The transition to motherhood: linking hormones, brain and behaviour.

We are witnessing a stark increase in scientific interest in the neurobiological processes associated with pregnancy and maternity. Convergent evidence suggests that around the time of labour, first-time mothers experience a specific pattern of neuroanatomical changes that are associated with maternal behaviour. Here we provide an overview of the human neurobiological adaptations of motherhood, focusing on the interplay between pregnancy-related steroid and peptide hormones, and neuroplasticity in the brain. We discuss which brain plasticity mechanisms might underlie the structural changes detected by MRI, which hormonal systems are likely to contribute to such neuroanatomical changes and how these brain mechanisms may be linked to maternal behaviour. This Review offers an overarching framework that can serve as a roadmap for future investigations.

Low Prevalence of NOTCH2NLC GGC Repeat Expansion in White Patients with Movement Disorders.

BACKGROUND: The objective of this study was to determine the prevalence of the GGC-repeat expansion in NOTCH2NLC in whites presenting with movement disorders. METHODS: We searched for the GGC-repeat expansion in NOTCH2NLC using repeat-primed polymerase chain reaction in 203 patients with essential tremor, 825 patients with PD, 194 patients with spinocerebellar ataxia, 207 patients with "possible" or "probable" MSA, and 336 patients with pathologically confirmed MSA. We also screened 30,008 patients enrolled in the 100,000 Genomes Project for the same mutation using ExpansionHunter, followed by repeat-primed polymerase chain reaction. All possible expansions were confirmed by Southern blotting and/or long-read sequencing. RESULTS: We identified 1 patient who carried the NOTCH2NLC mutation in the essential tremor cohort, and 1 patient presenting with recurrent encephalopathy and postural tremor/parkinsonism in the 100,000 Genomes Project. CONCLUSIONS: GGC-repeat expansion in NOTCH2NLC is rare in whites presenting with movement disorders. In addition, existing whole-genome sequencing data are useful in case ascertainment. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Heritability and genetic variance of dementia with Lewy bodies.

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

Just-in-time response to reward as a function of ADHD symptom severity.

AIM: Attention-deficit hyperactivity disorder (ADHD) neuroimaging studies have identified substantial differences in reward-related circuits on a trial-by-trial basis. However, no research to date has evaluated the effect of motivational context on neural activity in settings with intermittent reward in ADHD. The present study was designed to identify neural processes underlying both immediate effects of reward and sustained effects of reward associated with motivational context in adult ADHD patients. METHODS: We used a functional magnetic resonance imaging paradigm, including a time estimation task with constant versus intermittent reward conditions, in a sample of 21 medication-naïve adults with combined ADHD and 24 healthy adults. RESULTS: Although no between-group neural differences were detected, orbitofrontal activity dropped in association with high ADHD symptom severity during the transition from initial non-reward context blocks to subsequent reward context blocks. In turn, ADHD symptom severity predicted higher orbitofrontal activity in response to immediate reward versus no reward within reward context blocks. CONCLUSION: These results suggest that high ADHD symptom severity scorers adopted a 'just-in-time' strategy, involving the recruitment of reward processing brain areas in the face of immediate reward rather than a sustained response to motivational context.

Cortical morphometry in frontoparietal and default mode networks in math-gifted adolescents.

Math-gifted subjects are characterized by above-age performance in intelligence tests, exceptional creativity, and high task commitment. Neuroimaging studies reveal enhanced functional brain organization and white matter microstructure in the frontoparietal executive network of math-gifted individuals. However, the cortical morphometry of these subjects remains largely unknown. The main goal of this study was to compare the cortical morphometry of math-gifted adolescents with that of an age- and IQ-matched control group. We used surface-based methods to perform a vertex-wise analysis of cortical thickness and surface area. Our results show that math-gifted adolescents present a thinner cortex and a larger surface area in key regions of the frontoparietal and default mode networks, which are involved in executive processing and creative thinking, respectively. The combination of reduced cortical thickness and larger surface area suggests above-age neural maturation of these networks in math-gifted individuals. Hum Brain Mapp 37:1893-1902, 2016. © 2016 Wiley Periodicals, Inc.

