:To evaluate the preliminary effectiveness of the BRief Evaluation of Asthma THerapy intervention, a 7-min primary care provider-delivered shared decision-making protocol that uses motivational interviewing to address erroneous asthma disease and medication beliefs. DESIGN/METHODS:A multi-centre masked two-arm group-randomized clinical trial. METHODS:This 2-year pilot study is funded (September 2016) by the National Institute of Nursing Research. Eight providers will be randomized to one of two arms: the active intervention (N = 4) or a dose-matched attention control (N = 4). Providers will deliver the intervention to which they were randomized to 10 Black adult patients with uncontrolled asthma (N = 80). Patients will be followed three months postintervention to test the preliminary intervention effects on asthma control (primary outcome) and on medication adherence, lung function, and asthma-related quality of life (secondary outcomes). DISCUSSION/CONCLUSIONS:This study will evaluate the preliminary impact of a novel shared decision-making intervention delivered in a real world setting to address erroneous disease and medication beliefs as a means of improving asthma control in Black adults. Results will inform a future, large-scale randomized trial with sufficient power to test the intervention's effectiveness. IMPACT/CONCLUSIONS:Shared decision-making is an evidence-based intervention with proven effectiveness when implemented in the context of labour- and time-intensive research protocols. Medication adherence is linked with the marked disparities evident in poor and minority adults with asthma. Addressing this requires a novel multifactorial approach as we have proposed. To ensure sustainability, shared decision-making interventions must be adapted to and integrated into real-world settings. TRIAL REGISTRATION/BACKGROUND:Registered at clincialtrials.gov as NCT03036267 and NCT03300752.

OBJECTIVE:Disturbances in self-regulatory control are involved in the initiation and maintenance of addiction, including cannabis use disorder (CUD). In adults, chronic cannabis use is associated with disturbances in fronto-striatal circuits during tasks that require the engagement of self-regulatory control, including the resolution of cognitive conflict. Understudied are the behavioral and neural correlates of these processes earlier in the course of cannabis use, disentangled from effects of long-term use. The present study investigates the functioning of fronto-striatal circuits during the resolution of cognitive conflict in cannabis-using youth. METHOD/METHODS:Functional magnetic resonance imaging data was acquired from 28 cannabis-using (CU) youth and 32 age-matched healthy participants (HC) during the performance of a Simon task. General linear modeling was used to compare patterns of brain activation during correct responses to conflict stimuli across groups. Psychophysiological interaction analyses were used to examine conflict-related fronto-striatal connectivity across groups. Associations of fronto-striatal activation and connectivity with cannabis use measures were explored. RESULTS:Reduced conflict-related activity was detected in CU relative to HC youth in fronto-striatal regions, including ventromedial prefrontal cortex (vmPFC), striatum, pallidum and thalamus. Fronto-striatal connectivity did not differ across groups, but negative connectivity between vmPFC and striatum was detected in both groups. CONCLUSION/CONCLUSIONS:These findings are consistent with previous reports of cannabis-associated disturbances in fronto-striatal circuits in adults and point to the specific influence of cannabis on neurodevelopmental changes in youth. Future studies should examine whether fronto-striatal functioning is a reliable marker of CUD severity and potential target for circuit-based interventions.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, hammering version after version into shape. Acknowledging these biases, here are the 2018 articles that we think deserve your attention or at least a second read.

Why are certain individuals persistent in opposing immigration? The behavioral immune system framework implies that a psychological mechanism, which adapted to detect and avoid pathogen threats, is also reflected in contemporary social attitudes. Moreover, prejudice towards outgroups might be partially driven by implicit pathogen concerns related to the perceived dissimilarity with these groups' hygiene and food preparation practices. Disgust, a universal core emotion supposedly evolved to avoid pathogen threats, as well as olfaction, both play a pivotal role in evoking disgust. In an online study (N = 800), we investigated whether individual differences in body odor disgust sensitivity (BODS) correlate with negative attitudes towards a fictive refugee group. The data analysis plan and hypotheses were preregistered. Results show that body odor disgust sensitivity is associated with xenophobia: BODS was positively associated with negative attitudes towards the fictive group. This relationship was partially mediated by perceived dissimilarities of the group in terms of hygiene and food preparation. Our finding suggests prejudice might be rooted in sensory mechanisms.

BACKGROUND:Norwegian health, care, and welfare services are experiencing increased demands to deliver services that are safe, effective, of high quality, and that ensure user involvement. Yet, evidence-based treatment for common disorders such as depression, anxiety, trauma, and behavioral problems in children are not regularly used in clinical practice in Norway. Possible explanations for this are that many standard, evidence-based treatments may have difficulty addressing the complexity and comorbidity of referred children and the fact that children's treatment needs often shift during treatment. The Modular Approach to Therapy for children with Anxiety, Depression, Trauma and Conduct problems (MATCH-ADTC) was designed to address these challenges and reduce some of the barriers to therapists' use of evidence-based treatment in their practice. METHODS/DESIGN/METHODS:Participants will include 280 children (aged 6-14.5 years at intake) who receive treatment in child and adolescent mental health outpatient clinics in Norway, and their families. Families are randomly assigned to either the experimental group receiving treatment from therapists trained in MATCH, or to the comparison group receiving treatment from therapists delivering treatment as usual (TAU). Data on children's symptomology, child and family functioning, demographics, background information, and mental health outcomes are collected as well as frequent feedback on treatment response, plus video-recordings of treatment sessions and implementation quality scores from each participating clinic. Questionnaires are administered in six waves. DISCUSSION/CONCLUSIONS:MATCH has been tested in the US with promising results, but we do not know whether this treatment approach will produce similar results in Norway. The implications of this study are 1. Possibly better treatment outcomes and/or more efficient improvements for children and families treated in mental health outpatient clinics in Norway 2. Clinicians learning to use more evidence-based practices in their treatment 3. Implementation of standard procedures for obtaining feedback from children and families and sharing the feedback with clinicians 4. Increased understanding, at the end of the trial, of whether introducing MATCH improves outcomes for children and families treated in mental health outpatient clinics TRIAL REGISTRATION: ISRCTN, registration number: ISRCTN24029895 . Registered on 8 August 2016.