Analyzing the Quality of Life in Individuals with Fragile X Syndrome in Relation to Sleep and Mental Health.

The purpose of this paper was to examine the physical, emotional, social and school functioning domains of quality of life of individuals with Fragile X Syndrome, in relation to mental health and sleep patterns to gain a better understanding of how these aspects are affected by the disorder. This study included 119 individuals with Fragile X Syndrome who were given different cognitive examinations by a neuropsychologist or by parent-proxy questionnaires. This study focused on the Pediatric Quality of Life Inventory (PedsQoL), the Anxiety, Depression and Mood Scale (ADAMS), the Children's Sleep Habits Questionnaire (CSHQ), but did include other cognitive tests (Vineland Adaptive Behaviour Scales, Nonverbal IQ, Autism Diagnostic Observation Schedule). We identified significant associations between decreases in emotional, social and school domains of PedsQoL and the ADAMS subtests of Generalized Anxiety, Manic/Hyperactivity and Obsessive/Compulsivity, with the subtest of Depressed Mood having associations with lower physical and emotional domains. We also identified a significant impact between CSHQ subtests of Sleep Anxiety, Night Wakings, Daytime Sleepiness, and Parasomnia with the emotional and school domains of PedsQoL. There were associations connecting school functioning with Bedtime Resistance, and additional associations connecting emotional functioning with Sleep Duration and Sleep Onset Delay. Physical functioning was also associated with Sleep Anxiety. Our study shows how mental health and sleep defects impact improper sleep patterns and mental health which leads to decreases in the quality of life for individuals with FXS, and how it is important to screen for these symptoms in order to alleviate issues.

Associations between Prepartum and Postpartum Maternal Symptoms of Depression, Anxiety and Stress Related to COVID-19 Pandemic and Childhood Sensory Avoidance: Results from Conception Study.

BACKGROUND: Prepartum and postpartum maternal symptoms of stress, anxiety and depression are likely to influence the child's sensory processing through hormonal alterations and an influence on mother-child interactions. OBJECTIVE: We investigated the associations between maternal prepartum and postpartum symptoms of depression, anxiety and stress related to the COVID-19 pandemic and childhood sensory avoidance at 18 months. METHODS: Longitudinal data from 409 participants followed during the COVID-19 pandemic were used. They completed questionnaires during pregnancy and up to 18 months after delivery. Maternal distress symptoms were assessed prenatally and at 18 months postnatally using the Edinburgh Postnatal Depression Scale, the Generalized Anxiety Disorders 7-item Scale and a 10-point scale assessing the level of stress felt related to the COVID-19 pandemic. Child sensory avoidance was assessed at 18 months postpartum using the Infant/Toddler Sensory Profile-Second Edition. Pearson correlations and multiple regressions measured the associations between maternal distress symptoms and child sensory avoidance. RESULTS: Prepartum and 18-month postpartum maternal depression and anxiety were significantly correlated with childhood sensory avoidance (p < 0.05). Together, these variables explained 7.18% (F = 2.12, p < 0.05) of the variance of childhood sensory avoidance. CONCLUSIONS: These results support the contributory effect of prepartum and postpartum maternal distress on childhood sensory development.

Cumulative Dosage of Intrathecal Chemotherapy Agents Predicts White Matter Integrity in Long-Term Survivors of Acute Lymphoblastic Leukemia: A PETALE Study.