Sensation-to-cognition cortical streams in attention-deficit/hyperactivity disorder.

We sought to determine whether functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits are atypical in attention-deficit/hyperactivity disorder (ADHD). We applied a graph-theory method to the resting-state functional magnetic resonance imaging data of 120 children with ADHD and 120 age-matched typically developing children (TDC). Starting in unimodal primary cortex-visual, auditory, and somatosensory-we used stepwise functional connectivity to calculate functional connectivity paths at discrete numbers of relay stations (or link-step distances). First, we characterized the functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits in TDC and found that systems do not reach the level of integration achieved by adults. Second, we searched for stepwise functional connectivity differences between children with ADHD and TDC. We found that, at the initial steps of sensory functional connectivity streams, patients display significant enhancements of connectivity degree within neighboring areas of primary cortex, while connectivity to attention-regulatory areas is reduced. Third, at subsequent link-step distances from primary sensory cortex, children with ADHD show decreased connectivity to executive processing areas and increased degree of connections to default mode regions. Fourth, in examining medication histories in children with ADHD, we found that children medicated with psychostimulants present functional connectivity streams with higher degree of connectivity to regions subserving attentional and executive processes compared to medication-naïve children. We conclude that predominance of local sensory processing and lesser influx of information to attentional and executive regions may reduce the ability to organize and control the balance between external and internal sources of information in ADHD.

An independent components and functional connectivity analysis of resting state fMRI data points to neural network dysregulation in adult ADHD.

Spontaneous fluctuations can be measured in the brain that reflect dissociable functional networks oscillating at synchronized frequencies, such as the default mode network (DMN). In contrast to its diametrically opposed task-positive counterpart, the DMN predominantly signals during a state of rest, and inappropriate regulation of this network has been associated with inattention, a core characteristic of attention-deficit/hyperactivity disorder (ADHD). To examine whether abnormalities can be identified in the DMN component of patients with ADHD, we applied an independent components analysis to resting state functional magnetic resonance imaging data acquired from 22 male medication-naïve adults with ADHD and 23 neurotypical individuals. We observed a stronger coherence of the left dorsolateral prefrontal cortex (dlPFC) with the DMN component in patients with ADHD which correlated with measures of selective attention. The increased left dlPFC-DMN coherence also surfaced in a whole-brain replication analysis involving an independent sample of 9 medication-naïve adult patients and 9 controls. In addition, a post hoc seed-to-voxel functional connectivity analysis using the dlPFC as a seed region to further examine this region's suggested connectivity differences uncovered a higher temporal coherence with various other neural networks and confirmed a reduced anticorrelation with the DMN. These results point to a more diffuse connectivity between functional networks in patients with ADHD. Moreover, our findings suggest that state-inappropriate neural activity in ADHD is not confined to DMN intrusion during attention-demanding contexts, but also surfaces as an insufficient suppression of dlPFC signaling in relation to DMN activity during rest. Together with previous findings, these results point to a general dysfunction in the orthogonality of functional networks.

Genetic variants in ICAM1, PPARGC1A and MTHFR are potentially associated with different phenotypes of diabetic retinopathy.

