Faculty Bibliography

BACKGROUND:This study aims to understand suicidal ideation and suicide attempts among transgender individuals through an in-depth analysis of a nation-wide population general survey in China. METHODS:Transgender Men (TM) and Women (TW) were investigated through a cross-sectional survey. A structured questionnaire was used to investigate participants' demographic information, perceived sexuality conflicts, childhood adversity and mental health conditions. Logistic regression models were utilized to investigate risk factors associated with suicidal ideation and suicide attempts in these groups. We also conducted a quasi-meta-analysis in order to compare the prevalence of suicidal ideation and attempted suicide between general and transgender populations in China. RESULTS:A total of 1309 participants across 32 provinces and municipalities in China took part in this survey, out of 2060 valid questionnaires. In this transgender population, the lifetime prevalence of suicidal ideation and an attempt at suicide were 56.4% and 16.1%, respectively. This estimated prevalence rate is far greater than in Chinese community samples. For all transgender people, disliking birth-assigned sex, seeking sex reassignment surgery, having intense conflicts with parents, lifetime history of suffering from major depressive disorder, a recent episode of depression, self-harm, and seeking mental health services were significantly associated with increased risk of suicidal ideation. An education level of high school or equivalent, being married and/or separated/divorced, having intense conflicts with parents, or self-harm and seeking mental health services were all significantly associated with increased risk of suicide attempt. Although most risk factors for TM and TW were equivalent across groups, differences were observed in both suicidal ideation and suicide attempt models. LIMITATIONS:The cross-sectional study design and lack of follow-up data are limitations of this study. CONCLUSIONS:This is the first study to examine suicide within a Chinese transgender population. The clinical implications of these findings for Chinese mental health professionals are discussed. Also, the evidence from this study can be used to inform the practices of suicide prevention workers, and policy makers working with the transgender population.

Introduction: Fatigue is one of the most prevalent and largely under-assessed non-motor symptoms in PD. Current potential therapies have limited effectiveness. Presently, tDCS has shown potential to improve certain symptoms of PD. We designed an RS-tDCS protocol to allow study participation from a patient's home while maintaining clinical trial standards. We utilized a live video-conferencing platform and specially designed equipment that 'unlocks' one session at a time.Study objective: to assess feasibility and explore the therapeutic potential of remotely supervised tDCS (RS-tDCS) paired with cognitive training (CT) for Parkinson's disease (PD) related fatigue: preliminary results. Method(s): Preliminary analysis of eighteen PD patients, age 35-89 that participated in a double-blind, randomized, sham controlled study with RS-tDCS paired with CT. Each participant completed 10 tDCS sessions (20-minute, 2.0-mA, bi-frontal DLPFC montage, left anodal), over a span of two weeks. After completion, 10 additional open label sessions were offered. Tolerability, safety and compliance were evaluated. Preliminary clinical effects were measured with the fatigue severity scale (FSS). Result(s): A total of 18 participants completed 330 RS-tDCS sessions (Table1); one subject did not complete 10 optional sessions and one withdrew consent. Tolerability of 2.0 mA stimulation with <=6 on visual analog scale for pain (VAS-Pain) was 100%. Systematically recorded side effects were: tingling 22.4%, itching 8.2%, burning sensation 11.5%, dizziness 0.3%, headache 3.3%, sleepiness 0.3%, and nausea 0.9% (Figure1). No serious AEs were reported. Compliance was 100% as subjects completed all required visits with no attrition or interruptions. Preliminary fatigue clinical effects of 10 sessions showed a significant decrease of FSS (p < 0.05) only in the real RS-tDCS group (Figure2). Further analysis of 20 real RS-tDCS sessions (10 Rand_real +10 Open_label) showed a greater significant decrease in FSS (p < 0.05) (Figure2). Responders (>30% FSS improvement) were 44% after 10 RS-tDCS sessions and 62% after 20 sessions. Conclusion(s): At-home RS-tDCS therapy paired with CT is safe and well-tolerated by PD patients, with the advantages of ease of recruitment and subject compliance. Acceptability was achieved by easy setup and intuitive design of the device. At-home RS-tDCS therapy paired with CT shows potential to remediate fatigue symptoms in PD but the small sample size limits efficacy conclusions. Our paradigm may be influential in designing future studies that will facilitate clinical trials with a larger subject population and extended trial duration. Supported by Grant No. PDF-TRG-1722 from the Parkinson's Foundation.