Acute lymphoblastic leukemia (ALL) stands as the most prevalent form of pediatric cancer in North America, with a current five-year survival rate of 85%. While more children achieved ALL remission and transition into adulthood, the prevalence of long-term treatment-related effects, especially neurocognitive sequelae, remains significant. This study pursues two objectives. Firstly, it investigates if Magnetization Transfer Ratio (MTR), a method assessing myelin integrity, is sensitive to white matter (WM) microstructural changes in long-term ALL survivors and whether these relate to cognitive impairments. Secondly, it examines the dose-related effects of chemotherapy agents on the MTR and its relationship to other risk factors such as female sex, early age diagnosis, and cranial radiotherapy. Magnetization transfer imaging was utilized to assess WM integrity in 35 survivors at a mean of 18.9 years after the onset of ALL (range since diagnosis: 6.9-26.8). Additionally, 21 controls matched for age, sex, and education level, with no history of cancer, were included. MTR was extracted from both the entire brain's WM and the corpus callosum through semi-automated procedures. The results indicated lower MTR means in survivors, which is linked to cognitive function. Negative associations between MTR means and intrathecal agents' (MTX, cytarabine, and hydrocortisone) cumulative doses received were highlighted. This study offers valuable insights into the connections between myelin deterioration, cognitive impairment, and the implications of IT chemotherapy, enhancing our understanding of ALL survivorship dynamics. It underscores MTR's relevance in monitoring neurotoxicity during oncological drug follow-up examinations.

Using rare genetic mutations to revisit structural brain asymmetry.

Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities.

Impact of trametinib on the neuropsychological profile of NF1 patients.

PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

Maternal Mental Health in Pregnancy and Its Impact on Children's Cognitive Development at 18 Months, during the COVID-19 Pandemic (CONCEPTION Study).

BACKGROUND: The COVID-19 pandemic has significantly affected the mental health of pregnant persons. OBJECTIVE: We aimed to evaluate the impact of maternal mental health and antidepressant use on children's cognitive development. METHODS: We followed a cohort of children born during the COVID-19 pandemic. Maternal mental health was self-reported during pregnancy (Edinburgh Postnatal Depression Scale, General Anxiety Disorder-7, stress levels, and antidepressant use). The child's cognitive development was measured using the third edition of the Ages & Stages Questionnaires® (ASQ-3) at 18 months. Multivariate multinomial logistic regression models were built to assess the association between in utero exposure to maternal mental health and ASQ-3 domains: communication, gross motor, fine motor, problem-solving, and personal-social. RESULTS: Overall, 472 children were included in our analyses. After adjusting for potential confounders, a need for further assessment in communication (adjusted odds ratio (aOR) 12.2, 95% confidence interval (CI) (1.60;92.4)), and for improvement in gross motricity (aOR 6.33, 95%CI (2.06;19.4)) were associated with in utero anxiety. The need for improvement in fine motricity (aOR 4.11, 95%CI (1.00; 16.90)) was associated with antidepressant exposure. In utero depression was associated with a decrease in the need for improvement in problem solving (aOR 0.48, 95%CI (0.24; 0.98)). CONCLUSIONS: During the COVID-19 pandemic, maternal mental health appears to be associated with some aspects of children's cognitive development.

Contributing factors to well-being in a sample of long-term survivors of childhood acute lymphoblastic leukemia: the role of social support in emotional regulation.

Objectives: To understand why some long-term childhood cancer survivors experience positive adjustment in the long run,[Q1] this study aimed to (1) explore associations between well-being, health status, social support, and emotion regulation (ER) strategies in a cohort of long-term childhood lymphoblastic leukemia (cALL) survivors, (2) identify the individual contribution of each ER strategy to well-being (3) and their interaction with social support. Methods: We used data from 92 participants from the PETALE cohort (51% female, aged 24 ± 7 years). Measures included well-being (WHO-5), health status (15D), social support (SSQ-6), cognitive reappraisal and expressive suppression (ERQ), and emotional processing and expression (EAC). We modeled the odds of high well-being adjusting for health status in logistic regressions and explored the moderating role of social support with bootstrap techniques. Independent of clinical history, high well-being was associated with better health status, higher social support, more frequent use of cognitive reappraisal and emotional processing. Results: We found a main contribution of emotional processing to well-being (OR = 2.12, 95% CI = 1.09-5.37). The interaction between low suppression and high social support was significant (OR = .40, 95% CI = .13-.79). Probabilities for high well-being were 96% when expressive suppression was low and social support was high. Results suggest approaching one's own emotions may contribute to well-being in long-term childhood cancer survivors. Clinical implications: Combining curbing emotional suppression with promoting supportive social environment could be a promising target for future supportive care interventions in survivors.

