Faculty Bibliography

There is common agreement that many disorders of the central nervous system are 'complex', that is, there are many potential factors that influence the development of the disease, underlying mechanisms, and successful treatment. Most of these disorders, unfortunately, have no cure at the present time, and therapeutic strategies often have debilitating side effects. Interestingly, some of the 'complexities' of one disorder are found in another, and the similarities are often network defects. It seems likely that more discussions of these commonalities could advance our understanding and, therefore, have clinical implications or translational impact. With this in mind, the Fourth International Halifax Epilepsy Conference and Retreat was held as described in the prior paper, and this companion paper focuses on the second half of the meeting. Leaders in various subspecialties of epilepsy research were asked to address aging and dementia or psychosis in people with epilepsy (PWE). Commonalities between autism, depression, aging and dementia, psychosis, and epilepsy were the focus of the presentations and discussion. In the last session, additional experts commented on new conceptualization of translational epilepsy research efforts. Here, the presentations are reviewed, and salient points are highlighted.

As in life generally, so in scholarly publishing, the turn of the year inevitably encourages editors to reflect soberly and take honest stock of the progress their journals have made over the previous 12 months. In this frame of mind, my own thoughts turned to our beloved Journal of Child Psychology and Psychiatry. Of course I say ours because we who currently work at the journal, know it actually belongs to you, the world-wide community of child and adolescent psychologists and psychiatrists: We are only its stewards. We hold it in trust for the whole field. We understand the important role that it has served, in shaping the field of scientific child psychology and psychiatry. We know it has a special place in both your intellectual and working lives. We are aware how important it is to you that the journal continues, on your behalf, to help drive the promotion of science-driven and evidence-based solutions to the great, and, in some aspects, growing, burden of suffering imposed by childhood mental and neuro-developmental disorders. It is vital that we have your confidence that we do this in a transparent and fair way - without fear or favour - not letting our own preconceptions, prejudices or vested interests influence the content of what we publish - unless it is our prejudice towards, and vested interest in, finding out 'the truth of the matter'. We are acutely aware of the responsibility that all this places on our shoulders - a yoke we feel privileged to bear.

A systematic review with meta-analyses was performed to: 1) quantify the association between ADHD and risk of unintentional physical injuries in children/adolescents ("risk analysis"); 2) assess the effect of ADHD medications on this risk ("medication analysis"). We searched 114 databases through June 2017. For the risk analysis, studies reporting sex-controlled odds ratios (ORs) or hazard ratios (HRs) estimating the association between ADHD and injuries were combined. Pooled ORs (28 studies, 4,055,620 individuals without and 350,938 with ADHD) and HRs (4 studies, 901,891 individuals without and 20,363 with ADHD) were 1.53 (95% CI=1.40,1.67) and 1.39 (95% CI=1.06,1.83), respectively. For the medication analysis, we meta-analysed studies that avoided the confounding-by-indication bias [four studies with a self-controlled methodology and another comparing risk over time and groups (a "difference in differences" methodology)]. The pooled effect size was 0.879 (95% CI=0.838,0.922) (13,254 individuals with ADHD). ADHD is significantly associated with an increased risk of unintentional injuries and ADHD medications have a protective effect, at least in the short term, as indicated by self-controlled studies.

Emotional dysregulation (ED) is a dysfunction in modifying an emotional state in an adaptive and goal oriented way, with excitability, ease anger, and mood lability. It is present in up to 70% of adults with ADHD, regardless of other comorbidities, and substantially worsens the psychosocial outcomes of the disorder. Besides fronto-parietal circuits mediating top-down control, brain regions involved in bottom-up processes (e.g., amygdala, orbitofrontal cortex, and ventral striatum) are implicated in ED. We performed a systematic review/meta-analysis of double-blind randomized controlled trials of ADHD medications to assess their effects on ED in adults with ADHD. We searched an extensive set of databases, international trials registries, and contacted study authors/drug companies for unpublished data. We retained 21 trials. We found small-to-moderate effects (methylphenidate: SMD=0.34, 95% CI=0.23-0.45; atomoxetine: SMD=0.24, 95% CI=0.15-0.34; lisdexamfetamine: SMD=0.50, 95% CI=0.21-0.8). We suggest that, whilst ADHD medications are effective on ADHD core symptoms, they may be less effective on bottom-up mechanisms underlying ED. Further research on novel pharmacological and non-pharmacological strategies for ED in adults with ADHD is warranted.