PURPOSE: To explore phenotype-genotype correlations that may contribute to a better understanding of diabetic retinopathy (DR). PROCEDURES: An exploratory association study was performed to identify genetic variants associated with non-proliferative DR (NPDR) in 307 type 2 diabetic patients who were previously stratified into 3 different phenotypes of NPDR progression. The 307 patients were genotyped for 174 single nucleotide polymorphisms of 11 candidate genes (ACE, AGER, AKR1B1, ICAM1, MTHFR, NOS1, NOS3, PPARGC1A, TGFB1, TNF and VEGFA). RESULTS: Significant associations were observed for PPARGC1A rs16874120 with phenotype A (odds ratio, OR = 0.60, 95% confidence interval, CI 0.36-0.99), ICAM1 rs1801714 with phenotype B (OR = 3.32, 95% CI 1.05-10.50) and both PPARGC1A rs10213440 (OR = 2.00, 95% CI 1.07-3.73) and MTHFR rs1801133 (OR = 1.84, 95% CI 1.08-3.11) with phenotype C. CONCLUSIONS: RESULTS indicate that specific gene variants in ICAM1, PPARGC1A and MTHFR are associated with different NPDR phenotypes, being likely candidates to explain different disease mechanisms underlying the different phenotypes. This is the first study to show correlations between specific gene variants and NPDR phenotypes, opening new perspectives on DR.

Spontaneous Remission of High-Grade Non-Hodgkin Lymphoma After SARS-CoV-2 Infection: A Case Report.

ABSTRACT: Despite extensive research into COVID-19 since its emergence in late 2019, there is still much not fully understood about its long-term effects. When infected with SARS-CoV-2, cancer patients have been reported to be at higher risk for unfavorable outcomes. Nevertheless, evidence suggests that viruses may exhibit an antitumor effect in some cases, which has recently been anecdotally reported with SARS-CoV-2. We present the case of a patient with a recent high-grade non-Hodgkin lymphoma diagnosis and without any cancer-specific therapy, in whom a complete metabolic response on 2-[ 18 F]FDG PET/CT was observed after COVID-19.

Pregnancy renders anatomical changes in hypothalamic substructures of the human brain that relate to aspects of maternal behavior.

Animal studies have shown that pregnancy is associated with neural adaptations that promote maternal care. The hypothalamus represents a central structure of the mammalian maternal brain and hormonal priming of specific hypothalamic nuclei plays a key role in the induction and expression of maternal behavior. In humans, we have previously demonstrated that becoming a mother involves changes in grey matter anatomy, primarily in association areas of the cerebral cortex. In the current study, we investigated whether pregnancy renders anatomical changes in the hypothalamus. Using an advanced delineation technique, five hypothalamic substructures were defined in longitudinal MRI scans of 107 women extracted from two prospective pre-conception cohort studies, including 50 women who were scanned before and after pregnancy and 57 nulliparous control women scanned at a similar time interval. We showed that becoming a mother is associated with volume reductions in the anterior-superior, superior tuberal and posterior hypothalamus. In addition, these structural changes related to hormonal levels during pregnancy and specific aspects of self-reported maternal behavior in late pregnancy, including maternal-fetal attachment and nesting behavior. These findings show that pregnancy leads to changes in hypothalamic anatomy and suggest that these contribute to the development of maternal behavior in humans, supporting the conservation of key aspects of maternal brain circuitry and their role in maternal behavior across species.

Women's neuroplasticity during gestation, childbirth and postpartum.

Pregnancy is a unique neuroplastic period in adult life. This longitudinal study tracked brain cortical changes during the peripartum period and explored how the type of childbirth affects these changes. We collected neuroanatomic, obstetric and neuropsychological data from 110 first-time mothers during late pregnancy and early postpartum, as well as from 34 nulliparous women evaluated at similar time points. During late pregnancy, mothers showed lower cortical volume than controls across all functional networks. These cortical differences attenuated in the early postpartum session. Default mode and frontoparietal networks showed below-expected volume increases during peripartum, suggesting that their reductions may persist longer. Results also pointed to different cortical trajectories in mothers who delivered by scheduled C-section. The main findings were replicated in an independent sample of 29 mothers and 24 nulliparous women. These data suggest a dynamic trajectory of cortical decreases during pregnancy that attenuates in the postpartum period, at a different rate depending on the brain network and childbirth type.

Response inhibition and reward anticipation in medication-naïve adults with attention-deficit/hyperactivity disorder: a within-subject case-control neuroimaging study.