Genetic Factors and Long-term Treatment-Related Neurocognitive Deficits, Anxiety, and Depression in Childhood Leukemia Survivors: An Exome-Wide Association Study.

BACKGROUND: An increased risk of neurocognitive deficits, anxiety, and depression has been reported in childhood cancer survivors. METHODS: We analyzed associations of neurocognitive deficits, as well as anxiety and depression, with common and rare genetic variants derived from whole-exome sequencing data of acute lymphoblastic leukemia (ALL) survivors from the PETALE cohort. In addition, significant associations were assessed using stratified and multivariable analyses. Next, top-ranking common associations were analyzed in an independent SJLIFE replication cohort of ALL survivors. RESULTS: Significant associations were identified in the entire discovery cohort (N = 229) between the AK8 gene and changes in neurocognitive function, whereas PTPRZ1, MUC16, TNRC6C-AS1 were associated with anxiety. Following stratification according to sex, the ZNF382 gene was linked to a neurocognitive deficit in males, whereas APOL2 and C6orf165 were associated with anxiety and EXO5 with depression. Following stratification according to prognostic risk groups, the modulatory effect of rare variants on depression was additionally found in the CYP2W1 and PCMTD1 genes. In the replication SJLIFE cohort (N = 688), the male-specific association in the ZNF382 gene was not significant; however, a P value<0.05 was observed when the entire SJLIFE cohort was analyzed. ZNF382 was significant in males in the combined cohorts as shown by meta-analyses as well as the depression-associated gene EXO5. CONCLUSIONS: Further research is needed to confirm whether the current findings, along with other known risk factors, may be valuable in identifying patients at increased risk of these long-term complications. IMPACT: Our results suggest that specific genes may be related to increased neuropsychological consequences.

Adaptive, behavioral, and cognitive outcomes in individuals with fragile X syndrome with varying autism severity.

This study aimed to determine the association between severity of autism spectrum disorder (ASD) and cognitive, behavioral, and molecular measures in individuals with fragile X syndrome (FXS). Study inclusion criteria included individuals with FXS and (1) age 6-40 years, (2) full-scale IQ < 84, and (3) language ≥3-word phrases. ASD symptom severity was determined by Autism Diagnostic Observation Schedule-2 (ADOS-2). Other measures identified non-verbal IQ, adaptive skills, and aberrant behaviors. Molecular measures included blood FMR1 and CYFIP1 mRNA levels, FMRP and MMP9 levels. Analysis of variance (ANOVA) and Spearman's correlations were used to compare ASD severity groups. Data from 54 individuals was included with no/mild (N = 7), moderate (N = 18), and severe (N = 29) ASD. Individuals with high ASD severity had lower adaptive behavior scores (47.48 ± 17.49) than the no/mild group (69.00 ± 20.45, p = 0.0366); they also had more challenging behaviors, lethargy, and stereotypic behaviors. CYFIP1 mRNA expression levels positively correlated with the ADOS-2 comparison score(r2  = 0.33, p = 0.0349), with no significant correlations with other molecular markers. In conclusion, autism symptom severity is associated with more adverse cognitive and adaptive skills and specific behaviors in FXS, whereas CYFIP1 mRNA expression levels may be a potential biomarker for severity of ASD in FXS.

Intercorrelation of Molecular Biomarkers and Clinical Phenotype Measures in Fragile X Syndrome.

This study contributes to a greater understanding of the utility of molecular biomarkers to identify clinical phenotypes of fragile X syndrome (FXS). Correlations of baseline clinical trial data (molecular measures-FMR1 mRNA, CYFIP1 mRNA, MMP9 and FMRP protein expression levels, nonverbal IQ, body mass index and weight, language level, NIH Toolbox, adaptive behavior rating, autism, and other mental health correlates) of 59 participants with FXS ages of 6-32 years are reported. FMR1 mRNA expression levels correlated positively with adaptive functioning levels, expressive language, and specific NIH Toolbox measures. The findings of a positive correlation of MMP-9 levels with obesity, CYFIP1 mRNA with mood and autistic symptoms, and FMR1 mRNA expression level with better cognitive, language, and adaptive functions indicate potential biomarkers for specific FXS phenotypes. These may be potential markers for future clinical trials for targeted treatments of FXS.

