Can neuroimaging measures differentiate the disease course of anorexia nervosa? A systematic review.

Anorexia nervosa (AN) entails many uncertainties regarding the clinical outcome, due to large heterogeneity in the disease course. AN is associated with global decrease in brain volumes and altered brain functioning during acute illness. However, it is unclear whether structural and functional brain alterations can predict clinical outcome. We aimed to systematically review the predictive value of volumetric and functional brain outcome measures of structural and functional brain magnetic resonance imaging (MRI) on the disease course of AN. Four databases (Embase, Medline, Psycinfo, and Cochrane Central Register) were systematically searched. A total of 15 studies (structural MRI: n = 6, functional MRI: n = 9) were reviewed. In total 464 unique AN patients, and 328 controls were included. Follow-up time ranged between 1 and 43 months. Structural neuroimaging studies showed that lower brain volumes of the cerebellum, subcortical grey matter, and cortical white matter at admission predicted a worse clinical outcome. A smaller increase of the anterior cingulate cortex volume in the early phase of the disease predicted a worse clinical outcome. Lower overall gyrification, and a higher clustering coefficient predicted a worse clinical outcome. Functional MRI studies showed that frontal, parietal and temporal activity during task-based algorithms predicted follow-up body mass index, although results were bidirectional possibly due to the large heterogeneity in methodological approaches. Neuroimaging measures may predict the clinical outcome of AN. However, there is a lack of replication studies. Future studies are needed to validate the prognostic utility of neuroimaging measures in AN patients, and should harmonize demographic, clinical and neuroimaging features in order to enhance comparability.

The effect of prenatal lithium exposure on the neuropsychological development of the child.

OBJECTIVES: Lithium is an effective treatment for bipolar disorder, also during pregnancy to prevent the recurrence of episodes in the perinatal period. Little is known about the neuropsychological development of lithium-exposed offspring. The current study was designed to investigate neuropsychological functioning in lithium-exposed children with the aim to provide further knowledge on the long-term effects of lithium use during pregnancy. METHODS: Participants were offspring of women with a diagnosis of bipolar spectrum disorder, aged 6-14 years. In total, 99 children participated in the study, 56 were exposed to lithium in utero and 43 were not exposed to lithium. Neuropsychological tests were administered, including the Snijders-Oomen Nonverbal Intelligence Test and the NEPSY-II-NL assessment. Linear and negative binomial regression models were used to investigate the association between prenatal lithium exposure and neuropsychological functioning. In secondary analyses, the association between lithium blood level during pregnancy and neuropsychological functioning was assessed. Additionally, norm scores and percentiles for task outcomes were calculated. RESULTS: Lithium use during pregnancy was associated with the total number of mistakes made on the Auditory Attention task, but not statistically significant after full adjustment for potential confounding factors. No association between prenatal lithium exposure and IQ was found. Also, no relationship between lithium blood level during pregnancy and neuropsychological functioning was found after adjustment for potential confounders. Task outcomes in both groups were comparable to the general population. CONCLUSION: In this study, we found no evidence for significantly altered neuropsychological functioning of lithium-exposed children at the age of 6-14 years, when compared to non-lithium-exposed controls.

T cell composition and polygenic multiple sclerosis risk: A population-based study in children.

BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS) have altered T cell function and composition. Common genetic risk variants for MS affect proteins that function in the immune system. It is currently unclear to what extent T cell composition is affected by genetic risk factors for MS, and how this may precede a possible disease onset. Here, we aim to assess whether an MS polygenic risk score (PRS) is associated with an altered T cell composition in a large cohort of children from the general population. METHODS: We included genotyped participants from the population-based Generation R study in whom immunophenotyping of blood T cells was performed at the age of 6 years. Analyses of variance were used to determine the impact of MS-PRSs on total T cell numbers (n = 1261), CD4+ and CD8+ lineages, and subsets therein (n= 675). In addition, T-cell-specific PRSs were constructed based on functional pathway data. RESULTS: The MS-PRS negatively correlated with CD8+ T cell frequencies (p = 2.92 × 10-3 ), which resulted in a positive association with CD4+ /CD8+ T cell ratios (p = 8.27 × 10-9 ). These associations were mainly driven by two of 195 genome-wide significant MS risk variants: the main genetic risk variant for MS, HLA-DRB1*15:01 and an HLA-B risk variant. We observed no significant associations for the T-cell-specific PRSs. CONCLUSIONS: Our results suggest that MS-associated genetic variants affect T cell composition during childhood in the general population.

