Haloperidol, Olanzapine, and Risperidone Induce Morphological Changes in an In Vitro Model of Human Hippocampal Neurogenesis.

BACKGROUND: Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular level. We aimed to examine the effects of typical and atypical antipsychotics on human iPSC-derived neural progenitor cells (NPCs). METHODS: Proliferation and neurite outgrowth were measured by live cell imaging, and gene expression levels related to neuronal identity were analyzed by RT-QPCR and immunocytochemistry during differentiation into hippocampal dentate gyrus granule cells following treatment of low- and high-dose antipsychotics (haloperidol, olanzapine, and risperidone). RESULTS: Antipsychotics did not modify the growth properties of NPCs after 3 days of treatment. However, the characteristics of neurite outgrowth changed significantly in response to haloperidol and olanzapine. After three weeks of differentiation, mRNA expression levels of the selected neuronal markers increased (except for MAP2), while antipsychotics caused only subtle changes. Additionally, we found no changes in MAP2 or GFAP protein expression levels as a result of antipsychotic treatment. CONCLUSIONS: Altogether, antipsychotic medications promoted neurogenesis in vitro by influencing neurite outgrowth rather than changing cell survival or gene expression. This study provides insights into the effects of antipsychotics on neuronal differentiation and highlights the importance of considering neurite outgrowth as a potential target of action.

Nrem Slow-Wave Activity In Adolescents Is Differentially Associated With Adhd Levels And Normalized By Pharmacological Treatment.

BACKGROUND: A compelling hypothesis about ADHD etiopathogenesis is that the ADHD phenotype reflects a delay in cortical maturation. Slow-wave activity (SWA) of non-rapid eye movement (NREM) sleep electroencephalogram (EEG) is an electrophysiological index of sleep intensity reflecting cortical maturation. Available data on ADHD and SWA are conflicting and developmental differences, or the effect of pharmacological treatment are relatively unknown. METHODS: We examined, in samples (Mage=16.4, SD=1.2), of ever-medicated adolescents at-risk for ADHD (n=18, 72%boys), medication naïve adolescents at-risk for ADHD (n=15, 67%boys), and adolescents not at-risk for ADHD (n=31, 61%boys) matched for chronological age, whether controlling for non-ADHD pharmacotherapy, ADHD pharmacotherapy modulates the association between NREM SWA and ADHD risk in home sleep. RESULTS: Findings indicated medication naïve adolescents at-risk for ADHD exhibited greater first sleep cycle and entire night NREM SWA than both ever-medicated adolescents at-risk for ADHD and adolescents not at-risk for ADHD and no difference between ever-medicated, at-risk adolescents and not at-risk adolescents. CONCLUSIONS: Results support atypical cortical maturation in medication naïve adolescents at-risk for ADHD that appears to be normalized by ADHD pharmacotherapy in ever-medicated adolescents at-risk for ADHD. Greater NREM SWA may reflect a compensatory mechanism in middle-later adolescents at-risk for ADHD that normalizes an earlier occurring developmental delay.

Efficacy of a synbiotic in the management of adults with Attention-Deficit and Hyperactivity Disorder and/or Borderline Personality Disorder and high levels of irritability: Results from a multicenter, randomized, placebo-controlled, "basket" trial.