Subcortical Brain Alterations in Carriers of Genomic Copy Number Variants.

OBJECTIVE: Copy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs), including autism (ASD) and schizophrenia. Little is known about how different CNVs conferring risk for the same condition may affect subcortical brain structures and how these alterations relate to the level of disease risk conferred by CNVs. To fill this gap, the authors investigated gross volume, vertex-level thickness, and surface maps of subcortical structures in 11 CNVs and six NPDs. METHODS: Subcortical structures were characterized using harmonized ENIGMA protocols in 675 CNV carriers (CNVs at 1q21.1, TAR, 13q12.12, 15q11.2, 16p11.2, 16p13.11, and 22q11.2; age range, 6-80 years; 340 males) and 782 control subjects (age range, 6-80 years; 387 males) as well as ENIGMA summary statistics for ASD, schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, bipolar disorder, and major depression. RESULTS: All CNVs showed alterations in at least one subcortical measure. Each structure was affected by at least two CNVs, and the hippocampus and amygdala were affected by five. Shape analyses detected subregional alterations that were averaged out in volume analyses. A common latent dimension was identified, characterized by opposing effects on the hippocampus/amygdala and putamen/pallidum, across CNVs and across NPDs. Effect sizes of CNVs on subcortical volume, thickness, and local surface area were correlated with their previously reported effect sizes on cognition and risk for ASD and schizophrenia. CONCLUSIONS: The findings demonstrate that subcortical alterations associated with CNVs show varying levels of similarities with those associated with neuropsychiatric conditions, as well distinct effects, with some CNVs clustering with adult-onset conditions and others with ASD. These findings provide insight into the long-standing questions of why CNVs at different genomic loci increase the risk for the same NPD and why a single CNV increases the risk for a diverse set of NPDs.

Time-frequency analyses of repetition suppression and change detection in children with neurofibromatosis type 1.

Children with neurofibromatosis type 1 (NF1) are at increased risk of developing cognitive problems, including attention deficits and learning difficulties. Alterations in brain response to repetition and change have been evidenced in other genetic conditions associated with cognitive dysfunctions. Whether the integrity of these fundamental neural responses is compromised in school-aged children with NF1 is still unknown. In this study, we examined the repetition suppression (RS) and change detection responses in children with NF1 (n = 36) and neurotypical controls (n = 41) aged from 4 to 13 years old, using a simple sequence of vowels. We performed time-frequency analyses to compare spectral power and phase synchronization between groups, in the theta, alpha and beta frequency bands. Correlational analyses were performed between the neural responses and the level of intellectual functioning, as well as with behavioral symptoms of comorbid neurodevelopmental disorders measured through parental questionnaires. Children with NF1 showed preserved RS, but increased spectral power in the change detection response. Correlational analyses performed with measures of change detection revealed a negative association between the alpha-band spectral power and symptoms of inattention and hyperactivity. These findings suggest atypical neural response to change in children with NF1. Further studies should be conducted to clarify the interaction with comorbid neurodevelopmental disorders and the possible role of altered inhibitory mechanisms in this enhanced neural response.

Contribution of Fatigue to Cognitive Dysfunction in Childhood Acute Lymphoblastic Leukemia Survivors.

Late effects such as neurocognitive issues and fatigue have been reported in childhood acute lymphoblastic leukemia (cALL) survivors. Yet, their association is often poorly understood. In this study, we wished to (1) describe neurocognitive difficulties and fatigue in a well-characterized cohort of long-term cALL survivors and (2) explore the risk of having neurocognitive deficits as a function of fatigue. Childhood ALL survivors (N = 285) from three Canadian treatment centers completed the DIVERGT battery of cognitive tests and the PedsQL Multidimensional Fatigue Scale. We performed logistic regressions to assess the risk of a survivor to show cognitive deficits (<2.0 SD) depending on their fatigue levels. At least one cognitive deficit on the DIVERGT was present in 31% of participants. Domains primarily affected were working memory, fine motor skills, and verbal fluency. Sleep/rest fatigue in youths was higher than norms (d = 0.35). The risk for cognitive deficits increased independently with levels of fatigue in the domains of cognitive speed and flexibility, working memory, and verbal fluency. For every 10-point increase on general or sleep/rest fatigue on the 0-100 scale, there was a median +23-35% risk of showing a deficit among the 7 tasks significantly associated with fatigue. Fatigue may constitute a complementary target when searching to mitigate cognitive issues in this population.