Editors' Best of 2020.

There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, hammering version after version into shape. Acknowledging these biases, here are the 2020 articles that we think deserve your attention, or at least a second read.

Silent cerebral infarcts in patients with sickle cell disease: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Silent cerebral infarcts (SCIs) are the most common neurological complication in children and adults with sickle cell disease (SCD). In this systematic review, we provide an overview of studies that have detected SCIs in patients with SCD by cerebral magnetic resonance imaging (MRI). We focus on the frequency of SCIs, the risk factors involved in their development and their clinical consequences. METHODS: The databases of Embase, MEDLINE ALL via Ovid, Web of Science Core Collection, Cochrane Central Register of Trials via Wiley and Google Scholar were searched from inception to June 1, 2019. RESULTS: The search yielded 651 results of which 69 studies met the eligibility criteria. The prevalence of SCIs in patients with SCD ranges from 5.6 to 80.6% with most studies reported in the 20 to 50% range. The pooled prevalence of SCIs in HbSS and HbSß0 SCD patients is 29.5%. SCIs occur more often in patients with the HbSS and HbSß0 genotype in comparison with other SCD genotypes, as SCIs are found in 9.2% of HbSC and HbSß+ patients. Control subjects showed a mean pooled prevalence of SCIs of 9.8%. Data from included studies showed a statistically significant association between increasing mean age of the study population and mean SCI prevalence. Thirty-three studies examined the risk factors for SCIs. The majority of the risk factors show no clear association with prevalence, since more or less equal numbers of studies give evidence for and against the causal association. CONCLUSIONS: This systematic review and meta-analysis shows SCIs are common in patients with SCD. No clear risk factors for their development were identified. Larger, prospective and controlled clinical, neuropsychological and neuroimaging studies are needed to understand how SCD and SCIs affect cognition.

Our Vision: An Antiracist Journal.

Our renewed vision for the Journal is to be antiracist at every level. To achieve this, we will go beyond our long-standing charge to advance the knowledge of child development, children's mental health, and prevention and treatment of mental illness to solicit and disseminate research that addresses the systemic presence of racism and its influence on the health and well-being of children of color and their families. We acknowledge that our efforts as a journal to address these inequities have been insufficient and that dismantling the threads of White supremacy requires us to take a more active role. We pledge to do the work to advance research that understands the individual, cultural, and societal factors that contribute to the persistent disparities we have previously noted but failed to correct.

JAACAP's Role in Advancing the Science of Pediatric Mental Health and Promoting the Care of Youth and Families During the COVID-19 Pandemic.

As we pen these words, the COVID-19 pandemic is having profound impacts on human society. Based on decades of research, we know that the accompanying illness,1 death,2 social isolation,3,4 and malnutrition5 will have deep and lasting impacts on our children and adolescents, their families, and the communities in which they develop. The pandemic is exposing, with terrible clarity, the disparities in human society-racism,6 poverty,7,8 domestic violence,9,10 and child maltreatment and neglect11-and tragically will likely amplify the negative impacts that each has on child development and mental health.

Polygenic Multiple Sclerosis Risk and Population-Based Childhood Brain Imaging.

OBJECTIVE: Multiple sclerosis (MS) is a neurological disease with a substantial genetic component and immune-mediated neurodegeneration. Patients with MS show structural brain differences relative to individuals without MS, including smaller regional volumes and alterations in white matter (WM) microstructure. Whether genetic risk for MS is associated with brain structure during early neurodevelopment remains unclear. In this study, we explore the association between MS polygenic risk scores (PRS) and brain imaging outcomes from a large, population-based pediatric sample to gain insight into the underlying neurobiology of MS. METHODS: We included 8- to 12-year-old genotyped participants from the Generation R Study in whom T1-weighted volumetric (n = 1,136) and/or diffusion tensor imaging (n = 1,088) had been collected. PRS for MS were calculated based on a large genome-wide association study of MS (n = 41,505) and were regressed on regional volumes, global and tract-specific fractional anisotropy (FA), and global mean diffusivity using linear regression. RESULTS: No associations were observed for the regional volumes. We observed a positive association between the MS PRS and global FA (ß = 0.098, standard error [SE] = 0.030, p = 1.08 × 10-3 ). Tract-specific analyses showed higher FA and lower radial diffusivity in several tracts. We replicated our findings in an independent sample of children (n = 186) who were scanned in an earlier phase (global FA; ß = 0.189, SE = 0.072, p = 9.40 × 10-3 ). INTERPRETATION: This is the first study to show that greater genetic predisposition for MS is associated with higher global brain WM FA at an early age in the general population. Our results suggest a preadolescent time window within neurodevelopment in which MS risk variants act upon the brain. ANN NEUROL 2020;87:774-787.

