Faculty Bibliography

Non-invasive brain stimulation (NIBS), including transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS), is a potentially effective treatment strategy for a number of mental conditions. However, no quantitative evidence synthesis of randomized controlled trials (RCTs) of TMS or tDCS using the same criteria including several mental conditions is available. Based on 208 RCTs identified in a systematic review, we conducted a series of random effects meta-analyses to assess the efficacy of NIBS, compared to sham, for core symptoms and cognitive functioning within a broad range of mental conditions. Outcomes included changes in core symptom severity and cognitive functioning from pre- to post-treatment. We found significant positive effects for several outcomes without significant heterogeneity including TMS for symptoms of generalized anxiety disorder (SMD = -1.8 (95% CI: -2.6 to -1), and tDCS for symptoms of substance use disorder (-0.73, -1.00 to -0.46). There was also significant effects for TMS in obsessive-compulsive disorder (-0.66, -0.91 to -0.41) and unipolar depression symptoms (-0.60, -0.78 to -0.42) but with significant heterogeneity. However, subgroup analyses based on stimulation site and number of treatment sessions revealed evidence of positive effects, without significant heterogeneity, for specific TMS stimulation protocols. For neurocognitive outcomes, there was only significant evidence, without significant heterogeneity, for tDCS for improving attention (-0.3, -0.55 to -0.05) and working memory (-0.38, -0.74 to -0.03) in individuals with schizophrenia. We concluded that TMS and tDCS can benefit individuals with a variety of mental conditions, significantly improving clinical dimensions, including cognitive deficits in schizophrenia which are poorly responsive to pharmacotherapy.

Purpose : Automated segmentation of in-vivo lamina cribrosa (LC) has been challenging, owing to the complex 3D structure and decreased visibility in the lamina depth. Frangi's vesselness filter, which was originally developed for angiogram segmentation, have been successfully demonstrated in segmenting the ex-vivo LC from micro-CT and second harmonic generation microscopy images. In this project we are proposing a new approach of segmenting the in vivo LC from OCT scans, incorporating the Frangi's vesselness principle to facilitate in vivo LC image analysis in much greater detail compared to our previously described 3D analysis method. Methods : In-vivo spectral-domain OCT scans (Leica, Chicago, IL) were acquired from healthy non-human primates. Scans of varying degree of image quality were selected for the analysis and underwent automated brightness and local contrast enhancement. 3D Frangi's vesselness filter was applied using a fixed setting for scans of all qualities. Our previously described segmentation algorithm was then used to quantify the LC microstructure. The measurements generated from the Frangi analysis and from our own conventional method were compared with a standard reference (manually segmented LC by an expert). Paired t tests were performed to compare if the differences between standard reference and conventional method are greater than the differences between standard reference and Frangi analysis. The visibility of analyzable lamina and dice coefficient were also compared to the conventional method using the same test. Results : In vivo scans acquired from 5 rhesus macaques (3 males, 1 female, aged 4.3-10.7 yrs) were used for the analysis. No significant difference was detected for LC microstructure parameters between Frangi's approach and conventional method with respect to the standard reference, except for significantly higher pore count in Frangi's method (p=0.003; Table). Furthermore, visibility (Figure) was significantly higher for the Frangi method compared to the conventional approach (p<0.001) with no difference detected for the semantic segmentation, as reflected by the dice coefficient. Conclusions : The use of Frangi analysis substantially increase the analyzable lamina while providing similar quantification of the LC microstructure compared to our previous 3D analysis method. This improves the potential for automated and thorough volumetric analysis of in vivo OCT LC image

PURPOSE: The prognosis for SHH-medulloblastoma (MB) patients with Li-Fraumeni syndrome (LFS) is poor. Due to lack of comprehensive data for these patients, it is challenging to establish effective therapeutic recommendations. We here describe the largest retrospective cohort of pediatric LFS SHH-MB patients to date and their clinical outcomes.
PATIENTS AND METHODS: N=31 patients with LFS SHH-MB were included in this retrospective multicenter study. TP53 variant type, clinical parameters including treatment modalities, event-free survival (EFS) and overall survival (OS), as well as recurrence patterns and incidence of secondary neoplasms, were evaluated.
RESULT(S): All LFS-MBs were classified as SHH subgroup, in 30/31 cases based on DNA methylation analysis. The majority of constitutional TP53 variants (72%) represented missense variants, and all except two truncating variants were located within the DNA-binding domain. 54% were large cell anaplastic, 69% gross totally resected and 81% had M0 status. The 2-(y)ear and 5-(y)ear EFS were 26% and 8,8%, respectively, and 2y- and 5y-OS 40% and 12%. Patients who received post-operative radiotherapy (RT) followed by chemotherapy (CT) showed significantly better outcomes (2y-EFS:43%) compared to patients who received CT before RT (30%) (p<0.05). The 2y-EFS and 2y-OS were similar when treated with protocols including high-dose chemotherapy (EFS:22%, OS:44%) compared to patients treated with maintenance-type chemotherapy (EFS:31%, OS:45%). Recurrence occurred in 73.3% of cases independent of resection or M-status, typically within the radiation field (75% of RT-treated patients). Secondary malignancies developed in 12.5% and were cause of death in all affected patients.
CONCLUSION(S): Patients with LFS-MBs have a dismal prognosis. This retrospective study suggests that upfront RT may increase EFS, while intensive therapeutic approaches including high-dose chemotherapy did not translate into increased survival of this patient group. To improve outcomes of LFS-MB patients, prospective collection of clinical data and development of treatment guidelines are required

