Neurodevelopmental Psychiatric Disorders Research Articles

Prenatal treatment with corticosterone via maternal injection induces learning and memory impairments via delaying postsynaptic development in hippocampal CA1 neurons of rats.

Previously, we reported that prenatal exposure to high corticosterone induced attention-deficit hyperactivity disorder (ADHD)-like behaviors with cognitive deficits after weaning. In the present study, cellular mechanisms underlying cortisol-induced cognitive dysfunction were investigated using rat pups (Corti.Pups) born from rat mothers that were repetitively injected with corticosterone during pregnancy. In results, Corti.Pups exhibited the failure of behavioral memory formation in the Morris water maze (MWM) test and the incomplete long-term potentiation (LTP) of hippocampal CA1 neurons. Additionally, glutamatergic excitatory postsynaptic currents (EPSCs) were remarkably suppressed in Corti.Pups compared to normal rat pups. Incomplete LTP and weaker EPSCs in Corti.Pups were attributed to the delayed postsynaptic development of CA1 neurons, showing a higher expression of NR2B subunits and lower expression of PSD-95 and BDNF. These results indicated that the prenatal treatment with corticosterone to elevate cortisol level might potently downregulate the BDNF-mediated signaling critical for the synaptic development of hippocampal CA1 neurons during brain development, and subsequently, induce learning and memory impairment. Our findings suggest a possibility that the prenatal dysregulation of cortisol triggers the epigenetic pathogenesis of neurodevelopmental psychiatric disorders, such as ADHD and autism.

Sex-dependent emergence of prepubertal social dysfunction and augmented dopamine activity in a neurodevelopmental rodent model relevant for schizophrenia

Schizophrenia is a neurodevelopmental psychiatric disorder that often emerges in adolescence, is characterized by social dysfunction, and has an earlier onset in men. These features have been replicated in rats exposed to the mitotoxin methylazoxymethanol acetate (MAM) on gestational day (GD) 17, which as adults exhibit behavioral impairments and dopamine (DA) system changes consistent with a schizophrenia-relevant rodent model. In humans, social withdrawal is a negative symptom that often precedes disease onset and DA system dysfunction and is more pronounced in men. Children and adolescents at high-risk for schizophrenia exhibit social deficits prior to psychotic symptoms (i.e., prodromal phase), which can be used as a predictive marker for future psychopathology. Adult MAM rats also exhibit deficient social interaction, but less is known regarding the emergence of social dysfunction in this model, whether it varies by sex, and whether it is linked to disrupted DA function. To this end, we characterized the ontogeny of social and DA dysfunction in male and female MAM rats during the prepubertal period (postnatal days 33–43) and found sex-specific changes in motivated social behaviors (play, approach) and DA function. Male MAM rats exhibited reduced social approach and increased VTA DA neuron activity compared to saline-treated (SAL) males, whereas female MAM rats exhibited enhanced play behaviors compared to SAL females but no changes in social approach or VTA population activity during this period. These findings demonstrate sex differences in the emergence of social and DA deficits in the MAM model, in which females exhibit delayed emergence.

Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model.

Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspring's neurodevelopment and behavioral outcomes. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroinflammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (Macaca mulatta) born to MIA-exposed dams (n = 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (n = 10) or were untreated (n = 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.

In utero exposure to ADHD medication and long-term offspring outcomes.

Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.

Impact of 5-HT6 Receptor Subcellular Localization on Its Signaling and Its Pathophysiological Roles.

The serotonin (5-HT)6 receptor still raises particular interest given its unique spatio-temporal pattern of expression among the serotonin receptor subtypes. It is the only serotonin receptor specifically expressed in the central nervous system, where it is detected very early in embryonic life and modulates key neurodevelopmental processes, from neuronal migration to brain circuit refinement. Its predominant localization in the primary cilium of neurons and astrocytes is also unique among the serotonin receptor subtypes. Consistent with the high expression levels of the 5-HT6 receptor in brain regions involved in the control of cognitive processes, it is now well-established that the pharmacological inhibition of the receptor induces pro-cognitive effects in several paradigms of cognitive impairment in rodents, including models of neurodevelopmental psychiatric disorders and neurodegenerative diseases. The 5-HT6 receptor can engage several signaling pathways in addition to the canonical Gs signaling, but there is still uncertainty surrounding the signaling pathways that underly its modulation of cognition, as well as how the receptor's coupling is dependent on its cellular compartmentation. Here, we describe recent findings showing how the proper subcellular localization of the receptor is achieved, how this peculiar localization determines signaling pathways engaged by the receptor, and their pathophysiological influence.

