Faculty Bibliography

Episodic memory decline, olfactory identification deficits and the ApoE-e4 allele constitute risk factors for incident Alzheimers' Disease (AD). However, the relationships among these three risk factors are poorly understood, in part due to the paucity of large longitudinal datasets that involve such assessments. The present study used data from the Betula study (n=1225), which involves memory testing every five years. Participants completed an odor identification test, were genotyped for the ApoE gene, and had completed episodic memory testing for a 10-year period (3 testing occasions) leading up to the olfactory assessment. The episodic memory measure was a composite of five tasks, and decline was defined as an estimated change >1SD below the age norm. Participants were thus classified as "decliners" (n=125) or "non-decliners" (n=1100). Results showed that decliners had a poorer olfactory identification than nondecliners. However, when ApoE-e4 was taken into consideration, the association between memory decline and odor identification deficit was only present in ApoE-e4 carriers, whereas odor identification in memory decliners without e4 reached the same level as that of non-decliners. Future research on the role of olfaction in age-related memory impairment and dementia should consider the mediating role played by the ApoE-e4

INTRODUCTION: Our aim was to assess differences in movement measures in attention-deficit/hyperactivity disorder (ADHD) vs. typically developing (TD) controls. METHODS: We performed meta-analyses of published studies on motion measures contrasting ADHD with controls. We also conducted a case-control study with children/adolescents (n=61 TD, n=62 ADHD) and adults (n=30 TD, n=19 ADHD) using the McLean motion activity test, semi-structured diagnostic interviews and the behavior rating inventory of executive function and Conners (parent, teacher; self) rating scales. RESULTS: Meta-analyses revealed medium-to-large effect sizes for actigraph (standardized mean difference [SMD]: 0.64, 95% confidence interval (CI): 0.43, 0.85) and motion tracking systems (SDM: 0.92, 95% CI: 0.65, 1.20) measures in differentiating individuals with ADHD from controls. Effects sizes were similar in studies of children/adolescents ([SMD]: 0.75, 95% CI: 0.50, 1.01) and of adults ([SMD]: 0.73, 95% CI: 0.46, 1.00). In our sample, ADHD groups differed significantly in number of head movements (p=0.02 in children; p=0.002 in adults), displacement (p=0.009/p<0.001), head area (p=0.03/p<0.001), spatial complexity (p=0.06/p=0.02) and temporal scaling (p=0.05/p=0.04). Mean effect sizes were non-significantly larger (d=0.83, 95% CI: 0.20, 1.45) in adults vs. children/adolescents with ADHD (d=0.45, 95% CI: 0.08, 0.82). In the concurrent go/no-go task, reaction time variability was significantly greater in ADHD (p<0.05 in both age groups) than controls. CONCLUSIONS: Locomotor hyperactivity remains core to the construct of ADHD even in adults. Our results suggest that objective locomotion measures may be particularly useful in evaluating adults with possible ADHD.

Risky decision-making, particularly in the context of reward-seeking behavior, is strongly associated with the presence of substance use disorders (SUDs). However, there has been little research on the neural substrates underlying reward-related decision-making in drug-naive youth who are at elevated risk for SUDs. Participants comprised 23 high-risk (HR) youth with a well-established SUD risk phenotype and 27 low-risk healthy comparison (HC) youth, aged 10-14. Participants completed the balloon analog risk task (BART), a task designed to examine risky decision-making, during functional magnetic resonance imaging. The HR group had faster reaction times, but otherwise showed no behavioral differences from the HC group. HR youth experienced greater activation when processing outcome, as the chances of balloon explosion increased, relative to HC youth, in ventromedial prefrontal cortex (vmPFC). As explosion probability increased, group-by-condition interactions in the ventral striatum/anterior cingulate and the anterior insula showed increasing activation in HR youth, specifically on trials when explosions occurred. Thus, atypical activation increased with increasing risk of negative outcome (i.e., balloon explosion) in a cortico-striatal network in the HR group. These findings identify candidate neurobiological markers of addiction risk in youth at high familial and phenotypic risk for SUDs.

Attention-deficit/hyperactivity disorder (ADHD) is a persistent neurodevelopmental disorder that affects 5% of children and adolescents and 2.5% of adults worldwide. Throughout an individual's lifetime, ADHD can increase the risk of other psychiatric disorders, educational and occupational failure, accidents, criminality, social disability and addictions. No single risk factor is necessary or sufficient to cause ADHD. In most cases ADHD arises from several genetic and environmental risk factors that each have a small individual effect and act together to increase susceptibility. The multifactorial causation of ADHD is consistent with the heterogeneity of the disorder, which is shown by its extensive psychiatric co-morbidity, its multiple domains of neurocognitive impairment and the wide range of structural and functional brain anomalies associated with it. The diagnosis of ADHD is reliable and valid when evaluated with standard criteria for psychiatric disorders. Rating scales and clinical interviews facilitate diagnosis and aid screening. The expression of symptoms varies as a function of patient developmental stage and social and academic contexts. Although there are no curative treatments for ADHD, evidenced-based treatments can markedly reduce its symptoms and associated impairments. For example, medications are efficacious and normally well tolerated, and various non-pharmacological approaches are also valuable. Ongoing clinical and neurobiological research holds the promise of advancing diagnostic and therapeutic approaches to ADHD. For an illustrated summary of this Primer, visit: http://go.nature.com/J6jiwl.

