Faculty Bibliography

Child development research highlights caregiver regulation of infant physiology and behavior as a key feature of early life attachment, although mechanisms for maternal control of infant neural circuits remain elusive. Here we explored the neurobiology of maternal regulation of infant fear using neural network and molecular levels of analysis in a rodent model. Previous research has shown maternal suppression of amygdala-dependent fear learning during a sensitive period. Here we characterize changes in neural networks engaged during maternal regulation and the transition to infant self-regulation. Metabolic mapping of 2-deoxyglucose uptake during odor-shock conditioning in postnatal day (PN)14 rat pups showed that maternal presence blocked fear learning, disengaged mesolimbic circuitry, basolateral amygdala (BLA), and plasticity-related AMPA receptor subunit trafficking. At PN18, when maternal presence only socially buffers threat learning (similar to social modulation in adults), maternal presence failed to disengage the mesolimbic dopaminergic system, and failed to disengage both the BLA and plasticity-related AMPA receptor subunit trafficking. Further, maternal presence failed to block threat learning at PN14 pups following abuse, and mesolimbic dopamine engagement and AMPA were not significantly altered by maternal presence-analogous to compromised maternal regulation of children in abusive relationships. Our results highlight three key features of maternal regulation: (1) maternal presence blocks fear learning and amygdala plasticity through age-dependent suppression of amygdala AMPA receptor subunit trafficking, (2) maternal presence suppresses engagement of brain regions within the mesolimbic dopamine circuit, and (3) early-life abuse compromises network and molecular biomarkers of maternal regulation, suggesting reduced social scaffolding of the brain.

INTRODUCTION:With 116 000 people waiting for transplants and 8000 patients dying annually on waiting lists, the United States has a considerable organ shortage. An insufficient number of Americans have registered to become organ donors when obtaining driver's licenses or ID cards. Across states, there is considerable variability in organ donor registration rates as well as driver's license applications. METHODS:The purpose of this project was to describe the variability in the phrasing of the organ donor registration question by state bureaus of motor vehicles as well as other application questions that might influence this decision. In particular, the frequency of states employing empirically supported messages to increase donor registrations was ascertained. The content and phrasing of 46 different driver's license applications was coded in regard to seeking organ donor registrations. FINDINGS:No states used the empirically supported strategies of reciprocity, descriptive norms, or loss/gain framing from the interdisciplinary field of behavioral economics. Twelve states used injunctive norms to signify social approval for organ donation. Many state applications had lengthy organ donation sections and health questions that could discourage donor registrations. DISCUSSION:There is an extremely low use of empirically supported messages to increase organ donation registrations in driver's license applications in the United States. Opportunities exist for thoughtful consideration of the wording of driver's license applications. States interested in exploring ways to increase donations could undertake controlled variation of applications to test the effects of message framing on registration rates.

Identify correlates of nicotine dependence [lifetime (l) and ongoing (o)] in adults with attention-deficit/hyperactivity disorder (ADHD) in childhood. We conducted a 33-year prospective follow-up of boys (mean age 8) with combined type ADHD (n = 135/207, 65% original sample). Correlates of nicotine dependence in adulthood were selected from characteristics obtained in childhood and adolescence. Among selected childhood features, only immature behavior was significantly related to nicotine dependence (OR(o) = 0.29, p = 0.02), indexing decreased risk. In contrast, several adolescent variables significantly correlated (p < 0.01) with nicotine dependence at mean age 41, including alcohol substance use disorder (SUD, OR(l) = 4.97), non-alcohol SUD (OR(o) = 4.33/OR(l) = 10.93), parental antisocial personality disorder (OR(l) = 4.42), parental SUD (OR(l) = 3.58), dropped out of school (OR(l) = 2.29), impulsivity (OR(o) = 1.53/OR(l) = 1.59), hyperactivity (OR(o) = 1.38), and number of antisocial behaviors (OR(o) = 1.10/OR(l) = 1.14). Results highlight the role of adolescent psychopathology in the development of nicotine dependence, motivating prospective longitudinal efforts to better define the developmental trajectories of risk and protection.