The nucleusLocus Coeruleus (LC) is the major source of forebrain norepinephrine. LC is implicated in arousal, response to novelty, and cognitive functions, including decision-making and behavioral flexibility. One hypothesis is that LC activation promotes rapid shifts in cortical attentional networks following changes in environmental contingencies. Recent recordings further suggest LC is critical for mobilizing resources to deal with challenging situations. In the present study optogenetically identified LC neuronal activity was recorded in rats in a self-paced T-maze. Rats were trained on visual discrimination; then place-reward contingencies were instated. In the session where the animal shifted tasks the first time, the LC firing rate after visual cue onset increased significantly, even as the animal adhered to the previous rule. Firing rate also increased prior to crossing photodetectors that controlled stimulus onset and offset, and this was positively correlated with accelerations, consistent with a role in mobilizing effort. The results contribute to the growing evidence that the noradrenergic LC is essential for behavioral adaptation by promoting cognitive flexibility and mobilizing effort in face of changing environmental contingencies.

Introduction: Prior studies have shown beneficial effects of repetitive Transcranial Magnetic Stimulation (rTMS) on motor symptoms of Parkinson's disease (PD) [1]. In animal models, rTMS has also shown to enhance Brain-derived neurotrophic factor-Tropomyosin receptor kinase B (BDNF-TrkB) signaling by increasing the affinity of BDNF for its receptor [2]. Aerobic exercise (AEx) has demonstrated to improve motor symptoms of Parkinson's disease (PD) and BDNF-TrkB signaling has been proposed as a relevant contributing mechanism [3]. Objective(s): 1- To explore differences in BDNF-TrkB signaling between PD and healthy controls (HC). 2- To explore plasticity biomarkers and motor symptoms effects of AEx combined with repetitive TMS (rTMS) in PD (real Vs. sham). Method(s): First, we conducted a cross-sectional comparison of BDNF-TrkB signaling between HC and PD patients. Secondly, PD participants were assigned to a double-blind randomized study of AEx paired with rTMS or sham. AEx included 10 daily 40-minute sessions on a recumbent linear cross trainer. Immediately before each AEx session, PD participants receive a total of 3600 pulses of 5 Hz rTMS (real or sham) over primary motor cortex (left, right hands and lower limbs mid-line). Study outcomes were obtained at baseline, 1-day post-intervention (FU1) and 1-month post-intervention (FU2). BDNF-TrkB signaling was obtained from peripheral blood lymphocytes extracted between 9:00 to 10:00 am. Neurophysiological parameters were cortical silent period (cSP), motor threshold (MT) and paired-associative stimulation-25. Motor outcomes were measured with the Unified Parkinson's Disease Rating Scale (UPDRS) and Timed Up-and-Go (TUG) test. Result(s): Twenty one participants (16 PD and 5 HC) completed all study visits. All procedures were well tolerated. In the cross-sectional phase, analysis revealed that BDNF-TrkB signaling was 46.2% lower in PD compared to HC (p<0.01). In the prospective randomized phase, BDNF-TrkB signaling increased significantly compared to baseline in both study groups (FU1: real 43.3%, sham: 35.5%; FU2 real 30.8%, Sham 28.7%); however, there was no difference between groups. At FU2, cSP was significantly prolonged among PD participants receiving real rTMS vs sham (P=0.047). Secondary analysis per group showed that UPDRS III and TUG significantly improved at FU2 only in participants receiving real rTMS. Conclusion(s): Study showed that BDNF-TrkB signaling was clearly deficient in PD participants and partially restored after 2-week AEx (with/without rTMS). Prolongation of cSP in participant's receiving real rTMS could reflect more adequate restorative modulation. The addition of rTMS to AEx might improve motor benefits however does not provide additive effects over BDNF-TrkB signaling. Sponsor: Ofer Nemirovsky.

Genetic factors are strongly implicated in the susceptibility to develop externalizing syndromes such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, and substance use disorder (SUD). Variants in the ADGRL3 (LPHN3) gene predispose to ADHD and predict ADHD severity, disruptive behaviors comorbidity, long-term outcome, and response to treatment. In this study, we investigated whether variants within ADGRL3 are associated with SUD, a disorder that is frequently co-morbid with ADHD. Using family-based, case-control, and longitudinal samples from disparate regions of the world (n = 2698), recruited either for clinical, genetic epidemiological or pharmacogenomic studies of ADHD, we assembled recursive-partitioning frameworks (classification tree analyses) with clinical, demographic, and ADGRL3 genetic information to predict SUD susceptibility. Our results indicate that SUD can be efficiently and robustly predicted in ADHD participants. The genetic models used remained highly efficient in predicting SUD in a large sample of individuals with severe SUD from a psychiatric institution that were not ascertained on the basis of ADHD diagnosis, thus identifying ADGRL3 as a risk gene for SUD. Recursive-partitioning analyses revealed that rs4860437 was the predominant predictive variant. This new methodological approach offers novel insights into higher order predictive interactions and offers a unique opportunity for translational application in the clinical assessment of patients at high risk for SUD.