Irritability worsens prognosis and increases mortality in individuals with Attention-Deficit and Hyperactivity Disorder (ADHD) and/or Borderline Personality Disorder (BPD). However, treatment options are still insufficient. The aim of this randomized, double blind, placebo-controlled study was to investigate the superiority of a synbiotic over placebo in the management of adults with ADHD and/or BPD and high levels of irritability. The study was conducted between February 2019 and October 2020 at three European clinical centers located in Hungary, Spain and Germany. Included were patients aged 18-65 years old diagnosed with ADHD and/or BPD and high levels of irritability (i.e., an Affectivity Reactivity Index (ARI-S) ≥ 5, plus a Clinical Global Impression-Severity Scale (CGI-S) score ≥ 4). Subjects were randomized 1(synbiotic):1(placebo); the agent was administered each day, for 10 consecutive weeks. The primary outcome measure was end-of-treatment response (i.e., a reduction ≥ 30 % in the ARI-S total score compared to baseline, plus a Clinical Global Impression-Improvement (CGI-I) total score of < 3 (very much, or much improved) at week 10). Between-treatment differences in secondary outcomes, as well as safety were also investigated. Of the 231 included participants, 180 (90:90) were randomized and included in the intention-to-treat-analyses. Of these, 117 (65 %) were females, the mean age was 38 years, ADHD was diagnosed in 113 (63 %), BPD in 44 (24 %), both in 23 (13 %). The synbiotic was well tolerated. At week 10, patients allocated to the synbiotic experienced a significantly higher response rate compared to those allocated to placebo (OR: 0.2, 95 % CI:0.1 to 0.7; P = 0.01). These findings suggest that that (add-on) treatment with a synbiotic may be associated with a clinically meaningful improvement in irritability in, at least, a subgroup of adults with ADHD and/or BPD. A superiority of the synbiotic over placebo in the management of emotional dysregulation (-3.6, 95 % CI:-6.8 to -0.3; P = 0.03), emotional symptoms (-0.6, 95 % CI:-1.2 to -0.05; P = 0.03), inattention (-1.8, 95 % CI: -3.2 to -0.4; P = 0.01), functioning (-2.7, 95 % CI: -5.2 to -0.2; P = 0.03) and perceived stress levels (-0.6, 95 % CI: -1.2 to -0.05; P = 0.03) was also suggested. Higher baseline RANK-L protein levels were associated with a significantly lower response rate, but only in the synbiotic group (OR: 0.1, 95 % CI: -4.3 to - 0.3, P = 0.02). In the placebo group, higher IL-17A levels at baseline were significantly associated with a higher improvement in in particular, emotional dysregulation (P = 0.04), opening a door for new (targeted) drug intervention. However, larger prospective studies are warranted to confirm the findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03495375.

Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission.

Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.

MicroRNA-Mediated Suppression of Glial Cell Line-Derived Neurotrophic Factor Expression Is Modulated by a Schizophrenia-Associated Non-Coding Polymorphism.

Plasma levels of glial cell line-derived neurotrophic factor (GDNF), a pivotal regulator of differentiation and survival of dopaminergic neurons, are reportedly decreased in schizophrenia. To explore the involvement of GDNF in the pathogenesis of the disease, a case-control association analysis was performed between five non-coding single nucleotide polymorphisms (SNP) across the GDNF gene and schizophrenia. Of them, the 'G' allele of the rs11111 SNP located in the 3' untranslated region (3'-UTR) of the gene was found to associate with schizophrenia. In silico analysis revealed that the rs11111 'G' allele might create binding sites for three microRNA (miRNA) species. To explore the significance of this polymorphism, transient co-transfection assays were performed in human embryonic kidney 293T (HEK293T) cells with a luciferase reporter construct harboring either the 'A' or 'G' allele of the 3'-UTR of GDNF in combination with the hsa-miR-1185-1-3p pre-miRNA. It was demonstrated that in the presence of the rs11111 'G' (but not the 'A') allele, hsa-miR-1185-2-3p repressed luciferase activity in a dose-dependent manner. Deletion of the miRNA binding site or its substitution with the complementary sequence abrogated the modulatory effect. Our results imply that the rs11111 'G' allele occurring more frequently in patients with schizophrenia might downregulate GDNF expression in a miRNA-dependent fashion.

Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia.

Schizophrenia (SCZ) is a neuropsychiatric disorder, caused by a combination of genetic and environmental factors. The etiology behind the disorder remains elusive although it is hypothesized to be associated with the aberrant response to neurotransmitters, such as dopamine and glutamate. Therefore, investigating the link between dysregulated metabolites and distorted neurodevelopment holds promise to offer valuable insights into the underlying mechanism of this complex disorder. In this study, we aimed to explore a presumed correlation between the transcriptome and the metabolome in a SCZ model based on patient-derived induced pluripotent stem cells (iPSCs). For this, iPSCs were differentiated towards cortical neurons and samples were collected longitudinally at various developmental stages, reflecting neuroepithelial-like cells, radial glia, young and mature neurons. The samples were analyzed by both RNA-sequencing and targeted metabolomics and the two modalities were used to construct integrative networks in silico. This multi-omics analysis revealed significant perturbations in the polyamine and gamma-aminobutyric acid (GABA) biosynthetic pathways during rosette maturation in SCZ lines. We particularly observed the downregulation of the glutamate decarboxylase encoding genes GAD1 and GAD2, as well as their protein product GAD65/67 and their biochemical product GABA in SCZ samples. Inhibition of ornithine decarboxylase resulted in further decrease of GABA levels suggesting a compensatory activation of the ornithine/putrescine pathway as an alternative route for GABA production. These findings indicate an imbalance of cortical excitatory/inhibitory dynamics occurring during early neurodevelopmental stages in SCZ. Our study supports the hypothesis of disruption of inhibitory circuits to be causative for SCZ and establishes a novel in silico approach that enables for integrative correlation of metabolic and transcriptomic data of psychiatric disease models.

