Faculty Bibliography

Psychophysiological interaction (PPI) is a widely used regression-based method to study connectivity changes in different experimental conditions. A PPI effect is generated by point-by-point multiplication of a psychological variable (experimental design) and a physiological variable (time series of a seed region). If the psychological variable is non-centered with a constant component, the constant component will add a physiological variable to the PPI term. The physiological component would in theory be accounted for by the physiological main effect in the model. But due to imperfect deconvolution and convolution with hemodynamic response function, the physiological component in PPI may no longer be exactly the same as the physiological main effect. This issue was illustrated by analyzing two block-designed fMRI datasets, one simple visual checkerboard task and a set of different tasks designed to activate different hemispheres. When PPI was calculated with deconvolution but without centering, significant results were usually observed between regions that are known to have baseline functional connectivity. These results could be suppressed by simply centering the psychological variable when calculating the PPI term or adding a deconvolve-reconvolved version of the physiological covariate. The PPI results with centering and with deconvolve-reconvolved physiological covariate are consistent with an explicit test for differences in coupling between conditions. It was, therefore, suggested that centering of the psychological variable or the addition of a deconvolve-reconvolved covariate is necessary for PPI analysis. Hum Brain Mapp 38:1723-1740, 2017. © 2017 Wiley Periodicals, Inc.

The newly introduced Mixed Features Specifier of Major Depressive Episode and Disorder (MDE/MDD) is especially challenging in terms of pharmacological management. Prior to the publication of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, the symptoms of the mixed features specifier were intradepressive hypomanic symptoms, always and only associated with bipolar disorder (BD). Intradepressive hypomanic symptoms, mostly referred to as depressive mixed states (DMX), have been poorly characterized, and their treatment offers significant challenges. To understand the diagnostic context of DMX, we trace the nosological changes and collocation of intradepressive hypomanic symptoms, and examine diagnostic and prognostic implications of such mixed features. One of the reasons so little is known about the treatment of DMX is that depressed patients with rapid cycling, substance abuse disorder, and suicidal ideation/attempts are routinely excluded from clinical trials of antidepressants. The exclusion of DMX patients from clinical trials has prevented an assessment of the safety and tolerability of short- and long-term use of antidepressants. Therefore, the generalization of data obtained in clinical trials for unipolar depression to patients with intradepressive hypomanic features is inappropriate and methodologically flawed. A selective review of the literature shows that antidepressants alone have limited efficacy in DMX, but they have the potential to induce, maintain, or worsen mixed features during depressive episodes in BD. On the other hand, preliminary evidence supports the effective use of some atypical antipsychotics in the treatment of DMX.

Women who have experienced interpersonal violence (IPV) are at a higher risk to develop posttraumatic stress disorder (PTSD), with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and impaired social behavior. Previously, we had reported impaired maternal sensitivity and increased difficulty in identifying emotions (i.e. alexithymia) among IPV-PTSD mothers. One of the aims of the present study was to examine maternal IPV-PTSD salivary cortisol levels diurnally and reactive to their child's distress in relation to maternal alexithymia. Given that mother-child interaction during infancy and early childhood has important long-term consequences on the stress response system, toddlers' cortisol levels were assessed during the day and in response to a laboratory stressor. Mothers collected their own and their 12-48month-old toddlers' salivary samples at home three times: 30min after waking up, between 2-3pm and at bedtime. Moreover, mother-child dyads participated in a 120-min laboratory session, consisting of 3 phases: baseline, stress situation (involving mother-child separation and exposure to novelty) and a 60-min regulation phase. Compared to non-PTSD controls, IPV-PTSD mothers - but not their toddlers, had lower morning cortisol and higher bedtime cortisol levels. As expected, IPV-PTSD mothers and their children showed blunted cortisol reactivity to the laboratory stressor. Maternal cortisol levels were negatively correlated to difficulty in identifying emotions. Our data highlights PTSD-IPV-related alterations in the HPA system and its relevance to maternal behavior. Toddlers of IPV-PTSD mothers also showed an altered pattern of cortisol reactivity to stress that potentially may predispose them to later psychological disorders.

BACKGROUND:Studies have shown that pediatricians in all stages of training are uncomfortable managing patients at end of life. Our goal was to create and test a portable reference card to improve pediatric resident education in comprehensive care for children nearing end of life. METHODS:We evaluated the impact of the Pediatric End-of-Life Care Management Reference Card on residents' perceived comfort and knowledge through pre- and post-intervention surveys. The preintervention questionnaires and pocket cards were distributed to all first- and second-year residents, and then a follow-up survey was provided six months later. Based on Likert scales, questions focused on self-reported understanding of palliative care principles and knowledge regarding and comfort in performing end-of-life symptom management. RESULTS:Twenty-six pediatric residents completed pre- and post-intervention surveys. Following receipt of the reference card, no significant changes were noted consistently across all groups of residents. The majority of improvements were noted when comparing second to third year residents, including knowledge and comfort related to pain management, comfort in managing secretions and nausea, and documentation following death. The first to second year residents demonstrated improvement in knowing what language to use to tell a family that their child has died. CONCLUSION:This study demonstrates that a portable reference card may be a convenient, simple, and useful component of education for pediatric residents in end-of-life care management. This reference card is a foundation from which to develop a standardized educational tool. Additional research is required to assess the impact of this type of intervention in pediatric palliative care education.

