Faculty Bibliography

BACKGROUND: Gaining insight into possible gender differences in the clinical presentation of adults with attention-deficit/hyperactivity disorder (ADHD) is of relevance in order to conduct appropriate screening and treatment interventions in both genders. METHOD: The analyses compared (1) prevalence and sociodemographic correlates, (2) frequency of ADHD core symptoms, (3) rates of subtypes, (4) prevalence of comorbid mental health conditions, and (5) rates of risky/impulsive behaviors, as well as health and social correlates, in men and women with ADHD in a nationally representative, US population-based sample. Face-to-face psychiatric interviews were conducted according to DSM-IV criteria in 34,653 adults from the US National Epidemiologic Survey on Alcohol and Related Conditions (Wave 2, 2004-2005). RESULTS: While the prevalence of lifetime ADHD was significantly higher in men than in women (OR = 1.46, 95% CI = 1.22-1.76), the rate of persistent ADHD did not significantly differ across genders (OR = 1.23, 95% CI = 0.96-1.58). Compared to men with persistent ADHD, women with persistent ADHD, despite having lower rates of hyperactive symptoms, presented with similar ADHD subtypes profile and rates of risky behaviors (except for reckless driving), as well as with significantly more anxiety and perceived mental health impairment (P = .032). Results were similar when considering lifetime ADHD. CONCLUSIONS: Our findings show that, despite different symptom profiles and comorbidities, men and women have similar rates of current ADHD and of risky behaviors associated with the disorder. Women with ADHD should receive as much attention as their male counterparts.

Recognizing predictive relationships is critical for survival, but an understanding of the underlying neural mechanisms remains elusive. In particular, it is unclear how the brain distinguishes predictive relationships from spurious ones when evidence about a relationship is ambiguous, or how it computes predictions given such uncertainty. To better understand this process, we introduced ambiguity into an associative learning task by presenting aversive outcomes both in the presence and in the absence of a predictive cue. Electrophysiological and optogenetic approaches revealed that amygdala neurons directly regulated and tracked the effects of ambiguity on learning. Contrary to established accounts of associative learning, however, interference from competing associations was not required to assess an ambiguous cue-outcome contingency. Instead, animals' behavior was explained by a normative account that evaluates different models of the environment's statistical structure. These findings suggest an alternative view of amygdala circuits in resolving ambiguity during aversive learning.

Maladaptive learned responses and memories contribute to psychiatric disorders that constitute a significant socio-economic burden. Primary treatment methods teach patients to inhibit maladaptive responses, but do not get rid of the memory itself, which explains why many patients experience a return of symptoms even after initially successful treatment. This highlights the need to discover more persistent and robust techniques to diminish maladaptive learned behaviours. One potentially promising approach is to alter the original memory, as opposed to inhibiting it, by targeting memory reconsolidation. Recent research shows that reactivating an old memory results in a period of memory flexibility and requires restorage, or reconsolidation, for the memory to persist. This reconsolidation period allows a window for modification of a specific old memory. Renewal of memory flexibility following reactivation holds great clinical potential as it enables targeting reconsolidation and changing of specific learned responses and memories that contribute to maladaptive mental states and behaviours. Here, we will review translational research on non-human animals, healthy human subjects, and clinical populations aimed at altering memories by targeting reconsolidation using biological treatments (electrical stimulation, noradrenergic antagonists) or behavioural interference (reactivation-extinction paradigm). Both approaches have been used successfully to modify aversive and appetitive memories, yet effectiveness in treating clinical populations has been limited. We will discuss that memory flexibility depends on the type of memory tested and the brain regions that underlie specific types of memory. Further, when and how we can most effectively reactivate a memory and induce flexibility is largely unclear. Finally, the development of drugs that can target reconsolidation and are safe for use in humans would optimize cross-species translations. Increasing the understanding of the mechanism and limitations of memory flexibility upon reactivation should help optimize efficacy of treatments for psychiatric patients.