Amygdala Volume is Associated with ADHD Risk and Severity Beyond Comorbidities in Adolescents: Clinical Testing of Brain Chart Reference Standards.

Understanding atypicalities in ADHD brain correlates is a step towards better understanding ADHD etiology. Efforts to map atypicalities at the level of brain structure have been hindered by the absence of normative reference standards. Recent publication of brain charts allows for assessment of individual variation relative to age- and sex-adjusted reference standards and thus estimation not only of case-control differences but also of intraindividual prediction. METHODS: Aim was to examine, whether brain charts can be applied in a sample of adolescents (N = 140, 38% female) to determine whether atypical brain subcortical and total volumes are associated with ADHD at-risk status and severity of parent-rated symptoms, accounting for self-rated anxiety and depression, and parent-rated oppositional defiant disorder (ODD) as well as motion. RESULTS: Smaller bilateral amygdala volume was associated with ADHD at-risk status, beyond effects of comorbidities and motion, and smaller bilateral amygdala volume was associated with inattention and hyperactivity/impulsivity, beyond effects of comorbidities except for ODD symptoms, and motion. CONCLUSIONS: Individual differences in amygdala volume meaningfully add to estimating ADHD risk and severity. Conceptually, amygdalar involvement is consistent with behavioral and functional imaging data on atypical reinforcement sensitivity as a marker of ADHD-related risk. Methodologically, results show that brain chart reference standards can be applied to address clinically informative, focused and specific questions.

Inflammatory biotype of ADHD is linked to chronic stress: a data-driven analysis of the inflammatory proteome.

The association between Attention Deficit Hyperactivity Disorder (ADHD) and low-grade inflammation has been explored in children but rarely in adults. Inflammation is characteristic of some, but not all, patients with ADHD and might be influenced by ADHD medication but also lifestyle factors including nutrition, smoking, and stress. It is also still unclear if any specific symptoms are related to inflammation. Therefore, we assessed 96 inflammatory proteins in a deeply phenotyped cohort of 126 adult ADHD participants with a stable medication status using OLINK technology. A data-based, unsupervised hierarchical clustering method could identify two distinct biotypes within the 126 ADHD participants based on their inflammatory profile: a higher inflammatory potential (HIP) and a lower inflammatory protein potential (LIP) group. Biological processes that differed strongest between groups were related to the NF-κB pathway, chemokine signaling, IL-17 signaling, metabolic alterations, and chemokine attraction. A comparison of sample characteristics revealed that the HIP group was more likely to have higher levels of chronic stress (p < 0.001), a higher clinical global impression scale score (p = 0.030), and a higher risk for suicide (p = 0.032). Medication status did not influence protein levels significantly (p ≥ 0.074), but psychotropic co-medication (p ≤ 0.009) did. In conclusion, our data suggest the presence of two distinct biotypes in adults with ADHD. Higher levels of inflammatory proteins in ADHD are linked to higher levels of chronic perceived stress in a linear fashion. Further research on inflammation in adults with ADHD should take stress levels into account.

Probing the biological consequences of a previously undescribed de novo mutation of ZMYND11 in a schizophrenia patient by CRISPR genome editing and induced pluripotent stem cell based in vitro disease-modeling.

BACKGROUND: Schizophrenia (SCZ) is a severe neuropsychiatric disorder of complex, poorly understood etiology, associated with both genetic and environmental factors. De novo mutations (DNMs) represent a new source of genetic variation in SCZ, however, in most cases their biological significance remains unclear. We sought to investigate molecular disease pathways connected to DNMs in SCZ by combining human induced pluripotent stem cell (hiPSC) based disease modeling and CRISPR-based genome editing. METHODS: We selected a SCZ case-parent trio with the case individual carrying a potentially disease causing 1495C > T nonsense DNM in the zinc finger MYND domain-containing protein 11 (ZMYND11), a gene implicated in biological processes relevant for SCZ. In the patient-derived hiPSC line the mutation was corrected using CRISPR, while monoallelic or biallelic frameshift mutations were introduced into a control hiPSC line. Isogenic cell lines were differentiated into hippocampal neuronal progenitor cells (NPCs) and functionally active dentate gyrus granule cells (DGGCs). Immunofluorescence microscopy and RNA sequencing were used to test for morphological and transcriptomic differences at NPC and DGCC stages. Functionality of neurons was investigated using calcium-imaging and multi-electrode array measurements. RESULTS: Morphology in the mutant hippocampal NPCs and neurons was preserved, however, we detected significant transcriptomic and functional alterations. RNA sequencing showed massive upregulation of neuronal differentiation genes, and downregulation of cell adhesion genes. Decreased reactivity to glutamate was demonstrated by calcium-imaging. CONCLUSIONS: Our findings lend support to the involvement of glutamatergic dysregulation in the pathogenesis of SCZ. This approach represents a powerful model system for precision psychiatry and pharmacological research.