The first genome-wide association study of internet addiction; Revealed substantial shared risk factors with neurodevelopmental psychiatric disorders

BackgroundInternet addiction disorder (IAD) is listed as a disorder requiring further studies in the diagnostic and statistical manual of mental disorders (DSM-V). Psychological studies showed significant co-morbidity of IAD with depression, alcohol abuse, and anxiety disorder. Etiology and genetic bases of IAD are unclear. AimsPresent study aimed to investigate the genetic, psychological, and cognitive bases of a tendency to internet addiction. Methods and proceduresDNA was extracted from blood samples of IADs (N = 16,520) and 18,000 matched non-psychiatric subjects. Genotyping for the subjects was performed using SNP Array. Psychological, neuropsychological, and neurological characteristics were conducted. Outcomes and resultsSeventy-two SNPs in 24 genes have been detected significantly associated with IAD. Most of these SNPs were risk factors for psychiatric disorders. Most similarity detected with autism spectrum disorder, bipolar disorder and schizophrenia. Higher anxiety, stress, and neuroticism and deficits in working memory, attention, planning, and processing speed were detected in IADs. ConclusionsThis study is the first genome-wide association study of IAD that showed strong shared genetic bases with neurodevelopmental disabilities and psychiatric disorders. ImplicationsGenetic risk factors in IADs may cause several cognitive and neurodevelopmental brain function abnormalities, which lead to excessive Internet usage. It may suggest that IAD could be a marker for vulnerability to developmental psychiatric disorders.

Prevalence and Penetrance of Rare Pathogenic Variants in Neurodevelopmental Psychiatric Genes in a Health Care System Population.

Autism, schizophrenia, and other clinically distinct neurodevelopmental psychiatric disorders (NPDs) have shared genetic etiologies, including single-gene and multigenic copy number variants (CNVs). Because rare variants are primarily investigated in clinical cohorts, population-based estimates of their prevalence and penetrance are lacking. The authors determined the prevalence, penetrance, and NPD risk of pathogenic single-gene variants in a large health care system population. The authors analyzed linked genomic and electronic health record (EHR) data in a subset of 90,595 participants from Geisinger's MyCode Community Health Initiative, known as the DiscovEHR cohort. Loss-of-function pathogenic variants in 94 high-confidence NPD genes were identified through exome sequencing, and NPD penetrance was calculated using preselected EHR diagnosis codes. NPD risk was estimated using a case-control comparison of DiscovEHR participants with and without NPD diagnoses. Results from single-gene variant analyses were also compared with those from 31 previously reported pathogenic NPD CNVs. Pathogenic variants were identified in 0.34% of the DiscovEHR cohort and demonstrated a 34.3% penetrance for NPDs. Similar to CNVs, sequence variants collectively conferred a substantial risk for several NPD diagnoses, including autism, schizophrenia, and bipolar disorder. Significant NPD risk remained after participants with intellectual disability were excluded from the analysis, confirming the association with major psychiatric disorders in individuals without severe cognitive deficits. Collectively, rare single-gene variants and CNVs were found in >1% of individuals in a large health care system population and play an important contributory role in mental health disorders. Diagnostic genetic testing for pathogenic variants among symptomatic individuals with NPDs could improve clinical outcomes through early intervention and anticipatory therapeutic support.

