Faculty Bibliography

As the second most common type of variation in the human genome, insertions and deletions (indels) have been linked to many diseases, but the discovery of indels of more than a few bases in size from short-read sequencing data remains challenging. Scalpel (http://scalpel.sourceforge.net) is an open-source software for reliable indel detection based on the microassembly technique. It has been successfully used to discover mutations in novel candidate genes for autism, and it is extensively used in other large-scale studies of human diseases. This protocol gives an overview of the algorithm and describes how to use Scalpel to perform highly accurate indel calling from whole-genome and whole-exome sequencing data. We provide detailed instructions for an exemplary family-based de novo study, but we also characterize the other two supported modes of operation: single-sample and somatic analysis. Indel normalization, visualization and annotation of the mutations are also illustrated. Using a standard server, indel discovery and characterization in the exonic regions of the example sequencing data can be completed in approximately 5 h after read mapping.

Objectives: Poor access to necessary outpatient psychiatric care and therapeutic support services increasingly drive youth with autism and their families to the emergency department (ED) to seek psychiatric care, yet EDs nationwide have not risen to meet this increased demand. Patients with autism often require 1:1 monitoring, require restraint and seclusion more frequently than their peers who do not suffer from autism, and overall can be costly and difficult for EDs to manage. The dearth of outpatient resources for patients with autism makes discharge from the ED difficult, yet few inpatient units will accept these complex patients. Insurance companies often reimburse poorly or not at all for ED visits for behavioral complaints. Unlike specialized inpatient psychiatric units that have contracted increased rates for their high-needs patients, EDs, in general, receive no additional reimbursement for caring for youth with autism, despite their complexity. EDs that seek to provide more specialized care for youth with autism face not only administrative challenges, including the challenges of cross-departmental collaboration within the institution (including psychiatry, pediatrics, emergency medicine, occupational therapy, and child life), but also the difficulty of collaboration across different service systems that assist patients with autism. This program will review the service system challenges faced by children with autism and their families and by those looking to improve emergency care for these youth as well as strategies to overcome these barriers. Methods: This presentation will review administrative and cross-service challenges that forces patients with autism into the ED and that complicate efforts to care for them there. The presentation then will identify strategies for overcoming these hurdles by using cross-systems collaboration and advocacy. Results: Participants will gain tools to more effectively implement enhanced services for youth with autism in the ED. Conclusions: Although many barriers to improving emergency psychiatric care for youth with autism exist, they are not insurmountable with strong administrative leadership and advocacy

Objectives: Velo-cardio-facial syndrome (VCFS) is the most common genomic cause of psychosis and has an incidence of 1,960 established pregnancies. Within the VCFS critical region on chromosome 22, catechol-Omethyltransferase plays a major role in the inactivation of catecholamines. Elevated cerebrospinal fluid dopamine concentrations have been confirmed and have been hypothesized as a possible cause of psychosis. Inhibition of tyrosine hydroxylase, the rate-limiting step for catecholamine synthesis in the CNS using oral metyrosine (a-methyltyrosine or AMPT), has been reported to reduce VCFS-related psychosis. The aim of this study is to review our experience with 29 patients with VCFS-related psychosis who were treated with AMPT over the last 17 years. Methods: Subjects were recruited from registrations with the Virtual Center for Velo-Cardio-Facial Syndrome. All cases were confirmed to have a 22q11.2 deletion that included the critical region from low-copy repeats LCR1 through LCR2 by fluorescence in situ hybridization or chromosomal microarray (CMA). In those diagnosed with CMA (19 cases), all had the most common deletion from LCR1 through LCR4. All subjects had failed treatment with multiple other antipsychotic drugs. Response to AMPT was determined by reports from parents, guardians, and local clinicians by phone or video calls. The mean age of psychosis onset was 15.5 years (range 8-38). The first administration of AMPT ranged from 13 to 39 years (mean = 20.4 years). Results: Of the 29 cases, 22 had a positive response (76 percent). Ten (34.5 percent) had an excellent response, with complete resolution of psychosis; 2 (7 percent) had a very good response; and 17 (59 percent) were reported to have a good or fair response. Of the 10 excellent results, five were using AMPT as monotherapy and five used adjunctive medications (including mood stabilizers or an SSRI). All of the patients with good responses were using adjunctive medications. Conclusions: Although this study has limitations, the number of positive responses to AMPT as monotherapy or adjunctive therapy cannot be ignored. At the very least, when all other treatments have failed, consideration of treatment with AMPT would seem warranted. More research and structured clinical trials are needed, but an initial review of clinical outcomes is encouraging

