Faculty Bibliography

The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force created the TASK3 working groups to create common data elements (CDEs) for various aspects of preclinical epilepsy research studies, which could help improve standardization of experimental designs. This article concerns the parameters that can be measured to assess the physiologic condition of the animals that are used to study rodent models of epilepsy. Here we discuss CDEs for physiologic parameters measured in adult rats and mice such as general health status, temperature, cardiac and respiratory function, and blood constituents. We provide detailed CDE tables and case report forms (CRFs), and with this companion manuscript we discuss the monitoring of different aspects of physiology of the animals. The CDEs, CRFs, and companion paper are available to all researchers, and their use will benefit the harmonization and comparability of translational preclinical epilepsy research. The ultimate hope is to facilitate the development of biomarkers and new treatments for epilepsy.

Sleep is critical for proper memory consolidation. The locus coeruleus (LC) releases norepinephrine throughout the brain except when the LC falls silent throughout rapid eye movement (REM) sleep and prior to each non-REM (NREM) sleep spindle. We hypothesize that these transient LC silences allow the synaptic plasticity that is necessary to incorporate new information into pre-existing memory circuits. We found that spontaneous LC activity within sleep spindles triggers a decrease in spindle power. By optogenetically stimulating norepinephrine-containing LC neurons at 2 Hz during sleep, we reduced sleep spindle occurrence, as well as NREM delta power and REM theta power, without causing arousals or changing sleep amounts. Stimulating the LC during sleep following a hippocampus-dependent food location learning task interfered with consolidation of newly learned locations and reconsolidation of previous locations, disrupting next-day place cell activity. The LC stimulation-induced reduction in NREM sleep spindles, delta, and REM theta and reduced ripple-spindle coupling all correlated with decreased hippocampus-dependent performance on the task. Thus, periods of LC silence during sleep following learning are essential for normal spindle generation, delta and theta power, and consolidation of spatial memories.

Turban and van Schalkwyk assert in their Translations article, "'Gender Dysphoria' and Autism Spectrum Disorder: Is the Link Real?" that an over-representation of autism spectrum disorder (ASD) in gender dysphoria is unsupported based on current evidence. Turban and van Schalkwyk discuss 7 of the currently 19 available empirical studies (excluding reviews and case reports) of the over-occurrence of ASD and/or autism traits with gender dysphoria/diversity. They are correct to note that some ASD screeners may lack specificity; that is, a clinical-range total score could indicate non-ASD-related mental health conditions or other developmental difference. However, they do not account for the 7 available studies which specifically report rates of clinical diagnoses of ASD among unselected gender-diverse samples. We suggest also that many of the studies that assess ASD-symptoms in gender-diverse groups are more convincing than suggested by Turban and van Schalkwyk because they employ measures assessing the multi-dimensionality of ASD symptoms and report significant elevations not only for socially-related symptoms but also for the various components of restricted and repetitive behaviors and interests (RRBI) core to ASD. We come together to write this response as gender clinicians and researchers, autism clinicians and researchers, and key stakeholders, including autistic and autistic transgender self-advocates. We work and live with the co-occurrence of autism and gender diversity on a daily basis, and we are concerned that perpetuating misunderstanding about the co-occurrence places individuals at risk.