5.4 Exploring Gene Dosage Disorders in the Healthcare Setting

ObjectivesASD, schizophrenia, and other clinically distinct neurodevelopmental/psychiatric disorders (NPDs) have shared genetic etiologies, including copy number variants (CNVs) and single gene disorders. To date, rare variants that cause NPDs have primarily been investigated in clinically ascertained cohorts, therefore population-based estimates of their prevalence and penetrance are lacking. Here, we explored the prevalence, penetrance, and personal utility of NPD CNVs and single gene variants in a large healthcare system population.MethodsWe analyzed linked genomic and electronic health record (EHR) data from 90,595 participants in Geisinger’s MyCode® Community Health Initiative. Pathogenic variants involving 31 recurrent NPD CNVs and loss-of-function variants in 94 high-confidence NPD genes were identified through exome sequencing. NPD penetrance was calculated using preselected EHR diagnosis codes. We examined the personal utility of receiving these results in a selected set of NPD CNVs by evaluating the participants’ psychosocial reactions using a mixed-methods approach.ResultsIn this healthcare system population, CNVs and single gene variants that cause NPDs were prevalent (∼1.1% of participants) and penetrant. Participant responses to receiving these genomic results were positive overall, suggesting personal utility in learning this information and incorporating it into their health care.ConclusionsCollectively, rare NPD CNVs and single gene variants play an important contributory role in mental health disorders. Population screening for pathogenic variants to identify high-risk groups could improve clinical outcomes through early intervention and anticipatory therapeutic support.GS, ND, OTH ObjectivesASD, schizophrenia, and other clinically distinct neurodevelopmental/psychiatric disorders (NPDs) have shared genetic etiologies, including copy number variants (CNVs) and single gene disorders. To date, rare variants that cause NPDs have primarily been investigated in clinically ascertained cohorts, therefore population-based estimates of their prevalence and penetrance are lacking. Here, we explored the prevalence, penetrance, and personal utility of NPD CNVs and single gene variants in a large healthcare system population. ASD, schizophrenia, and other clinically distinct neurodevelopmental/psychiatric disorders (NPDs) have shared genetic etiologies, including copy number variants (CNVs) and single gene disorders. To date, rare variants that cause NPDs have primarily been investigated in clinically ascertained cohorts, therefore population-based estimates of their prevalence and penetrance are lacking. Here, we explored the prevalence, penetrance, and personal utility of NPD CNVs and single gene variants in a large healthcare system population. MethodsWe analyzed linked genomic and electronic health record (EHR) data from 90,595 participants in Geisinger’s MyCode® Community Health Initiative. Pathogenic variants involving 31 recurrent NPD CNVs and loss-of-function variants in 94 high-confidence NPD genes were identified through exome sequencing. NPD penetrance was calculated using preselected EHR diagnosis codes. We examined the personal utility of receiving these results in a selected set of NPD CNVs by evaluating the participants’ psychosocial reactions using a mixed-methods approach. We analyzed linked genomic and electronic health record (EHR) data from 90,595 participants in Geisinger’s MyCode® Community Health Initiative. Pathogenic variants involving 31 recurrent NPD CNVs and loss-of-function variants in 94 high-confidence NPD genes were identified through exome sequencing. NPD penetrance was calculated using preselected EHR diagnosis codes. We examined the personal utility of receiving these results in a selected set of NPD CNVs by evaluating the participants’ psychosocial reactions using a mixed-methods approach. ResultsIn this healthcare system population, CNVs and single gene variants that cause NPDs were prevalent (∼1.1% of participants) and penetrant. Participant responses to receiving these genomic results were positive overall, suggesting personal utility in learning this information and incorporating it into their health care. In this healthcare system population, CNVs and single gene variants that cause NPDs were prevalent (∼1.1% of participants) and penetrant. Participant responses to receiving these genomic results were positive overall, suggesting personal utility in learning this information and incorporating it into their health care. ConclusionsCollectively, rare NPD CNVs and single gene variants play an important contributory role in mental health disorders. Population screening for pathogenic variants to identify high-risk groups could improve clinical outcomes through early intervention and anticipatory therapeutic support.GS, ND, OTH Collectively, rare NPD CNVs and single gene variants play an important contributory role in mental health disorders. Population screening for pathogenic variants to identify high-risk groups could improve clinical outcomes through early intervention and anticipatory therapeutic support.