Recent advances of neuroimaging methodology and artificial intelligence have resulted in renewed interest in board games like chess and Baduk (called Go game in the West) and have provided clues as to the mechanisms behind the games. However, an interesting question that remains to be answered is whether the board game expertise as one of cognitive skills goes beyond just being good at the trained game and how it maps on networks associated with cognitive abilities that are not directly trained. To address this issue, we examined functional activity and connectivity in Baduk experts, compared to novices, while performing a visual n-back working memory (WM) task. We found that experts, compared to novices, had greater activation in superior parietal cortex during face WM, though there were no group differences in behavioral performances. Using a data-driven, whole-brain multivariate approach, we also found significant group differences in the multivariate pattern of connectivity in frontal pole and inferior parietal cortex, further showing greater connectivity between frontal and parietal regions and between frontal and temporal regions in experts. Our findings suggest that long-term trained Baduk experts have the reorganization of functional interactions between brain regions even for untrained cognitive ability.

Although birth weight is a potential causal risk factor for attention-deficit/hyperactivity disorder (ADHD) symptoms, both the specificity of this association and its mediating pathways are largely unknown. We carefully assessed youth with and without ADHD (i.e., Wave 1), and followed them prospectively for 2 years (i.e., Wave 2). We (a) tested the association of birth weight with Wave 2 ADHD symptoms, and (b) evaluated biologically plausible neurocognitive functions from Wave 1 as temporally ordered mediators of birth weight and Wave 2 ADHD symptoms in a multiple mediation framework. At Wave 1, 222 ethnically diverse youth (30% female; ages 5-10) completed the Digit Span, Vocabulary, Symbol Search, and Arithmetic subtests of the Wechsler Intelligence Scale for Children-IV. At both Wave 1 and Wave 2 (ages 7-13), multiple informants (i.e., parents, teachers) rated youth ADHD symptoms and co-occurring psychopathology using multiple methods (i.e., structured interview, rating scale). Controlling for demographic factors, gestational age, and co-occurring externalizing and internalizing psychopathology, birth weight inversely predicted Wave 2 ADHD symptoms across multiple methods and informants. Additionally, controlling for Wave 1 ADHD symptoms and relevant covariates, Wave 1 Arithmetic uniquely mediated the association of birth weight with multi-method/informant Wave 2 ADHD symptoms. These findings suggest that birth weight is a relatively specific risk factor for youth ADHD symptoms and they implicate individual differences in fluid reasoning as a preliminary causal mediator of this association. We discuss implications for future research evaluating causal mechanisms underlying risk factors for ADHD.

Neurotrophins play critical roles in the survival, maintenance and death of neurons. In particular, proneurotrophins have been shown to mediate cell death following brain injury induced by status epilepticus (SE) in rats. Previous studies have shown that pilocarpine-induced seizures lead to increased levels of proNGF, which binds to the p75NTR-sortilin receptor complex to elicit apoptosis. A screen to identify compounds that block proNGF binding and uptake into cells expressing p75 and sortilin identified lithium citrate as a potential inhibitor of proNGF and p75NTR-mediated cell death. In this study, we demonstrate that low, submicromolar doses of lithium citrate effectively inhibited proNGF-induced cell death in cultured neurons and protected hippocampal neurons following pilocarpine-induced SE in vivo. We analyzed specific mechanisms by which lithium citrate afforded neuroprotection and determined that lithium citrate prevented the association and internalization of the p75NTR-sortilin receptor complex. Our results demonstrate a novel mechanism by which low-dose treatments of lithium citrate are effective in attenuating p75NTR-mediated cell death in vitro and in vivo.