Importance/UNASSIGNED:Prenatal exposure to certain medications has been hypothesized to influence the risk of autism spectrum disorders (ASD). However, the underlying effects on the neurotransmitter systems have not been comprehensively assessed. Objective/UNASSIGNED:To investigate the association of early-life interference with different neurotransmitter systems by prenatal medication exposure on the risk of ASD in offspring. Design, Setting, and Participants/UNASSIGNED:This case-control study included children born from January 1, 1997, through December 31, 2007, and followed up for ASD until January 26, 2015, within a single Israeli health maintenance organization. Using publicly available data, 55 groups of medications affecting neurotransmitter systems and prescribed to pregnant women in this sample were identified. Children prenatally exposed to medications were compared with nonexposed children. Data were analyzed from March 1, 2017, through June 20, 2018. Main Outcome and Measures/UNASSIGNED:Hazard ratios (HRs) and 95% CIs of ASD risk associated with exposure to medication groups using Cox proportional hazards regression, adjusted for the relevant confounders (eg, birth year, maternal age, maternal history of psychiatric and neurologic disorders, or maternal number of all medical diagnoses 1 year before pregnancy). Results/UNASSIGNED:The analytic sample consisted of 96 249 individuals (1405 cases; 94 844 controls; mean [SD] age at the end of follow-up, 11.6 [3.1] years; 48.8% female), including 1405 with ASD and 94 844 controls. Of 34 groups of medications, 5 showed nominally statistically significant association with ASD in fully adjusted models. Evidence of confounding effects of the number of maternal diagnoses on the association between offspring exposure to medication and ASD was found. Adjusting for this factor, lower estimates of ASD risk among children exposed to cannabinoid receptor agonists (HR, 0.72; 95% CI, 0.55-0.95; P = .02), muscarinic receptor 2 agonists (HR, 0.49; 95% CI, 0.24-0.98; P = .04), opioid receptor κ and ε agonists (HR, 0.67; 95% CI, 0.45-0.99; P = .045), or α2C-adrenergic receptor agonists (HR, 0.43; 95% CI, 0.19-0.96; P = .04) were observed. Exposure to antagonists of neuronal nicotinic acetylcholine receptor α was associated with higher estimates of ASD risk (HR, 12.94; 95% CI, 1.35-124.25; P = .03). Conclusions and Relevance/UNASSIGNED:Most of the medications affecting neurotransmitter systems in this sample had no association with the estimates of ASD risk. Replication and/or validation using experimental techniques are required.

The ability to mentalize, or theory of mind (ToM), is sexually dimorphic in humans and impaired in schizophrenia. This sex-stratified study probed cognitive (indexed by intelligence) and affective (indexed by olfactory tasks) contributions to ToM performance in 37 individuals with schizophrenia and 31 healthy controls. The schizophrenia group showed impairments in mental state identification and inferring intentions compared to controls. Higher intelligence was correlated with mental state identification and inferring intentions in healthy females, whereas better smell identification was associated with mental state identification in healthy males. Conversely, higher intelligence was associated with mental state identification and inferring intentions in schizophrenia males, while better smell identification was correlated with mental state identification in schizophrenia females. These findings suggest that for ToM circuitry, the cognitive influences in healthy females and affective influences in healthy males are reversed in schizophrenia and may be displaced to lower circuitries by disease pathology. Symptom associations with emotion and cognition are also dimorphic, plausibly due to similar pathology superimposed on normal sex-specific circuitries. Males appear to rely on limbic processing for ToM, and disruption to this circuitry may contribute to development of negative symptoms. These findings highlight the importance of utilizing sex-stratified designs in schizophrenia research.

Early age of sexual debut is associated with an increase in negative outcomes, including higher incidence of nonconsensual sexual experiences, higher rates of sexually transmitted infections, and risky sexual practices. Little research has examined the role of parental psychopathology as a predictor of adolescent sexual activity, however. The current study aims to close this gap by examining the relationship between parental psychopathology and sexual activity in a longitudinal sample of youth. Participants were 685 adolescents from the Longitudinal Assessment of Manic Symptoms study, the majority of whom were male (67%) and White (65%). Analyses considering likelihood of sexual initiation included the full sample, whereas analyses considering predictors of the age of sexual debut included the 162 participants who reported ever having sexual intercourse (62% male, 51% White) via the Youth Risk Behavior Surveillance-High School version. Cox regression analyses suggested that maternal generalized anxiety disorder predicted decreased likelihood of initiating sex during the 8-year follow-up period, whereas paternal conduct disorder predicted increased likelihood of initiating sex. Multivariate linear regressions also showed that maternal conduct disorder predicted earlier age of sexual debut among those who had initiated, whereas paternal antisocial personality disorder predicted later age of sexual debut. These associations were observed in both male and female adolescents. Furthermore, these effects were largely not explained by the established relationship between youth psychopathology and sexual behavior. Results have implications for interventions aimed at decreasing sexual risk taking in vulnerable youth.