5.3 How Progress in Genetics Alters Both the Research and Clinical Landscape of Psychiatry

Genetic testing is increasingly becoming part of routine diagnostic workup for a wide range of conditions, often implemented (very) early in life. Given the pleiotropic function of many genes, pathogenic variants explaining physical conditions and abnormalities may also be associated with increased vulnerability of neurodevelopmental/psychiatric disorders (NPDs). One consequence of these developments mostly overlooked thus far, is that in an increasing number of children, a genetic test requested for a physical issue may reveal a pathogenic variant that incidentally also increases the risk of NPDs.

Effectiveness of neurofeedback training, behaviour management including attention enhancement training and medication in children with attention-deficit/hyperactivity disorder - A comparative follow up study.

Attention Deficit/ Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental psychiatric disorders of childhood. Treatment of ADHD includes medications and Behavioural interventions. Neurofeedback, a type of biofeedback, has been found to be useful in ADHD. It helps patients to control their brain waves consciously. However, it is not yet conclusive if it is efficacious in comparison to behavioural management training and medication. To compare the efficacy of neurofeedback training, behaviour management including attention enhancement training and medication in children with ADHD. Ninety children between 6 and 12 years with ADHD were taken and randomly divided into 3 treatment groups equally- neurofeedback, behaviour management and medication (methylphenidate). Conners 3-P Short Scale was applied for baseline assessment. The respective interventions were given and follow up was done at the end of 3 months by using Conners 3-P Short scale to assess the improvement in the symptoms. There were 6 dropouts, the final sample size was 84. The medication group showed the greatest reduction of symptoms in inattention, hyperactivity, executive functioning domain (core symptoms of ADHD). No statistically significant difference was observed between Neurofeedback and Behaviour Management in these domains. Learning problems improved in all three groups, neurofeedback being the most effective followed by medication. Both Neurofeedback and Medication groups showed similar effect which was higher than the Behavioural Management group in Peer Relation. Improvement in core ADHD symptoms have been observed with all 3 interventions with medication showing the greatest improvement Neurofeedback has been superior for learning problems. Thus, Neurofeedback can be an independent or combined intervention tool for children with ADHD in outpatient department of Psychiatry.

Glucocorticoid receptor dysregulation underlies 5-HT2AR-dependent synaptic and behavioral deficits in a mouse neurodevelopmental disorder model

Prenatal environmental insults increase the risk of neurodevelopmental psychiatric conditions in the offspring. Structural modifications of dendritic spines are central to brain development and plasticity. Using maternal immune activation (MIA) as a rodent model of prenatal environmental insult, previous results have reported dendritic structural deficits in the frontal cortex. However, very little is known about the molecular mechanism underlying MIA-induced synaptic structural alterations in the offspring. Using prenatal (E12.5) injection with polyinosinic-polycytidylic acid potassium salt as a mouse MIA model, we show here that upregulation of the serotonin 5-HT2A receptor (5-HT2AR) is at least in part responsible for some of the effects of prenatal insults on frontal cortex dendritic spine structure and sensorimotor gating processes. Mechanistically, we report that this upregulation of frontal cortex 5-HT2AR expression is associated with MIA-induced reduction of nuclear translocation of the glucocorticoid receptor (GR) and, consequently, a decrease in the enrichment of GR at the 5-HT2AR promoter. The translational significance of these preclinical findings is supported by data in postmortem human brain samples suggesting dysregulation of GR translocation in frontal cortex of schizophrenia subjects. We also found that repeated corticosterone administration augmented frontal cortex 5-HT2AR expression and reduced GR binding to the 5-HT2AR promoter. However, virally (adeno-associated virus) mediated augmentation of GR function reduced frontal cortex 5-HT2AR expression and improved sensorimotor gating processes via 5-HT2AR. Together, these data support a negative regulatory relationship between GR signaling and 5-HT2AR expression in the mouse frontal cortex that may carry implications for the pathophysiology underlying 5-HT2AR dysregulation in neurodevelopmental psychiatric disorders.