BACKGROUND: Experimental extinction serves as a model for psychiatric treatments based on associative learning. However, the effects of extinction are often transient, as evidenced by postextinction return of defensive behaviors. From a therapeutic perspective, an inherent problem with extinction may be that mere omission of threat is not sufficient to reduce future threat uncertainty. The current study tested an augmented form of extinction that replaced, rather than merely omitted, expected threat outcomes with novel nonthreat outcomes, with the goal of reducing postextinction return of defensive behaviors. METHODS: Thirty-two healthy male Sprague-Dawley rats and 47 human adults underwent threat conditioning to a conditioned stimulus paired with an electrical shock. Subjects then underwent a standard extinction protocol with shock omitted or an augmented extinction protocol wherein the shock was replaced by a surprising tone. Tests of postextinction recovery occurred 24 hours later in the absence of the tone. RESULTS: Replacing the shock with a novel nonthreat outcome, as compared with shock omission, reduced postextinction recovery (freezing in rats and anticipatory skin conductance responses in humans) when tested 24 hours later. Self-reported intolerance of uncertainty was positively correlated with recovery following standard extinction in humans, providing new evidence that postextinction recovery is related to sensitivity to future threat uncertainty. CONCLUSIONS: These findings provide cross-species evidence of a novel strategy to enhance extinction that may have broad implications for how to override associative learning that has become maladaptive and offer a simple technique that could be straightforwardly adapted and implemented in clinical situations.

Psychostimulants such as methylphenidate and amphetamine are the first-line pharmacologic treatments for Attention-Deficit/Hyperactivity Disorder (ADHD). They are considered prototypical cognitive enhancers but their effects on standard laboratory indices of cognitive function are modest when administered acutely, and even less substantial chronically. However, large-scale observational studies in patients with ADHD have detected stimulant-associated decreases of criminal acts, transportation accidents, slightly improved academic performance, and possible protection against drug abuse. These effects likely reflect modulation of broader domains such as emotional regulation and motivation which have been under-examined. Efforts to clarify the ontological relations between cognitive tasks and their underlying constructs should be incorporated into the Research Domain Criteria project and similar harmonization initiatives.

The "ten ironic rules for statistical reviewers" presented by Friston (2012) prompted a rebuttal by Lindquist et al. (2013), which was followed by a rejoinder by Friston (2013). A key issue left unresolved in this discussion is the use of cross-validation to test the significance of predictive analyses. This note discusses the role that cross-validation-based and related hypothesis tests have come to play in modern data analyses, in neuroimaging and other fields. It is shown that such tests need not be suboptimal and can fill otherwise-unmet inferential needs.

STUDY OBJECTIVES: To evaluate the frequency, severity, and associations of symptoms of attention-deficit/hyperactivity disorder (ADHD) in children with narcolepsy with and without cataplexy. DESIGN: Cross-sectional survey. SETTING: Four French national reference centers for narcolepsy. PATIENTS: One hundred eight consecutively referred children aged younger than 18 y with narcolepsy, with (NwC, n = 86) or without cataplexy (NwoC, n = 22), and 67 healthy controls. INTERVENTIONS: The participants, their families, and sleep specialists completed a structured interview and questionnaires about sleep, daytime sleepiness, fatigue, and ADHD symptoms (ADHD-rating scale based upon Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR] symptoms), and use of psychostimulants for the treatment of narcolepsy (administered in 68.2%). Polysomnographic measures were collected. MEASUREMENTS AND RESULTS: Clinically significant levels of ADHD symptoms were found in 4.8% of controls compared with 35.3% in patients with NwoC (P < 0.001) and 19.7% in patients with NwC (P < 0.01). Total ADHD scores were 6.4 (95% confidence interval [CI]: 4.5, 9.0) in controls compared with 14.2 (95% CI: 10.6, 18.9; P < 0.001), in patients with NwoC and 12.2 (95% CI: 9.8, 15.3; P < 0.01) in patients with NwC; subscores of inattention and hyperactivity/impulsivity were also significantly higher in both narcolepsy groups compared with controls. No difference was found between the NwC and NwoC groups for any ADHD measure. ADHD symptom severity was associated with increased levels of sleepiness, fatigue, and insomnia. Compared with the 34 untreated patients, the 73 patients treated with psychostimulants (modafinil in 91%) showed a trend toward lower narcolepsy symptoms but not lower ADHD symptoms. CONCLUSIONS: Pediatric patients with narcolepsy have high levels of treatment-resistant ADHD symptoms. The optimal treatment for ADHD symptoms in these patients warrants further evaluation in longitudinal intervention studies.

Schizophrenia is a debilitating syndrome with high heritability. Genomic studies reveal more than a hundred genetic variants, largely nonspecific and of small effect size, and not accounting for its high heritability. De novo mutations are one mechanism whereby disease related alleles may be introduced into the population, although these have not been leveraged to explore the disease in general samples. This paper describes a framework to find high impact genes for schizophrenia. This study consists of two different datasets. First, whole exome sequencing was conducted to identify disruptive de novo mutations in 14 complete parent-offspring trios with sporadic schizophrenia from Jerusalem, which identified 5 sporadic cases with de novo gene mutations in 5 different genes (PTPRG, TGM5, SLC39A13, BTK, CDKN3). Next, targeted exome capture of these genes was conducted in 48 well-characterized, unrelated, ethnically diverse schizophrenia cases, recruited and characterized by the same research team in New York (NY sample), which demonstrated extremely rare and potentially damaging variants in three of the five genes (MAF<0.01) in 12/48 cases (25%); including PTPRG (5 cases), SCL39A13 (4 cases) and TGM5 (4 cases), a higher number than usually identified by whole exome sequencing. Cases differed in cognition and illness features based on which mutation-enriched gene they carried. Functional de novo mutations in protein-interaction domains in sporadic schizophrenia can illuminate risk genes that increase the propensity to develop schizophrenia across ethnicities.