Much of the early research in aversive learning concerned motivation and reinforcement in avoidance conditioning and related paradigms. When the field transitioned toward the focus on Pavlovian threat conditioning in isolation, this paved the way for the clear understanding of the psychological principles and neural and molecular mechanisms responsible for this type of learning and memory that has unfolded over recent decades. Currently, avoidance conditioning is being revisited, and with what has been learned about associative aversive learning, rapid progress is being made. We review, below, the literature on the neural substrates critical for learning in instrumental active avoidance tasks and conditioned aversive motivation.

BACKGROUND: Rare gene variants are important sources of schizophrenia vulnerability that likely interact with polygenic susceptibility loci. This study examined if novel or rare missense coding variants in any of four different signaling genes in sporadic schizophrenia cases were associated with clinical phenotypes in an exceptionally well-characterized sample. METHOD: Structured interviews, cognition, symptoms and life course features were assessed in 48 ethnically-diverse cases with psychosis who underwent targeted exome sequencing of PTPRG (Protein Tyrosine Phosphatase, Receptor Type G), SLC39A13 (Solute Carrier Family 39 (Zinc Transporter) Member 13), TGM5 (transglutaminase 5) and ARMS/KIDINS220 (Ankyrin repeat-rich membrane spanning protein or Kinase D-Interacting Substrate of 220kDa). Cases harboring rare missense coding polymorphisms or novel mutations in one or more of these genes were compared to other cases not carrying any rare missense coding polymorphisms or novel mutations in these genes and healthy controls. FINDINGS: Fifteen of 48 cases (31.25%) carried rare or novel missense coding variants in one or more of these genes. The subgroups significantly differed in important features, including specific working memory deficits for PTPRG (n=5); severe negative symptoms, global cognitive deficits and poor educational attainment, suggesting a developmental disorder, for SLC39A13 (n=4); slow processing speed, childhood attention deficit disorder and milder symptoms for TGM5 (n=4); and global cognitive deficits with good educational attainment suggesting neurodegeneration for ARMS/KIDINS220 (n=5). Case vignettes are included in the appendix. INTERPRETATION: Genes prone to missense coding polymorphisms and/or mutations in sporadic cases may highlight influential genes for psychosis and illuminate heterogeneous pathways to schizophrenia. Ethnicity appears less important at the level of genetic variability. The sequence variations that potentially alter the function of specific genes or their signaling partners may contribute to particular subtypes of psychosis. This approach may be applicable to other complex disorders.

Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (>/=7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naive youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.

The current study investigated age differences in free viewing gaze behavior. Adults and 6-, 9-, 12-, and 24-month-old infants watched a 60-s Sesame Street video clip while their eye movements were recorded. Adults displayed high inter-subject consistency in eye movements; they tended to fixate the same places at the same. Infants showed weaker consistency between observers and inter-subject consistency increased with age. Across age groups, the influence of both bottom-up features (fixating visually-salient areas) and top-down features (looking at faces) increased. Moreover, individual differences in fixating bottom-up and top-down features predicted whether infants' eye movements were consistent with those of adults, even when controlling for age. However, this relation was moderated by the number of faces available in the scene, suggesting that the development of adult-like viewing involves learning when to prioritize looking at bottom-up and top-down features.

The study by Leventakou and colleagues is emblematic of a welcome change in focus in attention-deficit/hyperactivity disorder (ADHD) research. First, the authors focused on the overlooked association between ADHD and aberrant eating patterns, reflecting an emerging change in the conceptualization of ADHD as a condition affecting not only high-level cognitive processes but also more basic functions such as eating and sleeping, as well as the underlying complex metabolic and possibly inflammatory pathways. Second, the authors focused, for the first time, on the relationship between ADHD and eating disorders in preschoolers, which is of relevance for the design of preventive strategies. Third, they zoomed closely to several types of aberrant eating behaviours; besides confirming the association of ADHD symptoms to emotional overeating, they also found an intriguing relationship between impulsivity and food fussiness. Further changes in perspective focusing on the underlying mechanisms, as well as using a wide-angle lens to capture the longitudinal relationship between ADHD and aberrant eating behaviours will not only provide a more detailed (clinical) picture of individuals with ADHD but will also hopefully lead to more effective preventive/treatment strategies.