Association of complement component 4 with neuroimmune abnormalities in the subventricular zone in schizophrenia and autism spectrum disorders

An early inflammatory insult is the most recognized risk factor associated with neurodevelopmental psychiatric disorders, even more so than genetic variants. Notably, complement component 4 (C4), a molecule involved in inflammatory responses, has been strongly associated with schizophrenia (SZ) and its role in other neurodevelopmental disorders, such as autism (ASD), is an area of active investigation. However, while C4 in SZ has been implicated in the context of synaptic pruning, little is known about its neuroinflammatory role. The subventricular zone (SVZ) is a region heavily involved in neurodevelopment and neuroimmune interactions through the lifespan; thus, it is a region wherein C4 may play a vital role in disease pathology. Using in situ hybridization with radioactive riboprobes and RNAscope, we identified robust astrocytic expression of C4 in the SVZ and in the septum pellucidum. C4 was also expressed in ependyma, neurons, and Ki67+ progenitor cells. Examination of mRNA levels showed elevated C4 in both ASD and SZ, with higher expression in SZ compared to controls. Targeted transcriptomic analysis of inflammatory pathways revealed a strong association of complement system genes with SZ, and to a lesser extent, ASD, as well as generalized immune dysregulation without a strong association with known infectious pathways. Analysis of differentially expressed genes (DEGs) showed that ASD DEGs were enriched in adaptive immune system functions such as Th cell differentiation, while SZ DEGs were enriched in innate immune system functions, including NF-κB and toll like receptor signaling. Moreover, the number of Ki67+ cells was significantly higher in ASD compared to SZ and controls. Taken together, these results support a role for C4 into inflammatory-neuroimmune dysregulation observed in SZ and ASD pathology.

One-year results from the vaccination campaign against COVID-19 infection in 47 million individuals with severe mental disorders and other chronic diseases.

Severe mental disorders have been associated with increased COVID-19 mortality. The aim of this study was to evaluate the results of the vaccination campaign against COVID-19 after 1 year using exhaustive population-based data. In this nationwide population-based study, we used data from the French national medico-administrative database (SNDS) and the COVID Vaccine teleservice from January 4, 2021 (date of activation of the teleservice) to January 30th, 2022. As of January 30th, 2022, the rate of first injection in France was 80.2% (54 million people) and the rate of booster vaccination was 78.3% (52.7 million people). Except for opioid use disorder, all individuals with chronic illnesses or risk factors for poor COVID-19 outcome (e.g., smoking and obesity) had higher rates of vaccination than the general population (from 83.4 to 94.5% vs. 78.3%). However, the four diseases ranking last for both initial and booster vaccinations were mental disorders: alcohol use disorders (86 and 84.3%), neurodevelopmental psychiatric disorders (85.3 and 83.7%), schizophrenia-spectrum disorder (85 and 83.4%) and opioid use disorders (72.9 and 69.4%). Except for opioid disorders, all patients with mental disorders had higher rates of vaccination compared to the general population. However, these rates were lower than other chronic diseases at risk of severe COVID-19 outcomes. Vaccination campaigns must redouble their efforts to improve vaccination penetration in patients with mental disorders.

Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.

Neuroinflammatory Signatures of Complement Component 4 in the Subventricular Zone of Autism Spectrum Disorder and Schizophrenia

Abstract Early inflammatory insults are the most recognized environmental risk factor associated with neurodevelopmental psychiatric disorders. The subventricular zone (SVZ) is a region heavily involved in neurodevelopment and neuroimmune interactions through the lifespan. Complement component 4 (C4), a classical molecule involved in inflammatory responses, has been associated with schizophrenia (SZ) by genetic studies. However, whether C4 is involved in other neurodevelopmental disorders, such as autism (ASD), is a matter of current studies. Moreover, while C4 in SZ has been studied in the context of synaptic pruning, little is known about its neuroinflammatory role. Using in situ hybridization with radioactive riboprobes and RNAscope, we identified robust astrocytic expression of C4 in the SVZ and in the septum pellucidum. C4 was also expressed in ependyma, neurons, and Ki67+ cells, but not microglia, with higher expression in SZ as compared to controls and ASD. Moreover, the number of Ki67+ cells was significantly higher in ASD compared to SZ and controls. Targeted transcriptomic analysis of inflammatory pathways revealed a strong association of complement system genes with SZ, and to a lesser extent ASD, as well as generalized inflammation without an association with known infectious pathways. Additional analysis of differentially expressed genes (DEGs) showed that ASD DEGs were enriched in adaptive immune system functions such as Th cell differentiation, while SZ DEGs were enriched in innate immune system functions, including NF-κB and toll like receptor signaling. Taken together, these results support a role for C4 into inflammatory-neuroimmune dysregulation observed in SZ and ASD pathology. Supported by National Institutes of Mental Health grant P50 MH103222 (Silvio O. Conte Center for Translational Mental Health Research).