In the last 15 years, there has been a marked increase in the number of available stimulant formulations with the emphasis on long-acting formulations, and the introduction of several novel delivery systems such as orally dissolving tablets, chewable tablets, extended-release liquid formulations, transdermal patches, and novel "beaded" technology. All of these formulations involve changes to the pharmaceutical delivery systems of the two existing compounds most commonly employed to treat attention-deficit/hyperactivity disorder (ADHD), amphetamine (AMP) and methylphenidate (MPH). In addition to these new formulations, our knowledge about the individual differences in response has advanced and contributes to a more nuanced approach to treatment. The clinician can now make increasingly informed choices about these formulations and more effectively individualize treatment in a way that had not been possible before. In the absence of reliable biomarkers that can predict individualized response to ADHD treatment, clinical knowledge about differences in MPH and AMP pharmacodynamics, pharmacokinetics, and metabolism can be utilized to personalize treatment and optimize response. Different properties of these new formulations (delivery modality, onset of action, duration of response, safety, and tolerability) will most likely weigh heavily into the clinician's choice of formulation. To manage the broad range of options that are now available, clinicians should familiarize themselves in each of these categories for both stimulant compounds. This review is meant to serve as an update and a guide to newer stimulant formulations and includes a brief review of ADHD and stimulant properties.

Although pharmacological therapies are recommended as a key component in the treatment of attention-deficit hyperactivity disorder, their use continues to prompt intense debate. Despite considerable research efforts, several gaps in the knowledge base and several questions over the quality of evidence exist. Particular issues surrounding pharmacological treatments include uncertainties about long-term effectiveness and safety, safety profiles in adults, and the comparative effectiveness of different medications. In this Review, we focus on four key methodological issues for future research: (1) the use of appropriate trial designs; the need for (2) outcome measures targeting effectiveness beyond symptom control and (3) safety outcome measures; and (4) the application of clinical and administrative research databases to assess real-world outcomes. Potential solutions include increased use of randomised placebo-controlled withdrawal trials and large pharmacoepidemiological studies that use electronic health-care records on the long-term effectiveness and safety of medications. Pragmatic head-to-head randomised trials would also provide direct evidence on comparative effectiveness and safety profiles.

Autofluorescence is the emission of light by naturally occurring tissue components on the absorption of incident light. Autofluorescence within the eye is associated with several disorders, such as Age-related Macular Degeneration (AMD) which is a leading cause of central vision loss. Its pathogenesis is incompletely understood, but endogenous fluorophores in retinal tissue might play a role. Hyperspectral fluorescence microscopy of ex-vivo retinal tissue can be used to determine the fluorescence emission spectra of these fluorophores. Comparisons of spectra in healthy and diseased tissues can provide important insights into the pathogenesis of AMD. However, the spectrum from each pixel of the hyperspectral image is a superposition of spectra from multiple overlapping tissue components. As spectra cannot be negative, there is a need for a non-negative blind source separation model to isolate individual spectra. We propose a tensor formulation by leveraging multiple excitation wavelengths to excite the tissue sample. Arranging images from different excitation wavelengths as a tensor, a non-negative tensor decomposition can be performed to recover a provably unique low-rank model with factors representing emission and excitation spectra of these materials and corresponding abundance maps of autofluorescent substances in the tissue sample. We iteratively impute missing values common in fluorescence measurements using Expectation-Maximization and use L₂ regularization to reduce ill-posedness. Further, we present a framework for performing group hypothesis testing on hyperspectral images, finding significant differences in spectra between AMD and control groups in the peripheral macula. In the absence of ground truth, i.e. molecular identification of fluorophores, we provide a rigorous validation of chosen methods on both synthetic and real images where fluorescence spectra are known. These methodologies can be applied to the study of other pathologies presenting autofluorescence that can be captured by hyperspectral imaging.