Adverse childhood experiences (ACEs) are associated with poor mental health in adulthood. Comprehensive prevalence data encompassing all 10 ACE questionnaire items has not previously been described in a hospital-based outpatient psychiatric clinic. This study assessed the prevalence of 10 ACEs in such a clinic and correlated ACEs with indicators of case severity. For 252 patients newly evaluated in an urban clinic, a retrospective chart review was completed and data was collected on ACE questionnaire responses, psychiatric, substance-related, and medical diagnoses, psychiatric hospitalizations, suicide attempts, and suicide and violence risk. Patients in the clinic had an average of 3.4 ACEs, higher than national community sample averages of 1.6. The percentages of patients with at least one, two, and four ACEs were 82% (n = 207), 68% (n = 172), and 42% (n = 106) respectively (compared with 61%, 38%, and 15% nationally). ACEs had statistically significant correlations with an increased number of psychiatric diagnoses, substance use disorders, medical illnesses, suicide attempts, and suicide risk level. This study demonstrated that patients seeking psychiatric care from a hospital-based outpatient clinic are likely to be traumatized to a degree far exceeding what is typical in the general population. While a high prevalence of ACEs in a psychiatric population is an expected finding given the literature to date, this is the first study presenting data on the prevalence of ACEs in such a hospital-based community clinic. Additionally this study reinforces prior research correlating childhood adversity and case severity.

OBJECTIVE/UNASSIGNED:Autism spectrum disorder (ASD) is heritable, and younger siblings of ASD probands are at higher likelihood of developing ASD themselves. Prospective MRI studies of siblings report that atypical brain development precedes ASD diagnosis, although the link between brain maturation and genetic factors is unclear. Given that familial recurrence of ASD is predicted by higher levels of ASD traits in the proband, the authors investigated associations between proband ASD traits and brain development among younger siblings. METHODS/UNASSIGNED:In a sample of 384 proband-sibling pairs (89 pairs concordant for ASD), the authors examined associations between proband ASD traits and sibling brain development at 6, 12, and 24 months in key MRI phenotypes: total cerebral volume, cortical surface area, extra-axial cerebrospinal fluid, occipital cortical surface area, and splenium white matter microstructure. Results from primary analyses led the authors to implement a data-driven approach using functional connectivity MRI at 6 months. RESULTS/UNASSIGNED:Greater levels of proband ASD traits were associated with larger total cerebral volume and surface area and larger surface area and reduced white matter integrity in components of the visual system in siblings who developed ASD. This aligned with weaker functional connectivity between several networks and the visual system among all siblings during infancy. CONCLUSIONS/UNASSIGNED:The findings provide evidence that specific early brain MRI phenotypes of ASD reflect quantitative variation in familial ASD traits. Multimodal anatomical and functional convergence on cortical regions, fiber pathways, and functional networks involved in visual processing suggest that inherited liability has a role in shaping the prodromal development of visual circuitry in ASD.

Child welfare (CW) agencies are charged with ensuring children's safety; when children live with families impacted by intimate partner violence (IPV), this task can be complex. To better understand how U.S. CW agencies identify and make decisions about child maltreatment (CM) in the presence of IPV, this mixed-methods study used national data (N = 248,654) to investigate whether IPV was more likely to be documented as co-occurring with certain types of CM. This study also explored the intersection of IPV and CM using 19 semi-structured interviews with child welfare stakeholders to gain insight into the mechanisms underpinning reporting processes. Multinomial logistical regression showed that after controlling for other risk factors, children living in a household with IPV were more likely to be determined to be physically abused and emotionally maltreated than neglected, and less likely to be determined to be sexually abused than neglected, compared with children who did not live in a household with IPV. Those children were also more likely to be determined to be emotionally maltreated than physically abused, and less likely to be determined to be sexually abused than physically abused, compared with children who did not live in a household with IPV (all results, p < .0001). Qualitative results revealed IPV and children's exposure to IPV may be categorized as different types of CM by CW agencies and staff, and that this categorization can vary by agency and staff level. Participants also described challenges to addressing IPV within CW systems. Findings suggest national CW data may obscure when IPV and CM co-occur versus when a given type of CM is serving as a proxy for the presence of or children's exposure to IPV, presenting challenges to interpreting child welfare data. Recommendations are presented to improve CW data accuracy and ensure the safety of children and families impacted by IPV.