Editors' Best of 2019.

There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, hammering version after version into shape. Acknowledging these biases, here are the 2019 articles that we think deserve your attention or at least a second read.

Executive functioning and neurodevelopmental disorders in early childhood: a prospective population-based study.

BACKGROUND: Executive functioning deficits are common in children with neurodevelopmental disorders. However, prior research mainly focused on clinical populations employing cross-sectional designs, impeding conclusions on temporal neurodevelopmental pathways. Here, we examined the prospective association of executive functioning with subsequent autism spectrum disorder (ASD) traits and attention-deficit/hyperactivity disorder (ADHD) traits. METHODS: This study included young children from the Generation R Study, a general population birth cohort. The Brief Rating Inventory of Executive Function-Preschool Version was used to assess parent-reported behavioral executive functioning when the children were 4 years old. ASD traits were assessed at age 6 (n = 3938) using the parent-reported Social Responsiveness Scale. The Teacher Report Form was used to assess ADHD traits at age 7 (n = 2749). Children with high scores were screened to determine possible clinical ASD or ADHD diagnoses. We were able to confirm an ASD diagnosis for n = 56 children by retrieving their medical records and established an ADHD diagnosis for n = 194 children using the Diagnostic Interview Schedule for Children-Young Child version (DISC-YC). Data were analyzed using hierarchical linear and logistic regressions. RESULTS: Impaired executive functioning was associated with more ASD and ADHD traits across informants (for ASD traits and diagnoses: ß = 0.33, 95% CI [0.30-0.37]; OR = 2.69, 95% CI [1.92-3.77], respectively; for ADHD traits and diagnoses: ß = 0.12, 95% CI [0.07-0.16]; OR = 2.32, 95% CI [1.89-2.85], respectively). Deficits in all subdomains were associated with higher levels of ASD traits, whereas only impaired inhibition, working memory, and planning/organization were associated with more ADHD traits. CONCLUSIONS: The findings of the current study suggest a graded association of executive functioning difficulties along the continuum of ASD and ADHD and that problems in executive functioning may be a precursor of ASD and ADHD traits from an early age onwards.

Brain Development and Stochastic Processes During Prenatal and Early Life: You Can't Lose It if You've Never Had It; But It's Better to Have It and Lose It, Than Never to Have Had It at All.

Brain development, although largely driven by genetic processes, also is influenced by environmental factors. However, there has been little discussion in the psychiatric literature on the role of stochastic, or chance, events that take place during neurodevelopment. Studies suggest that the brain capitalizes on and regulates the extent of stochastic processes during development. Furthermore, because neurodevelopment is influenced by environmental factors, there is emerging evidence that fostering those positive environmental factors during prenatal and early life could optimize neurodevelopment and provide greater resilience, including those potentially resulting from stochastic processes. Evidence for the role of environmental factors in optimizing early brain development is supported by work in large population-based studies of child development, randomized control trials in high-risk populations, and early-life adoption studies. The public health message is that creating an environment that fosters optimal brain development during prenatal and early life could prevent psychopathology and provide the developing brain the best chance against negative stochastic processes and potential stressors that are inevitable later in life.

Editors' Best of 2018.

There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, hammering version after version into shape. Acknowledging these biases, here are the 2018 articles that we think deserve your attention or at least a second read.

Study Registration: Encouraging the Practice of Hypothetical-Deductive Research in the Journal.

Earlier this year, we shared with you our commitment to supporting the dissemination of research that is well designed, carefully conducted, and properly interpreted, and our belief that authors, reviewers, editors, publishers, and readers should jointly strive to ensure the integrity of the science that we publish.1 Toward this end, we are pleased to announce a new submission type beginning in 2019: Registered Reports.

Genetic associations with childhood brain growth, defined in two longitudinal cohorts.