Objectives: Human infants born prematurely experience repeated noxious medical procedures, but maternal contact can attenuate the behavioral response to these procedures. However, the mechanisms by which the mother reduces pain or the enduring impact of using the mother as an analgesic stimulus are unknown. By use of an animal model of early life pain with and without the mother, we monitored behavior at different points across the lifespan. Methods: Infant rats were given mild tail shocks (0.5 mA, 1 second every 4 minutes for 32 minutes) either with the mother present or absent for five consecutive days. Two age ranges were chosen to represent the sensitive period for pain programming (PN5-9) and the age at which maternal presence has major neurobehavioral effects, including suppression of amygdala activity (PN10-14). In infancy, neural pain responses were assessed via cFos expression in brain areas associated with pain, as well as behavioral measures related to pain response. In adulthood, pain thresholds, social behavior, and unlearned fear behavior were assessed as a function of infant pain experience. Results: Activity and ultrasonic vocalizations after treatment from PN5-9 and PN10-14 were reduced by the mother's presence during exposure to painful shock. After treatment at PN10-14 pups only, Fos expression in the periaqueductal gray and basolateral and medial amygdala was elevated by the shock alone and reduced by the mother. Adults treated at PN5-9 had reduced carrageenan-induced hyperalgesia and reduced social behavior but no changes in fear behavior if they had undergone pain-mother pairings. In contrast, when treated at PN10-14, the adult had no change in hyperalgesia and showed disruption of social behavior. Shock with or without the mother decreased unlearned fear responding only if treated at PN10-14. The social behavior deficits were normalized by 2 weeks of environmentally enriched rearing after weaning. Conclusions: Our results provide evidence that maternal presence during early life pain reduces pain responses in both infancy and adulthood, but it is also associated with long-term changes in emotionality. The results of these studies aid in our understanding of the impact of nursery procedures that are used to attenuate pain on later outcomes focused on affective behaviors and potentially provide a strategy to reduce those effects

Objectives: Most staff in a psychiatric emergency service, even CAPs, have little experience with the emergency evaluation, crisis management, and behavioral treatment of patients with autism. This presentation will teach participants about the evaluation and behavioral management of patients with autism in a child/adolescent psychiatric emergency setting through staff training to improve care for these patients. Methods: This presentation will cover autism-specific evaluation strategies and tools geared to a psychiatric emergency setting for children and adolescents. This evaluation, as well as behavioral interventions and staff trainings, part of a larger Autism Clinical Care Pathway, will be described in depth. Results: Knowledge of specific evaluation concepts and strategies can be extremely useful in a child/adolescent psychiatric emergency setting, both in terms of acquiring a better understanding of patients' immediate treatment needs and strategies for behaviorally managing this population. Multidisciplinary staff training on the basics of autism, behavioral management, and staff collaboration is an important part of promoting improved care for youth with autism in a psychiatric emergency service setting. Conclusions: Given the difficulties managing patients with autism in an emergency setting, specific evaluation procedures and behavioral interventions can be beneficial. Moreover, this information can be conveyed through staff training in a way that is feasible and promotes safety

Objectives: Organizational Skills Training (OST), is a 10-week psychosocial intervention found effective in improving organizational, time management, and planning (OTMP) skills in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Little is known about the feasibility of identifying brain markers for treatment response. Using resting state fMRI (R-fMRI), we aimed to examine neuronal correlates of post-treatment change as a first step toward larger controlled studies of objective predictors of treatment response. Methods: We examined pre- and post-OST R-fMRI data of 15 children (12 males; mean age: 9+/-1 year) with ADHD and significant impairments in OTMP skills indexed by total scores on Children's Organizational Skills Scales-Parent (COSS-P) or Teacher (COSS-T). Our primary outcome measure was the change in COSS-P scores. As secondary summary outcome measure, we used prepost Z-score differences averaged across COSS-T, Homework Problems Checklist, Academic Progress Report and Academic Performance Rating scales. We selected a priori the intrinsic functional connectivity (iFC) of the dorsal anterior cingulate cortex (dACC), based on its role on cognitive control. Multivariate distance matrix regression (MDMR) analysis additionally allowed for whole-brain explorations. Follow-up iFC analyses were conducted on regions with significant within-subject post-OST differences by MDMR analysis. Results: COSS-P decreased significantly (t=7.1, p< 0.0001). In a cluster involving striatum bilaterally, dACC iFC decreased post-OST; these decreases were positively correlated with COSS-P improvements (r=.34, NS) and to improvements in the summary outcome (r=.63; p<0.03). MDMR analyses revealed iFC changes in the right medial and lateral precentral cortex. Followup seed-based iFC analyses of this region showed significant decreases in cortico-striatal iFC post-OST. Conclusions: Results support the feasibility of identifying changes in brain iFC after OST. Two distinct analysis converged on decreased corticosubcortical iFC post-treatment which related to change in clinical measures. As decreases in striato-cortical iFC characterize typical development, results suggest regionally-specific enhanced maturational effects of OST