BACKGROUND: Previous research suggests that ADHD patients are characterized by both reduced activity in the inferior frontal gyrus (IFG) during response inhibition tasks (such as the Go-NoGo task), and reduced activity in the ventral striatum during reward anticipation tasks (such as the Monetary-Incentive-Delay [MID] task). However, no prior research has applied either of these paradigms in medication-naïve adults with ADHD, nor have these been implemented in an intrasubject manner. METHODS: The sample consisted of 19 medication-naïve adults with ADHD and 19 control subjects. Main group analyses were based on individually defined regions of interest: the IFG and the VStr for the Go-NoGo and the MID task respectively. In addition, we analyzed the correlation between the two measures, as well as between these measures and the clinical symptoms of ADHD. RESULTS: We observed reduced bilateral VStr activity in adults with ADHD during reward anticipation. No differences were detected in IFG activation on the Go-NoGo paradigm. Correlation analyses suggest that the two tasks are independent at a neural level, but are related behaviorally in terms of the variability of the performance reaction time. Activity in the bilateral VStr but not in the IFG was associated negatively with symptoms of hyperactivity/impulsivity. CONCLUSIONS: Results underline the implication of the reward system in ADHD adult pathophysiology and suggest that frontal abnormalities during response inhibition performance may not be such a pivotal aspect of the phenotype in adulthood. In addition, our findings point toward response variability as a core feature of the disorder.

Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia.

Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia (SACS and KIF1C) and with ataxia and neuropathy or AOA (PNKP). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in KIF1A, CACNA1A, or ATP1A3, reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration.

Whole-exome sequencing of Finnish patients with vascular cognitive impairment.

Cerebral small vessel disease (CSVD) is the most important cause of vascular cognitive impairment (VCI). Most CSVD cases are sporadic but familial monogenic forms of the disorder have also been described. Despite the variants identified, many CSVD cases remain unexplained genetically. We used whole-exome sequencing in an attempt to identify novel gene variants underlying CSVD. A cohort of 35 Finnish patients with suspected CSVD was analyzed. Patients were screened negative for the most common variants affecting function in NOTCH3 in Finland (p.Arg133Cys and p.Arg182Cys). Whole-exome sequencing was performed to search for a genetic cause of CSVD. Our study resulted in the detection of possibly pathogenic variants or variants of unknown significance in genes known to associate with CSVD in six patients, accounting for 17% of cases. Those genes included NOTCH3, HTRA1, COL4A1, and COL4A2. We also identified variants with predicted pathogenic effect in genes associated with other neurological or stroke-related conditions in seven patients, accounting for 20% of cases. This study supports pathogenic roles of variants in COL4A1, COL4A2, and HTRA1 in CSVD and VCI. Our results also suggest that vascular pathogenic mechanisms are linked to neurodegenerative conditions and provide novel insights into the molecular basis of VCI.

Study Protocol-Coping With the Pandemics: What Works Best to Reduce Anxiety and Depressive Symptoms.

Background: The coronavirus disease 2019 (COVID-19) pandemic and lockdown might increase anxiety and depressive symptoms in most individuals. Health bodies recommend several coping behaviors to protect against such symptoms, but evidence on the relationship between these behaviors and symptoms mostly comes from cross-sectional studies in convenience samples. We will conduct a prospective longitudinal study of the associations between coping behaviors and subsequent anxiety and depressive symptoms during the COVID-19 pandemic in a representative sample of the Spanish general adult population. Methods: We will recruit 1,000 adult participants from all autonomous communities of Spain and with sex, age, and urbanicity distributions similar to those of their populations and assess anxiety and depressive symptoms and coping behaviors using fortnightly questionnaires and real-time methods (ecological momentary assessments) for 1 year. The fortnightly questionnaires will inquire about anxiety and depressive symptoms [General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9)] and the frequency of 10 potential coping behaviors (e.g., follow a routine) during the past 2 weeks. In addition, we will collect several variables that could confound or moderate these associations. These will include subjective well-being [International Positive and Negative Affect Schedule Short Form (I-PANAS-SF) and Satisfaction with Life Scale (SWLS)], obsessive-compulsive symptoms [Obsessive Compulsive Inventory-Revised (OCI-R)], personality and emotional intelligence [International Personality Item Pool (IPIP) and Trait Emotional Intelligence Questionnaire Short Form (TEIQue-SF)], sociodemographic factors (e.g., work status, housing-built environment), and COVID-19 pandemic-related variables (e.g., hospitalizations or limitations in social gatherings). Finally, to analyze the primary relationship between coping behaviors and subsequent anxiety and depressive symptoms, we will use autoregressive moving average (ARMA) models. Discussion: Based on the study results, we will develop evidence-based, clear, and specific recommendations on coping behaviors during the COVID-19 pandemic and lockdown. Such suggestions might eventually help health bodies or individuals to manage current or future pandemics.