Genome-wide association studies (GWASs) are unraveling the genetics of adult brain neuroanatomy as measured by cross-sectional anatomic magnetic resonance imaging (aMRI). However, the genetic mechanisms that shape childhood brain development are, as yet, largely unexplored. In this study we identify common genetic variants associated with childhood brain development as defined by longitudinal aMRI. Genome-wide single nucleotide polymorphism (SNP) data were determined in two cohorts: one enriched for attention-deficit/hyperactivity disorder (ADHD) (LONG cohort: 458 participants; 119 with ADHD) and the other from a population-based cohort (Generation R: 257 participants). The growth of the brain's major regions (cerebral cortex, white matter, basal ganglia, and cerebellum) and one region of interest (the right lateral prefrontal cortex) were defined on all individuals from two aMRIs, and a GWAS and a pathway analysis were performed. In addition, association between polygenic risk for ADHD and brain growth was determined for the LONG cohort. For white matter growth, GWAS meta-analysis identified a genome-wide significant intergenic SNP (rs12386571, P = 9.09 × 10-9 ), near AKR1B10. This gene is part of the aldo-keto reductase superfamily and shows neural expression. No enrichment of neural pathways was detected and polygenic risk for ADHD was not associated with the brain growth phenotypes in the LONG cohort that was enriched for the diagnosis of ADHD. The study illustrates the use of a novel brain growth phenotype defined in vivo for further study.

Prenatal exposure to selective serotonin reuptake inhibitors and non-verbal cognitive functioning in childhood.

Selective serotonin reuptake Inhibitors (SSRIs) are frequently used during pregnancy. Evidence about the long-term consequences of prenatal SSRI exposure on child neurodevelopment is controversial. We prospectively investigated whether prenatal SSRI exposure was associated with childhood non-verbal cognition in a population-based study, and contrasted it to exposure to depressive symptoms (without SSRIs). We included 71 children prenatally exposed to SSRIs, 385 children prenatally exposed to maternal depressive symptoms and 5427 unexposed children. Child executive functioning was assessed by maternal report at 4 years ( n=4020). Non-verbal intelligence was measured at 5 years ( n=5001) and children were tested with a neuropsychological battery at 7 years ( n=1194). Prenatal SSRI exposure was not related to maternal reported executive function at 4 years, nor was it related with observed non-verbal intelligence at age 5 or neuropsychological function at 7 years. Exposure to untreated maternal depressive symptoms was related to maternal reported shifting problems and emotional control problems at 4 years. No associations between exposure to depressive symptoms and observed non-verbal IQ at 5 years or neuropsychological function at 7 years were found. This population-based study suggests that neither SSRI use nor untreated depressive symptoms during pregnancy had a major impact on child non-verbal cognition.

PRENATAL EXPOSURE TO MATERNAL AND PATERNAL DEPRESSIVE SYMPTOMS AND BRAIN MORPHOLOGY: A POPULATION-BASED PROSPECTIVE NEUROIMAGING STUDY IN YOUNG CHILDREN.

BACKGROUND: Prenatal depressive symptoms have been associated with multiple adverse outcomes. Previously, we demonstrated that prenatal depressive symptoms were associated with impaired growth of the fetus and increased behavioral problems in children aged between 1.5 and 6 years. In this prospective study, we aimed to assess whether prenatal maternal depressive symptoms at 3 years have long-term consequences on brain development in a cohort of children aged 6-10 years. As a contrast, the association of paternal depressive symptoms during pregnancy and brain morphology was assessed to serve as a marker of background confounding due to shared genetic and environmental family factors. METHODS: We assessed parental depressive symptoms during pregnancy with the Brief Symptom Inventory. At approximately 8 years of age, we collected structural neuroimaging data, using cortical thickness, surface area, and gyrification as outcomes (n = 654). RESULTS: We found that exposure to prenatal maternal depressive symptoms during pregnancy was associated with a thinner superior frontal cortex in the left hemisphere. Additionally, prenatal maternal depressive symptoms were related to larger caudal middle frontal area in the left hemisphere. Maternal depressive symptoms at 3 years were not associated with cortical thickness, surface area, or gyrification in the left and right hemispheres. No effects of paternal depressive symptoms on brain morphology were observed. CONCLUSIONS: Prenatal maternal depressive symptoms were associated with differences in brain morphology in children. It is important to prevent, identify, and treat depressive symptoms during pregnancy as it may have long-term consequences on child brain development.