BACKGROUND:Hikikomori is a severe form of social withdrawal, originally described in Japan but recently reported in other countries. Debate exists as to what extent hikikomori is viewed as a problem outside of the Japanese context. OBJECTIVE:We aimed to explore perceptions about hikikomori outside Japan by analyzing Western language content from the popular social media platform, Twitter. METHODS:We conducted a mixed methods analysis of all publicly available tweets using the hashtag #hikikomori between February 1 and August 16, 2018, in 5 Western languages (Catalan, English, French, Italian, and Spanish). Tweets were first classified as to whether they described hikikomori as a problem or a nonproblematic phenomenon. Tweets regarding hikikomori as a problem were then subclassified in terms of the type of problem (medical, social, or anecdotal) they referred to, and we marked if they referenced scientific publications or the presence of hikikomori in countries other than Japan. We also examined measures of interest in content related to hikikomori, including retweets, likes, and associated hashtags. RESULTS:A total of 1042 tweets used #hikikomori, and 656 (62.3%) were included in the content analysis. Most of the included tweets were written in English (44.20%) and Italian (34.16%), and a majority (56.70%) discussed hikikomori as a problem. Tweets referencing scientific publications (3.96%) and hikikomori as present in countries other than Japan (13.57%) were less common. Tweets mentioning hikikomori outside Japan were statistically more likely to be retweeted (P=.01) and liked (P=.01) than those not mentioning it, whereas tweets with explicit scientific references were statistically more retweeted (P=.01) but not liked (P=.10) than those without that reference. Retweet and like figures were not statistically significantly different among other categories and subcategories. The most associated hashtags included references to Japan, mental health, and the youth. CONCLUSIONS:Hikikomori is a repeated word in non-Japanese Western languages on Twitter, suggesting the presence of hikikomori in countries outside Japan. Most tweets treat hikikomori as a problem, but the ways they post about it are highly heterogeneous.

BACKGROUND:Twitter is an indicator of real-world performance, thus, is an appropriate arena to assess the social consideration and attitudes toward psychosis. OBJECTIVE:The aim of this study was to perform a mixed-methods study of the content and key metrics of tweets referring to psychosis in comparison with tweets referring to control diseases (breast cancer, diabetes, Alzheimer, and human immunodeficiency virus). METHODS:Each tweet's content was rated as nonmedical (NM: testimonies, health care products, solidarity or awareness and misuse) or medical (M: included a reference to the illness's diagnosis, treatment, prognosis, or prevention). NM tweets were classified as positive or pejorative. We assessed the appropriateness of the medical content. The number of retweets generated and the potential reach and impact of the hashtags analyzed was also investigated. RESULTS:We analyzed a total of 15,443 tweets: 8055 classified as NM and 7287 as M. Psychosis-related tweets (PRT) had a significantly higher frequency of misuse 33.3% (212/636) vs 1.15% (853/7419; P<.001) and pejorative content 36.2% (231/636) vs 11.33% (840/7419; P<.001). The medical content of the PRT showed the highest scientific appropriateness 100% (391/391) vs 93.66% (6030/6439; P<.001) and had a higher frequency of content about disease prevention. The potential reach and impact of the tweets related to psychosis were low, but they had a high retweet-to-tweet ratio. CONCLUSIONS:We show a reduced number and a different pattern of contents in tweets about psychosis compared with control diseases. PRT showed a predominance of nonmedical content with increased frequencies of misuse and pejorative tone. However, the medical content of PRT showed high scientific appropriateness aimed toward prevention.

The relationship between ADHD and suicidal spectrum behaviors (SSBs) remains uncertain. We conducted the first meta-analysis on the association between ADHD and SSBs taking possible confounders into account. Based on a pre-registered protocol (PROSPERO-CRD42018093003), we searched Pubmed, Ovid and Web of Knowledge databases through April 6^th, 2018, with no language/publication type restrictions, and contacted study authors for unpublished data/information. From a pool of 2,798 references, we retained 57 studies. Random-effects models were performed. Study quality was rated using the Newcastle-Ottawa Scale. After pooling crude ORs, we found a significant association between ADHD and suicidal attempts (2.37, 95% CI = 1.64 to 3.43; I² = 98.21), suicidal ideations (3.53, 2.94 to 4.25; I²â€‰= 73.73), suicidal plans (4.54, 2.46 to 8.37; I² = 0), and completed suicide (6.69, 3.24 to 17.39; I² = 87.53). Results did not substantially change when pooling adjusted ORs. Findings were also in general robust to sensitivity analyses to assess possible moderators. Awareness of the association between ADHD and SSBs should contribute to more effectively prevent SSBs.

Transcranial magnetic stimulation (TMS), a research tool with various effects on brain cells, can depolarize cerebral neurons noninvasively. This method offers temporal and spatial resolution and can be combined with other neurocognitive and neuro-experimental techniques. Prefrontal TMS therapy repeated daily for four to six weeks is a neuromodulation technique approved by the US Food and Drug Administration for the treatment of major depressive disorder (MDD) in patients resistant to medications. This technique utilizes electromagnetic induction to excite neuronal cells. Several recent studies have enhanced our understanding of this novel treatment intervention. This report reviews recent studies on the mechanism of action, patient eligibility, effectiveness, and safety of TMS in treating depression.