Objectives: It is estimated that 25 percent of children and adolescents suffer from a sleep problem at some point before entering adulthood. Research shows that over 95 percent of CAPs prescribe at least one sleep medication monthly, yet numerous studies show that CBT-I works just as well as medication, is extremely cost effective, and has longer-lasting benefits. However, unfortunately, most CAPs are not trained in CBT-I. This workshop will teach participants when and for whom CBT-I is an appropriate treatment intervention; the six primary components of CBT-I; and how to design CBT-I treatment plans for a variety of adolescent and young adult patients diagnosed with insomnia. Methods: This workshop will be based upon a comprehensive literature review and the clinical expertise of the instructors. In advance of the workshop, registered participants will be sent a variety of standardized rating scales so that they may begin to assess their own sleep in preparation for learning how to improve the sleep of their patients. Results: CBT-I consists of an easily taught series of evidence-based skills that are portable and time and cost effective. The goals of CBT-I are to alter the factors that perpetuate insomnia and include the following: 1) behavioral training in stimulus control, sleep restriction, and sleep hygiene; 2) cognitive training in managing dysfunctional thoughts and maladaptive behaviors related to sleep, such as unrealistic expectations and rumination over the consequences of insomnia; and 3) physiological factors, such as hyperarousal and somatic and mental tension. Conclusions: This workshop will provide instruction on the use of CBT-I for adolescents and adults, and practitioners will be guided through a series of applied exercises to enhance their therapeutic skills

Objectives: During infancy, rapid learning associated with attachment and orientation to a caregiver is essential to survival. This developmental period also prevents the acquisition of avoidance learning. In rodent models, this developmental time window occurs prior to post-natal day 10 (PND 10), during which pups display heightened preference learning accompanied by decreased aversion learning. PND 10 rats presented with odor-shock pairings fail to avoid the odor associated with shock, and show a preference for the paired odor. Older pups (PND 12) given odorshock pairings develop an aversion to the odor at subsequent test. One key developmental mechanism that appears to direct the change from a preference for the odor associated with shock to an aversion, involves the activation of the amygdala by corticosterone. Corticosterone is low in pups during the sensitive period and increases at PND 10. We investigated synaptic markers which may be important for establishing the avoidance memory and that are likely activated by corticosterone. Protein kinase M zeta (PKMzeta), which is important for late-phase LTP and long-term memory, is also upregulated during stress (Sebastian et al 2013, PLoS One, vol 8, e79077). Therefore, we investigated the role of PKMzeta in avoidance vs preference learning in rat pups using the paired odor-0.5mA shock fear-conditioning paradigm. Methods: PND 8 and PND 12 pups were given either paired (simultaneous odor and shock) or unpaired (shock 2 min after odor) training and tested 24hr later on a Y maze with one arm containing the conditioned stimulus (CS) odor and the other a familiar odor. Immediately after Y maze test, pups were sacrificed and amygdalae were harvested. The tissues were separated into cytosolic and synaptic cellular fractions. Each fraction was analyzed by Western blots. Results: Pups in the unpaired condition showed no preference for either arm. PND 8 pups in the paired condition preferred the CS odor and PND 12 pups in the paired condition avoided the CS odor (p<0.01). PND 12 in the paired condition had higher cytosolic PKMzeta in the amygdala compared to unpaired pups (p<0.05) with no change in synaptic PKMzeta. PN8 paired did not show any changes in cytosolic or synaptic PKMzeta Conclusions: Increased PKMzeta expression following the sensitive period plays a role in the activation process of the amygdala and the formation of aversive memories

Objectives: The goal of this session is to describe how using positive emotions, novelty, and mindfulness may be a more useful and evidenced- based way to begin the diagnostic interview. In Martin Seligman's 1998 inaugural address to the annual meeting of the American Psychological Association, he called for a major investment into the study of well-being. Since that time, the study of positive emotions, novelty, and mindfulness are no longer just the domain of self-help gurus. The growing scientific literature highlights how the use of talking about what is "right" may be the optimal way to engage a patient in the diagnostic interview. Methods: Considerable research has focused on the benefits of positive emotions, novelty, and mindfulness that includes increased attention, desire to learn, and desire to connect with other people, a significant advantage for both the patient and the clinician conducting an assessment. Results: The field of positive psychology has developed several theories surrounding the benefits of positive emotions, novelty, and mindfulness for the development of relationships and goal setting that may enhance the rapport and development of a positive therapeutic alliance. We will review the literature and offer some practical techniques to support clinicians conducting a positive strength-based interview. Conclusions: This presentation will provide a review of positive psychology and how its growing knowledge of positive emotions, novelty, and mindfulness may support the development of a diagnostic interview and increase the quality of the doctor-patient relationship