Faculty Bibliography

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 x 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Pharmacological treatments play an important role in the multimodal treatment of ADHD. Currently, there is a lack of up-to-date and comprehensive evidence on how available ADHD drugs compare and rank in terms of efficacy and tolerability, in children or adolescents as well as in adults. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs), to rank pharmacological treatments for ADHD according to their efficacy and tolerability profiles. METHODS AND ANALYSIS: We will search a broad range of electronic databases, including PubMed, MEDLINE, EMBASE, PsycINFO, ERIC and Web of Science, with no date or language restrictions. We will also search for unpublished studies using international clinical trial registries and contacting relevant drug companies. We will identify and include available parallel-group, cross-over and cluster randomised trials that compare methylphenidate, dexmethylphenidate, amphetamine derivatives (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, bupropion or modafinil (as oral therapy) either with each other or to placebo, in children, adolescents or adults with ADHD. Primary outcomes will be efficacy (indicated by reduction in severity of ADHD core symptoms measured on a standardised scale) and tolerability (the proportion of patients who left a study early due to side effects). Secondary outcomes will be global functioning, acceptability (proportion of patients who left the study early by any cause) and changes in blood pressure and body weight. NMA will be conducted in STATA within a frequentist framework. The quality of RCTs will be evaluated using the Cochrane risk of bias tool, and the quality of the evidence will be assessed using the GRADE approach. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. ETHICS AND DISSEMINATION: No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and possibly presented at relevant national and international conferences. TRIAL REGISTRATION NUMBER: CRD42014008976.

It has been suggested that neurological problems more frequent in those born preterm are expressed prior to birth, but owing to technical limitations, this has been difficult to test in humans. We applied novel fetal resting-state functional MRI to measure brain function in 32 human fetuses in utero and found that systems-level neural functional connectivity was diminished in fetuses that would subsequently be born preterm. Neural connectivity was reduced in a left-hemisphere pre-language region, and the degree to which connectivity of this left language region extended to right-hemisphere homologs was positively associated with the time elapsed between fMRI assessment and delivery. These results provide the first evidence that altered functional connectivity in the preterm brain is identifiable before birth. They suggest that neurodevelopmental disorders associated with preterm birth may result from neurological insults that begin in utero.

Pavlovian aversive conditioning requires learning of the association between a conditioned stimulus (CS) and an unconditioned, aversive stimulus (US) but also involves encoding the time interval between the two stimuli. The neurobiological bases of this time interval learning are unknown. Here, we show that in rats, the dorsal striatum and basal amygdala belong to a common functional network underlying temporal expectancy and learning of a CS-US interval. Importantly, changes in coherence between striatum and amygdala local field potentials (LFPs) were found to couple these structures during interval estimation within the lower range of the theta rhythm (3-6 Hz). Strikingly, we also show that a change to the CS-US time interval results in long-term changes in cortico-striatal synaptic efficacy under the control of the amygdala. Collectively, this study reveals physiological correlates of plasticity mechanisms of interval timing that take place in the striatum and are regulated by the amygdala.

It is generally accepted that women tend to ruminate more than men do and these thought patterns are often associated with depressive symptoms (Nolen-Hoeksema et al., ). Based on these findings, we considered whether the relationship between rumination and depression is stronger in women than in men and if so, whether this might explain the higher prevalence of major depressive disorder (MDD) in women and finally, whether the association can be disrupted through a mind/body intervention. Adult men and women, most of whom were clinically depressed, participated in an intervention known as MAP Training, which combines "mental" training with silent meditation and "physical" training with aerobic exercise (Shors et al., ). After eight weeks of training, both men and women reported significantly fewer symptoms of depression and fewer ruminative thoughts (Alderman et al., ). Statistical correlations between depressive symptoms and ruminative thoughts were strong and significant (rho > 0.50; p < 0.05) for both men and women before and after MAP Training. However, only in women did depressive symptoms relate to "reflective" ruminations, which involve analyses of past events, feelings, and behaviors. This is also the only relationship that dissipated after the intervention. In general, these analyses suggest that the strength of the relationship between depressive symptoms and rumination does not necessarily explain sex differences in depression; but because the relationship is strong, targeting rumination through intervention can reduce the incidence of MDD, which is more prevalent among women. © 2016 Wiley Periodicals, Inc.