Impulsivity Moderates the Effect of Neurofeedback Training on the Contingent Negative Variation in Autism Spectrum Disorder.

BackgroundThe contingent negative variation (CNV) is a well-studied indicator of attention- and expectancy-related processes in the human brain. An abnormal CNV amplitude has been found in diverse neurodevelopmental psychiatric disorders. However, its role as a potential biomarker of successful clinical interventions in autism spectrum disorder (ASD) remains unclear.MethodsIn this randomized controlled trial, we investigated how the CNV changes following an intensive neurofeedback training. Therefore, twenty-one adolescents with ASD underwent 24 sessions of slow cortical potential (SCP) neurofeedback training. Twenty additional adolescents with ASD formed a control group and received treatment as usual. CNV waveforms were obtained from a continuous performance test (CPT), which all adolescents performed before and after the corresponding 3-month long training period. In order to utilize all available neural time series, trial-based area under the curve values for all four electroencephalogram (EEG) channels were analyzed with a hierarchical Bayesian model. In addition, the model included impulsivity, inattention, and hyperactivity as potential moderators of change in CNV.ResultsOur model implies that impulsivity moderates the effects of neurofeedback training on CNV depending on group. In the control group, the average CNV amplitude decreased or did not change after treatment as usual. In the experimental group, the CNV changed depending on the severity of comorbid impulsivity symptoms. The average CNV amplitude of participants with low impulsivity scores decreased markedly, whereas the average CNV amplitude of participants with high impulsivity increased.ConclusionThe degree of impulsivity seems to play a crucial role in the changeability of the CNV following an intensive neurofeedback training. Therefore, comorbid symptomatology should be recorded and analyzed in future EEG-based brain training interventions.Clinical Trial Registrationhttps://www.drks.de, identifier DRKS00012339.

Understanding the Role of the Gut Microbiome in Brain Development and Its Association With Neurodevelopmental Psychiatric Disorders.

The gut microbiome has a tremendous influence on human physiology, including the nervous system. During fetal development, the initial colonization of the microbiome coincides with the development of the nervous system in a timely, coordinated manner. Emerging studies suggest an active involvement of the microbiome and its metabolic by-products in regulating early brain development. However, any disruption during this early developmental process can negatively impact brain functionality, leading to a range of neurodevelopment and neuropsychiatric disorders (NPD). In this review, we summarize recent evidence as to how the gut microbiome can influence the process of early human brain development and its association with major neurodevelopmental psychiatric disorders such as autism spectrum disorders, attention-deficit hyperactivity disorder, and schizophrenia. Further, we discuss how gut microbiome alterations can also play a role in inducing drug resistance in the affected individuals. We propose a model that establishes a direct link of microbiome dysbiosis with the exacerbated inflammatory state, leading to functional brain deficits associated with NPD. Based on the existing research, we discuss a framework whereby early diet intervention can boost mental wellness in the affected subjects and call for further research for a better understanding of mechanisms that govern the gut-brain axis may lead to novel approaches to the study of the pathophysiology and treatment of neuropsychiatric disorders.