EEG repetition and change detection responses in infancy predict adaptive functioning in preschool age: a longitudinal study.

Neurodevelopmental disorders (NDDs) are mostly diagnosed around the age of 4-5 years, which is too late considering that the brain is most susceptive to interventions during the first two years of life. Currently, diagnosis of NDDs is based on observed behaviors and symptoms, but identification of objective biomarkers would allow for earlier screening. In this longitudinal study, we investigated the relationship between repetition and change detection responses measured using an EEG oddball task during the first year of life and at two years of age, and cognitive abilities and adaptive functioning during preschool years (4 years old). Identification of early biomarkers is challenging given that there is a lot of variability in developmental courses among young infants. Therefore, the second aim of this study is to assess whether brain growth is a factor of interindividual variability that influences repetition and change detection responses. To obtain variability in brain growth beyond the normative range, infants with macrocephaly were included in our sample. Thus, 43 normocephalic children and 20 macrocephalic children were tested. Cognitive abilities at preschool age were assessed with the WPPSI-IV and adaptive functioning was measured with the ABAS-II. Time-frequency analyses were conducted on the EEG data. Results indicated that repetition and change detection responses in the first year of life predict adaptive functioning at 4 years of age, independently of head circumference. Moreover, our findings suggested that brain growth explains variability in neural responses mostly in the first years of life, so that macrocephalic children did not display repetition suppression responses, while normocephalic children did. This longitudinal study demonstrates that the first year of life is an important period for the early screening of children at risk of developing NDDs.

Inter-individual variability during neurodevelopment: an investigation of linear and nonlinear resting-state EEG features in an age-homogenous group of infants.

Electroencephalography measures are of interest in developmental neuroscience as potentially reliable clinical markers of brain function. Features extracted from electroencephalography are most often averaged across individuals in a population with a particular condition and compared statistically to the mean of a typically developing group, or a group with a different condition, to define whether a feature is representative of the populations as a whole. However, there can be large variability within a population, and electroencephalography features often change dramatically with age, making comparisons difficult. Combined with often low numbers of trials and low signal-to-noise ratios in pediatric populations, establishing biomarkers can be difficult in practice. One approach is to identify electroencephalography features that are less variable between individuals and are relatively stable in a healthy population during development. To identify such features in resting-state electroencephalography, which can be readily measured in many populations, we introduce an innovative application of statistical measures of variance for the analysis of resting-state electroencephalography data. Using these statistical measures, we quantified electroencephalography features commonly used to measure brain development-including power, connectivity, phase-amplitude coupling, entropy, and fractal dimension-according to their intersubject variability. Results from 51 6-month-old infants revealed that the complexity measures, including fractal dimension and entropy, followed by connectivity were the least variable features across participants. This stability was found to be greatest in the right parietotemporal region for both complexity feature, but no significant region of interest was found for connectivity feature. This study deepens our understanding of physiological patterns of electroencephalography data in developing brains, provides an example of how statistical measures can be used to analyze variability in resting-state electroencephalography in a homogeneous group of healthy infants, contributes to the establishment of robust electroencephalography biomarkers of neurodevelopment through the application of variance analyses, and reveals that nonlinear measures may be most relevant biomarkers of neurodevelopment.

Using rare genetic mutations to revisit structural brain asymmetry.

Asymmetry between the left and right brain is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variant studies, which typically exert small effects on brain phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We quantitatively dissected the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior mapping highlights the consequences of genetically controlled brain lateralization on human-defining cognitive traits.

Rare CNVs and phenome-wide profiling highlight brain structural divergence and phenotypical convergence.