OBJECTIVE: Sleep disordered breathing (SDB) has not been well studied in urban adolescents with asthma in community settings. Nor has the association of SDB symptoms and asthma severity been studied. We characterized self-reported symptoms suggesting SDB and investigated the association of SDB symptoms, probable asthma, and asthma severity. METHODS: 9,565 adolescents from 21 inner-city high schools were screened for an asthma intervention study. Students reported on symptoms suggesting SDB using questions from the 2007 NHANES, if they were ever diagnosed with asthma, and on asthma symptoms. Using generalized linear mixed models with logit link with school as a random intercept and adjusting for age, gender, and race/ethnicity, we examined associations of SDB symptoms, and demographic characteristics, probable asthma, and asthma severity. RESULTS: 12% reported SDB symptoms. Older and bi-racial participants (compared to Caucasian) had higher odds of symptoms suggesting SDB (p<.001). Compared to those without probable asthma, adolescents with probable asthma had 2.63 greater odds of reporting SDB symptoms (p<.001). Among those with probable asthma, the odds of reporting SDB symptoms increased with asthma severity. When exploring daytime severity and severity due to night wakening separately, results were similar. All results remained significant when controlling for age, gender, and ethnicity. CONCLUSIONS: In a large urban community cohort of predominately ethnic minority adolescents, self-reported SDB symptoms were associated with probable asthma and increased asthma severity. This study highlights the importance of SDB as a modifiable co-morbidity of asthma.

Numerous studies have demonstrated differences between males and females in hippocampal structure, function, and plasticity. There also are many studies about the different predisposition of a males and females for disorders where the hippocampus plays an important role. Many of these reports focus on area CA1, but other subfields are also very important, and unlikely to be the same as area CA1 based on what is known. Here we review basic studies of male and female structure, function, and plasticity of area CA3 pyramidal cells of adult rats. The data suggest that the CA3 pyramidal cells of males and females are distinct in structure, function, and plasticity. These sex differences cannot be simply explained by the effects of circulating gonadal hormones. This view agrees with previous studies showing that there are substantial sex differences in the brain that cannot be normalized by removing the gonads and depleting peripheral gonadal hormones. Implications of these comparisons for understanding sex differences in hippocampal function and dysfunction are discussed. (c) 2016 Wiley Periodicals, Inc.

This investigation explored the relationship between food allergies and social anxiety in a school-based sample of adolescents. A total of 849 participants, including 87 endorsing food allergies, completed standardized questionnaires assessing social anxiety symptoms. Food allergic participants answered questions assessing allergy characteristics, worry and avoidance related to allergen exposure and allergy disclosure, and parental worry and control. Boys with food allergies reported higher social anxiety than boys without food allergies, though no differences were found in girls. Social anxiety was correlated with parental worry and control. Findings may inform anxiety prevention programs for youth with food allergies.

Beginning with his Interpersonal World of the Infant (1985), Daniel Stern suggested that the infant is driven from birth to connect intersubjectively with his caregivers. By the final three months of the first year of life, as the infant begins to use protodeclarative pointing and jointly attends to the outer world, he also begins to jointly attend with his caregiver to their respective intrapsychic worlds, the mental states of his caregiver and himself. Clinically, analysts observe at this crucial point of development of secondary intersubjectivity mothers who, more often than not, respond only selectively and often unpredictably to their infants. In many instances, this may be motivated out of a mother's own need for regulation of emotion and arousal as we have shown in our empirical research. This article elaborates on clinical observations that, for the infant or young child to feel his traumatized mother's affective presence, he must try to enter mother's state of mind, while simultaneously, mother is seeking to self-regulate in the wake or the revival of trauma-associated memory traces, this at the expense of mutual regulation of emotion and arousal. We call this phenomenon traumatically skewed intersubjectivity. We find that children coconstruct with their traumatized mothers a new, shared traumatic experience by virtue of the toddler's efforts to share an intersubjective experience with a mother who is acting in response to posttraumatic reexperiencing. The problem is that the infant or young child has no point of reference to decipher the traumatized mother's social communication. And so, what is enacted leads to a new, shared traumatic event. Both the child's anxiety and aggression can, in this setting, easily become dysregulated, further triggering mother's anxiety and avoidance, leading thus to a vicious cycle that contributes to intergenerational transmission of trauma. Clinical examples and implications for psychoanalytically-oriented parent-infant psychotherapy will be discussed.