Amygdala sensitivity for negative information as a neural marker for negative memory bias across psychiatric diagnoses

Self-referent negative memory bias is a known risk factor for depression, but recent evidence suggests its function as a transdiagnostic cognitive depressotypic marker. The amygdala's sensitivity for negative information is considered a neurobiological depressotypic marker. However, their relationship remains unknown. We transdiagnostically investigated the association between the amygdala's sensitivity, self-referent negative memory bias and its two components: negative endorsement bias and negative recall bias. Patients (n= 125) with (multimorbid) stress-related and neurodevelopmental psychiatric disorders and healthy controls (n= 78) performed an fMRI task to assess the amygdala's sensitivity for negative information and a task outside the scanner for the biases. Linear regression models assessed their associations. The left amygdala's sensitivity for negative information was significantly positively associated with negative recall bias in patients, but not controls. There were no significant associations with self-referent negative memory bias or negative endorsement bias or between the two depressotypic markers. Thus, the left amygdala's sensitivity for negative information may be considered a neural marker of negative memory bias across psychiatric diagnoses. Further research on the interactons with known determinants such as genetic predisposition is required to fully understand the relationship between the amygdala's sensitivity for negative information and these biases.

Clemastine Induces an Impairment in Developmental Myelination.

Abnormalities in myelination are associated to behavioral and cognitive dysfunction in neurodevelopmental psychiatric disorders. Thus, therapies to promote or accelerate myelination could potentially ameliorate symptoms in autism. Clemastine, a histamine H1 antagonist with anticholinergic properties against muscarinic M1 receptor, is the most promising drug with promyelinating properties. Clemastine penetrates the blood brain barrier efficiently and promotes remyelination in different animal models of neurodegeneration including multiple sclerosis, ischemia and Alzheimer’s disease. However, its role in myelination during development is unknown. We showed that clemastine treatment during development increased oligodendrocyte differentiation in both white and gray matter. However, despite the increase in the number of oligodendrocytes, conduction velocity of myelinated fibers of corpus callosum decreased in clemastine treated mice. Confocal and electron microscopy showed a reduction in the number of myelinated axons and nodes of Ranvier and a reduction of myelin thickness in corpus callosum. To understand the mechanisms leading to myelin formation impairment in the presence of an excess of myelinating oligodendrocytes, we focused on microglial cells that also express muscarinic M1 receptors. Importantly, the population of CD11c+ microglia cells, necessary for myelination, as well as the levels of insulin growth factor-1 decrease in clemastine-treated mice. Altogether, these data suggest that clemastine impact on myelin development is more complex than previously thought and could be dependent on microglia-oligodendrocyte crosstalk. Further studies are needed to clarify the role of microglia cells on developmental myelination.

Genes To Mental Health (G2MH): A Framework to Map the Combined Effects of Rare and Common Variants on Dimensions of Cognition and Psychopathology.

Rare genomic disorders (RGDs) confer elevated risk for neurodevelopmental psychiatric disorders. In this era of intense genomics discoveries, the landscape of RGDs is rapidly evolving. However, there has not been comparable progress to date in scalable, harmonized phenotyping methods. As a result, beyond associations with categorical diagnoses, the effects on dimensional traits remain unclear for many RGDs. The nature and specificity of RGD effects on cognitive and behavioral traits is an area of intense investigation: RGDs are frequently associated with more than one psychiatric condition, and those studied to date affect, to varying degrees, a broad range of developmental and cognitive functions. Although many RGDs have large effects, phenotypic expression is typically influenced by additional genomic and environmental factors. There is emerging evidence that using polygenic risk scores in individuals with RGDs offers opportunities to refine prediction, thus allowing for the identification of those at greatest risk of psychiatric illness. However, translation into the clinic is hindered by roadblocks, which include limited genetic testing in clinical psychiatry, and the lack of guidelines for following individuals with RGDs, who are at high risk of developing psychiatric symptoms. The Genes to Mental Health Network (G2MH) is a newly funded National Institute of Mental Health initiative that will collect, share, and analyze large-scale data sets combining genomics and dimensional measures of psychopathology spanning diverse populations and geography. The authors present here the most recent understanding of the effects of RGDs on dimensional behavioral traits and risk for psychiatric conditions and discuss strategies that will be pursued within the G2MH network, as well as how expected results can be translated into clinical practice to improve patient outcomes.