RATIONALE/BACKGROUND:Weight gain during treatment with antipsychotics is a prominent side-effect, especially with some second-generation antipsychotics, such as olanzapine and clozapine, and pharmacological treatments which ameliorate this side-effect are important to investigate. Decreases in histaminergic transmission in the brain induced by antipsychotics may be one of the mechanisms contributing to weight gain. Since betahistine is a histaminergic agonist, it may potentially counteract the weight gain effects of antipsychotics. METHOD/METHODS:We conducted a double-blind placebo-controlled study to evaluate the effects of 12 weeks of treatment with betahistine (N = 29) or placebo (N = 22) in adolescents and adults on anthropomorphically measured weight-related parameters, appetite, and fasting glucose-lipid and leptin levels in 51 patients treated with first and/or second-generation antipsychotics who had gained weight during treatment or had high body-mass-index (BMI). Psychopathology and side-effects were also assessed with relevant scales. RESULTS:In a sub-group of patients being treated with olanzapine or clozapine (n = 26), betahistine was significantly (P < .05) better than placebo in preventing increases in weight (3.1 kg less weight gain than placebo), BMI, and waist circumference. Betahistine did not decrease weight or BMI in patients treated with other antipsychotics. There was also no effect of betahistine on preventing weight or BMI gain in the total combined sample of all subjects. Betahistine did not significantly improve appetite or glucose-lipid measures in either subgroup. There were no significant differences in side-effects or psychopathology changes in the betahistine- vs. placebo-treated patients. CONCLUSIONS:These results suggest that betahistine may potentially be a useful adjunctive drug for decreasing weight gain in patients treated with antipsychotics that are potent histamine antagonists, such as olanzapine or clozapine, but may not be useful for this purpose in patients on other antipsychotic medications. The results justify larger placebo-controlled studies to further confirm these effects before specific recommendations can be made for routine use.

A traditional childrearing practice-"gahvora" cradling-in Tajikistan and other parts of Central Asia purportedly restricts movement of infants' body and limbs. However, the practice has been documented only informally in anecdotal reports. Thus, this study had two research questions: (1) To what extent are infants' movements restricted in the gahvora? (2) How is time in the gahvora distributed over a 24-hour day in infants from 1-24 months of age? To answer these questions, we video-recorded 146 mothers cradling their infants and interviewed them using 24-hour time diaries to determine the distribution of time infants spent in the gahvora within a day and across age. Infants' movements were indeed severely restricted. Although mothers showed striking uniformity in how they restricted infants' movements, they showed large individual differences in amount and distribution of daily use. Machine learning algorithms yielded three patterns of use: day and nighttime cradling, mostly nighttime cradling, and mostly daytime cradling, suggesting multiple functions of the cradling practice. Across age, time in the gahvora decreased, yet 20% of 12- to 24-month-olds spent more than 15 hours bound in the gahvora. We discuss the challenges and benefits of cultural research, and how the discovery of new phenomena may defy Western assumptions about childrearing and development. Future work will determine whether the extent and timing of restriction impacts infants' physical and psychological development.

In many studies of attention-deficit hyperactivity disorder (ADHD), stimulus encoding and processing (perceptual function) and response selection (executive function) have been intertwined. To dissociate deficits in these functions, we introduced a task that parametrically varied low-level stimulus features (orientation and color) for fine-grained analysis of perceptual function. It also required participants to switch their attention between feature dimensions on a trial-by-trial basis, thus taxing executive processes. Furthermore, we used a response paradigm that captured task-irrelevant motor output (TIMO), reflecting failures to use the correct stimulus-response rule. ADHD participants had substantially higher perceptual variability than controls, especially for orientation, as well as higher TIMO. In both ADHD and controls, TIMO was strongly affected by the switch manipulation. Across participants, the perceptual variability parameter was correlated with TIMO, suggesting that perceptual deficits are associated with executive function deficits. Based on perceptual variability alone, we were able to classify participants into ADHD and controls with a mean accuracy of about 77%. Participants' self-reported General Executive Composite score correlated not only with TIMO but also with the perceptual variability parameter. Our results highlight the role of perceptual deficits in ADHD and the usefulness of computational modeling of behavior in dissociating perceptual from executive processes.