BACKGROUND: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0.0156. FINDINGS: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0.15), amygdala (d=-0.19), caudate (d=-0.11), hippocampus (d=-0.11), putamen (d=-0.14), and intracranial volume (d=-0.10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0.95) and thalamus (p=0.39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohen's d=-0.19 vs -0.10), amygdala (d=-0.18 vs -0.14), caudate (d=-0.13 vs -0.07), hippocampus (d=-0.12 vs -0.06), putamen (d=-0.18 vs -0.08), and intracranial volume (d=-0.14 vs 0.01). There was no difference between children and adults for the pallidum (p=0.79) or thalamus (p=0.89). Case-control differences in adults were non-significant (all p>0.03). Psychostimulant medication use (all p>0.15) or symptom scores (all p>0.02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0.5). INTERPRETATION: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING: National Institutes of Health.

Modeling subject-specific shape change is one of the most important challenges in longitudinal shape analysis of disease progression. Whereas anatomical change over time can be a function of normal aging; anatomy can also be impacted by disease related degeneration. Shape changes to anatomy may also be affected by external structural changes from neighboring structures, which may cause non-linear pose variations. In this paper, we propose a framework to analyze disease related shape changes by coupling extrinsic modeling of the ambient anatomical space via spatiotemporal deformations with intrinsic shape properties from medial surface analysis. We compare intrinsic shape properties of a subject-specific shape trajectory to a normative 4D shape atlas representing normal aging to separately quantify shape changes related to disease. The spatiotemporal shape modeling establishes inter/intra subject anatomical correspondence, which in turn enables comparisons between subjects and the 4D shape atlas, and also quantitative analysis of disease related shape change. The medial surface analysis captures intrinsic shape properties related to local patterns of deformation. The proposed framework simultaneously models extrinsic longitudinal shape changes in the ambient anatomical space, as well as intrinsic shape properties to give localized measurements of degeneration. Six high risk subjects and six controls are randomly sampled from a Huntington's disease image database for quantitative and qualitative comparison.

Leikauf, J. E., & Solanto, M. V. (2016). Sluggish Cognitive Tempo, Internalizing Symptoms, and Executive Function in Adults With ADHD. Journal of Attention Disorders. Advance online publication. doi: 10.1177/1087054716659361.

This paper is the third in a series of investigations into (1) the nature and development of unconscious fantasy, (2) its place in a contemporary model of mind that, parenthetically, suggests a possible solution to the problem of theoretical pluralism, and (3) its mode of operation in the mind. The aim of these investigations is to update the notion of unconscious fantasy, an indispensable construct in psychoanalytic theories that assume out-of-awareness mentation, and to situate that construct within contemporary views of mental functioning in disciplines such as philosophy of mind, cognitive science, and developmental psychology. At the same time, data accessible only through psychoanalytic work challenge these fields with findings that indicate the need for further investigation. This paper argues that experimental evidence on the phenomenon of "priming" lends support to one of the seminal claims in our field, one frequently attacked as an outmoded shibboleth: that is, that the past matters, whether encoded in declarative or in procedural memory. In common parlance, we are "primed" to respond to some situations in predetermined ways; the past primes us to experience the present in often unique and personal ways. There is evidence too that the priming mechanism and the encoding of subjective experience in declarative and procedural memory operate from very early in life.

We compared 2 rating scales with different manic symptom items on diagnostic accuracy for detecting pediatric bipolar spectrum disorder (BPSDs) in outpatient mental health clinics. Participants were 681 parents/guardians of eligible children (465 male, mean age = 9.34) who completed the Parent General Behavior Inventory-10-item Mania (PGBI-10 M) and mania subscale of the Child and Adolescent Symptom Inventory-Revised (CASI-4R). Diagnoses were based on KSADS interviews with parent and youth. Receiver operating characteristic (ROC) analyses and diagnostic likelihood ratios (DLRs) determined discriminative validity and provided clinical utility, respectively. Logistic regressions tested for incremental validity in the CASI-4R mania subscale and PGBI-10 M in predicting youth BPSD status above and beyond demographic and common diagnostic comorbidities. Both CASI-4R and PGBI-10 M scales significantly distinguished BPSD (N = 160) from other disorders (CASI-4R: Area under curve (AUC) = .80, p < 0.0005; PGBI-10 M: AUC = 0.79, p < 0.0005) even though scale items differed. Both scales performed equally well in differentiating BPSDs (Venkatraman test p > 0.05). Diagnostic likelihood ratios indicated low scores on either scale (CASI: 0-5; PGBI-10 M: 0-6) cut BPSD odds to 1/5 of those with high scores (CASI DLR- = 0.17; PGBI-10 M DLR- = 0.18). High scores on either scale (CASI: 14+; PGBI-10 M: 20+) increased BPSD odds about fourfold (CASI DLR+ = 4.53; PGBI-10 M DLR+ = 3.97). Logistic regressions indicated the CASI-4R mania subscale and PGBI-10 M each provided incremental validity in predicting youth BPSD status. The CASI-4R is at least as valid as the PGBI-10 M to help identify BPSDs, and can be considered as part of an assessment battery to screen for pediatric BPSDs.