Copy number variations (CNVs) are rare genomic deletions and duplications that can affect brain and behaviour. Previous reports of CNV pleiotropy imply that they converge on shared mechanisms at some level of pathway cascades, from genes to large-scale neural circuits to the phenome. However, existing studies have primarily examined single CNV loci in small clinical cohorts. It remains unknown, for example, how distinct CNVs escalate vulnerability for the same developmental and psychiatric disorders. Here we quantitatively dissect the associations between brain organization and behavioural differentiation across 8 key CNVs. In 534 CNV carriers, we explored CNV-specific brain morphology patterns. CNVs were characteristic of disparate morphological changes involving multiple large-scale networks. We extensively annotated these CNV-associated patterns with ~1,000 lifestyle indicators through the UK Biobank resource. The resulting phenotypic profiles largely overlap and have body-wide implications, including the cardiovascular, endocrine, skeletal and nervous systems. Our population-level investigation established brain structural divergences and phenotypical convergences of CNVs, with direct relevance to major brain disorders.

Subcortical brain alterations in carriers of genomic copy number variants.

Objectives: Copy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs) including autism (ASD) and schizophrenia (SZ). Overall, little is known about how different CNVs conferring risk for the same condition may affect subcortical brain structures and how these alterations relate to the level of disease risk conferred by CNVs. To fill this gap, we investigated gross volume, and vertex level thickness and surface maps of subcortical structures in 11 different CNVs and 6 different NPDs. Methods: Subcortical structures were characterized using harmonized ENIGMA protocols in 675 CNV carriers (at the following loci: 1q21.1, TAR, 13q12.12, 15q11.2, 16p11.2, 16p13.11, and 22q11.2) and 782 controls (Male/Female: 727/730; age-range: 6-80 years) as well as ENIGMA summary-statistics for ASD, SZ, ADHD, Obsessive-Compulsive-Disorder, Bipolar-Disorder, and Major-Depression. Results: Nine of the 11 CNVs affected volume of at least one subcortical structure. The hippocampus and amygdala were affected by five CNVs. Effect sizes of CNVs on subcortical volume, thickness and local surface area were correlated with their previously reported effect sizes on cognition and risk for ASD and SZ. Shape analyses were able to identify subregional alterations that were averaged out in volume analyses. We identified a common latent dimension - characterized by opposing effects on basal ganglia and limbic structures - across CNVs and across NPDs. Conclusion: Our findings demonstrate that subcortical alterations associated with CNVs show varying levels of similarities with those associated with neuropsychiatric conditions. We also observed distinct effects with some CNVs clustering with adult conditions while others clustered with ASD. This large cross-CNV and NPDs analysis provide insight into the long-standing questions of why CNVs at different genomic loci increase the risk for the same NPD, as well as why a single CNV increases the risk for a diverse set of NPDs.

Impact of Macrocephaly, as an Isolated Trait, on EEG Signal as Measured by Spectral Power and Multiscale Entropy during the First Year of Life.

Macrocephaly has been associated with neurodevelopmental disorders; however, it has been mainly studied in the context of pathological or high-risk populations and little is known about its impact, as an isolated trait, on brain development in general population. Electroencephalographic (EEG) power spectral density (PSD) and signal complexity have shown to be sensitive to neurodevelopment and its alterations. We aimed to investigate the impact of macrocephaly, as an isolated trait, on EEG signal as measured by PSD and multiscale entropy during the first year of life. We recorded high-density EEG resting-state activity of 74 healthy full-term infants, 50 control (26 girls), and 24 macrocephalic (12 girls) aged between 3 and 11 months. We used linear regression models to assess group and age effects on EEG PSD and signal complexity. Sex and brain volume measures, obtained via a 3D transfontanellar ultrasound, were also included into the models to evaluate their contribution. Our results showed lower PSD of the low alpha (8-10 Hz) frequency band and lower complexity in the macrocephalic group compared to the control group. In addition, we found an increase in low alpha (8.5-10 Hz) PSD and in the complexity index with age. These findings suggest that macrocephaly as an isolated trait has a significant impact on brain activity during the first year of life.