SUMMARY/CONCLUSIONS:Poor research integrity is increasingly recognised as a serious problem in science. We outline some evidence for this claim and introduce the Royal College of Psychiatrists (RCPsych) journals' Research Integrity Group, which has been created to address this problem.

LAY ABSTRACT/UNASSIGNED:Youth suicide is a major problem in the United States and globally, but little is known about suicide risk in autistic youth and youth with intellectual disability specifically. Using data from the National Emergency Department Sample, which is the largest database of emergency department visits in the United States, we found that emergency department visits with a suicidal ideation or intentional self-inflicted injury diagnosis were more common in autistic youth and youth with intellectual disability than in youth without these diagnoses (i.e. the comparison group). This was true when examining both suicidal ideation diagnoses and intentional self-inflicted injury diagnoses at emergency department visits. In addition, the number of emergency department visits with a suicidal ideation or intentional self-inflicted injury diagnosis increased more from 2006 to 2014 in autistic youth and youth with intellectual disability compared with the comparison group. We also found both similarities and differences when examining factors, such as age, sex, and co-occurring mental health conditions, related to emergency department visits with a suicidal ideation or intentional self-inflicted injury diagnosis across groups that may be helpful for understanding suicide risk. It is urgent that we improve our understanding, assessment, and treatment of suicidality and self-harm in these groups through more research and clinical efforts.

BACKGROUND:Child maltreatment recidivism substantially increases the likelihood of adverse life outcomes, but there is little evidence that family preservation services are effective at reducing recidivism. Mothers in child welfare have very high rates of trauma exposure; maternal post-traumatic stress disorder (PTSD) is an intervention target that has the potential to reduce abuse and neglect. The Safe Mothers, Safe Children (SMSC) intervention program involves the delivery of an innovative combination of interventions, including Skills Training in Affective and Interpersonal Regulation (STAIR) and Parent-Child Interaction Therapy (PCIT). The combined intervention, Parenting-STAIR (P-STAIR), targets maternal PTSD and comorbid depression symptoms to reduce the adverse effects of PTSD on parenting, improve positive parenting skills, and prevent maltreatment recidivism. METHODS:This study is a two-arm randomized controlled trial: P-STAIR (23 sessions) versus supportive counseling (23 sessions). Participants are mothers receiving child welfare family preservation services (FPS), with a child in the age range of 1-8 years old and meeting diagnostic criteria for PTSD (with/without depression). Clinical assessment occurs at pre-treatment (baseline), two in-treatment assessments (mid-assessment #1 after module 9 and mid-assessment #2 after module 15), post-treatment, and at a 6-month follow-up. Recidivism will be measured using the New York State Child Welfare Registry (NYSCWR). We will enroll a total of 220 participants over 4 years: half (N = 110) randomly assigned to the P-STAIR condition and half (N = 110) to the supportive counseling condition. DISCUSSION/CONCLUSIONS:This is the first RCT to investigate the efficacy of P-STAIR. The findings for the trial have the potential to contribute to the expansion of evidence-based practices for maternal PTSD, maltreatment, and child welfare.

OBJECTIVES:Negative symptom studies frequently use single composite scores as indicators of symptom severity and as primary endpoints in clinical trials. Factor analytic and external validation studies do not support this practice but rather suggest a multidimensional construct. The current study used structural equation modeling (SEM) to compare competing dimensional models of negative symptoms to determine the number of latent dimensions that best capture variance in biological, psychological, and clinical variables known to have associations with negative symptoms. METHODS:Three independent studies (total n = 632) compared unidimensional, two-factor, five-factor, and hierarchical conceptualizations of negative symptoms in relation to cognition, psychopathology, and community functioning (Study 1); trait emotional experience and defeatist performance beliefs (Study 2); and glutamate and gamma-aminobutyric acid levels in the anterior cingulate cortex quantified using proton magnetic resonance spectroscopy (Study 3). RESULTS:SEM favored the five-factor and hierarchical models over the unidimensional and two-factor models regardless of the negative symptom measure or external validator. The five dimensions-anhedonia, asociality, avolition, blunted affect, and alogia-proved vital either as stand-alone domains or as first-order domains influenced by second-order dimensions-motivation and pleasure and emotional expression. The two broader dimensions sometimes masked important associations unique to the five narrower domains. Avolition, anhedonia, and blunted affect showed the most domain-specific associations with external variables across study samples. CONCLUSIONS:Five domains and a hierarchical model reflect the optimal conceptualization of negative symptoms in relation to external variables. Clinical trials should consider using the two dimensions as primary endpoints and the five domains as secondary endpoints.