BVVL/ FL: features caused by SLC52A3 mutations; WDFY4 and TNFSF13B may be novel causative genes.

Brown-Vialetto-Van Laere (BVVL) and Fazio-Londe are disorders with amyotrophic lateral sclerosis-like features, usually with recessive inheritance. We aimed to identify causative mutations in 10 probands. Neurological examinations, genetic analysis, audiometry, magnetic resonance imaging, biochemical and immunological testings, and/or muscle histopathology were performed. Mutations in known causative gene SLC52A3 were found in 7 probands. More importantly, only 1 mutated allele was observed in several patients, and variable expressivity and incomplete penetrance were clearly noted. Environmental insults may contribute to variable presentations. Putative causative mutations in other genes were identified in 3 probands. Two of the genes, WDFY4 and TNFSF13B, have immune-related functions. Inflammatory responses were implicated in the patient with the WDFY4 mutation. Malfunction of the immune system and mitochondrial anomalies were shown in the patient with the TNFSF13B mutation. Prevalence of heterozygous SLC52A3 BVVL causative mutations and notable variability in expressivity of homozygous and heterozygous genotypes are being reported for the first time. Identification of WDFY4 and TNFSF13B as candidate causative genes supports conjectures on involvement of the immune system in BVVL and amyotrophic lateral sclerosis.

SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma.

Purpose: Affecting children by age 3, primary congenital glaucoma (PCG) can cause debilitating vision loss by the developmental impairment of aqueous drainage resulting in high intraocular pressure (IOP), globe enlargement, and optic neuropathy. TEK haploinsufficiency accounts for 5% of PCG in diverse populations, with low penetrance explained by variable dysgenesis of Schlemm's canal (SC) in mice. We report eight families with TEK-related PCG, and provide evidence for SVEP1 as a disease modifier in family 8 with a higher penetrance and severity. Methods: Exome sequencing identified coding/splice site variants with an allele frequency less than 0.0001 (gnomAD). TEK variant effects were assayed in construct-transfected HEK293 cells via detection of autophosphorylated (active) TEK protein. An enucleated eye from an affected member of family 8 was examined via histology. SVEP1 expression in developing outflow tissues was detected by immunofluorescent staining of 7-day mouse anterior segments. SVEP1 stimulation of TEK expression in human umbilical vascular endothelial cells (HUVECs) was measured by TaqMan quantitative PCR. Results: Heterozygous TEK loss-of-function alleles were identified in eight PCG families, with parent-child disease transmission observed in two pedigrees. Family 8 exhibited greater disease penetrance and severity, histology revealed absence of SC in one eye, and SVEP1:p.R997C was identified in four of the five affected individuals. During SC development, SVEP1 is secreted by surrounding tissues. SVEP1:p.R997C abrogates stimulation of TEK expression by HUVECs. Conclusions: We provide further evidence for PCG caused by TEK haploinsufficiency, affirm autosomal dominant inheritance in two pedigrees, and propose SVEP1 as a modifier of TEK expression during SC development, affecting disease penetrance and severity.