OBJECTIVE:Dasotraline is a potent inhibitor of presynaptic dopamine and norepinephrine reuptake with a pharmacokinetic profile characterized by slow absorption and a long elimination half-life. The aim of this study was to evaluate the efficacy and safety of dasotraline in children with attention-deficit/hyperactivity disorder (ADHD). METHODS:Children aged 6-12 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD were randomized to 6 weeks of double-blind once-daily treatment with dasotraline (2 or 4 mg) or placebo. The primary efficacy endpoint was change from baseline in the ADHD Rating Scale Version IV-Home Version (ADHD RS-IV HV) total score at week 6. RESULTS:A total of 342 patients were randomized to dasotraline or placebo (mean age 9.1 years, 66.7% male). Treatment with dasotraline was associated with significant improvement at study endpoint in the ADHD RS-IV HV total score for the 4 mg/day dose versus placebo (-17.5 vs. -11.4; p < 0.001; effect size [ES], 0.48), but not for the 2 mg/day dose (-11.8 vs. -11.4; ns; ES, 0.03). A regression analysis confirmed a significant linear dose-response relationship for dasotraline. Significant improvement for dasotraline 4 mg/day dose versus placebo was also observed across the majority of secondary efficacy endpoints, including the Clinical Global Impression (CGI)-Severity score, the Conners Parent Rating Scale-Revised scale (CPRS-R) ADHD index score, and subscale measures of hyperactivity and inattentiveness. Discontinuation rates due to adverse events (AEs) were higher in the dasotraline 4 mg/day group (12.2%) compared with the 2 mg/day group (6.3%) and placebo (1.7%). The most frequent AEs associated with dasotraline were insomnia, decreased appetite, decreased weight, and irritability. Psychosis-related symptoms were reported as AEs by 7/219 patients treated with dasotraline in this study. There were no serious AEs or clinically meaningful changes in blood pressure or heart rate on dasotraline. CONCLUSION/CONCLUSIONS:In this placebo-controlled study, treatment with dasotraline 4 mg/day significantly improved ADHD symptoms and behaviors, including attention and hyperactivity, in children aged 6-12 years. The most frequently reported AEs observed on dasotraline included insomnia, decreased appetite, decreased weight, and irritability.

BACKGROUND:Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. METHODS:Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. RESULTS:). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. CONCLUSIONS:CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

The use of global, standardized instruments is conventional among clinicians and researchers interested in assessing neurocognitive development. Exclusively relying on these tests for evaluating effects may underestimate or miss specific effects on early cognition. The goal of this review is to identify alternative measures for possible inclusion in future clinical trials and interventions evaluating early neurocognitive development. The domains included for consideration are attention, memory, executive function, language, and socioemotional development. Although domain-based tests are limited, as psychometric properties have not yet been well-established, this review includes tasks and paradigms that have been reliably used across various developmental psychology laboratories.

INTRODUCTION/BACKGROUND:The exact mechanisms underlying the established association between ADHD and obesity remain unclear. Food addiction and binge eating may contribute to this link. We examined for the first time the association between childhood/adult ADHD and food addiction/binge eating in patients with obesity, as well as the association between ADHD and sleep apnea syndrome. METHODS:We included 105 obese patients from the Nutrition Department of the University Hospital of Tours (France) between January and December 2014. We assessed categorical diagnoses of childhood/adulthood ADHD (semi-structured interview DIVA 2.0), food addiction (Yale Food Addiction Scale 2.0), binge eating (Binge Eating Scale), obstructive sleep apnea (clinical assessment), and BMI (clinical assessment). RESULTS:Patients with adult ADHD were at significantly higher risk of food addiction than patients without adult ADHD (28.6% vs. 9.1%; p = .016). Adult and childhood ADHD were significantly associated with self-reported food addiction, food addiction scores and binge eating scores, with a larger effect size for adult (ORs: 4.00 [1.29-12.40], 1.37 [1.14-1.65] and 1.08 [1.03-1.14], respectively) than childhood (ORs: 3.32 [1.08-10.23], 1.29 [1.08-1.55] and 1.06 [1.01-1.11], respectively) ADHD. ADHD diagnosis was not significantly correlated to obstructive sleep apnea. Mean age of onset of ADHD preceded mean age of onset of obesity. CONCLUSION/CONCLUSIONS:ADHD diagnosis is associated with food addiction and binge eating, with a larger effect size for adult than childhood ADHD. Our results provide a strong rationale for further longitudinal research on the link between ADHD, food addiction, binge eating and obesity, paving the way for evidence-based therapeutic interventions for these patients.