Psychometric properties of the Hungarian childhood trauma questionnaire short form and its validity in patients with adult attention-deficit hyperactivity disorder or borderline personality disorder.

BACKGROUND: Compelling evidence supports the role of childhood traumatization in the etiology of psychiatric disorders, including adult attention-deficit hyperactivity disorder (aADHD) and borderline personality disorder (BPD). The aim of this study was to examine the psychometric properties of the Hungarian version of the Childhood Trauma Questionnaire Short Form (H-CTQ-SF) and to investigate the differences between patients diagnosed with aADHD and BPD in terms of early traumatization. METHODS: Altogether 765 (mean age = 32.8 years, 67.7% women) patients and control subjects were enrolled from different areas of Hungary. Principal component analysis and confirmatory factor analysis were carried out to explore the factor structure of H-CTQ-SF and test the validity of the five-factor structure. Discriminative validity was assessed by comparing clinical and non-clinical samples. Subsequently, aADHD and BPD subgroups were compared with healthy controls to test for the role of early trauma in aADHD without comorbid BPD. Convergent validity was explored by measuring correlations with subscales of the Personality Inventory for DSM-5 (PID-5). RESULTS: The five scales of the H-CTQ-SF demonstrated adequate internal consistency and reliability values. The five-factor model fitted the Hungarian version well after exclusion of one item from the physical neglect scale because of its cross-loading onto the emotional neglect subscale. The H-CTQ-SF effectively differentiated between the clinical and non-clinical samples. The BPD, but not the aADHD group showed significant differences in each CTQ domain compared with the healthy control group. All CTQ domains, except for physical abuse, demonstrated medium to high correlations with PID-5 emotional lability, anxiousness, separation insecurity, withdrawal, intimacy avoidance, anhedonia, depressivity, suspiciousness, and hostility subscales. CONCLUSIONS: Our study confirmed the psychometric properties of the H-CTQ-SF, an easy-to-administer, non-invasive, ethically sound questionnaire. In aADHD patients without comorbid BPD, low levels of traumatization in every CTQ domain were comparable to those of healthy control individuals. Thus, the increased level of traumatization found in previous studies of aADHD might be associated with the presence of comorbid BPD. Our findings also support the role of emotional neglect, emotional abuse and sexual abuse in the development of BPD.

Differential neurocognitive profiles in adult attention-deficit/hyperactivity disorder subtypes revealed by the Cambridge Neuropsychological Test Automated Battery.

Adult attention-deficit/hyperactivity disorder (aADHD) represents a heterogeneous entity incorporating different subgroups in terms of symptomatology, course, and neurocognition. Although neurocognitive dysfunction is generally associated with aADHD, its severity, association with self-reported symptoms, and differences between subtypes remain unclear. We investigated 61 outpatients (65.6% male, mean age 31.5 ± 9.5) diagnosed using DSM-5 criteria together with age-, sex-, and education-matched healthy controls (HC) (n = 58, 63.8% male, mean age 32.3 ± 9.6). Neurocognitive alterations were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and compared between groups using the generalized linear model (GLM) method. Multivariate effects were tested by principal component analysis combined with multivariate pattern analysis. Self-reported symptom severity was tested for correlations with neurocognitive performance. GLM analyses revealed nominally significant differences between the aADHD and HC groups in several domains, however, only the Rapid Visual Information Processing measures survived correction, indicating impaired sustained attention and response inhibition in the aADHD group. Comparison of the predominantly inattentive and the hyperactive-impulsive/combined subtypes yielded nominally significant differences with higher levels of dysfunction in the inattentive group. In the stepwise discriminant analysis aADHD and HC groups were best separated with 2 factors representing sustained attention and reaction time. We found only weak correlations between symptom severity and CANTAB factors. aADHD patients are neuropsychologically heterogeneous and subtypes show different neurocognitive profiles. Differences between the aADHD and HC groups were driven primarily by the inattentive subtype. Sustained attention and its factor derivative showed the most significant alterations in aADHD patients.

Intact predictive processing in autistic adults: evidence from statistical learning.

Impairment in predictive processes gained a lot of attention in recent years as an explanation for autistic symptoms. However, empirical evidence does not always underpin this framework. Thus, it is unclear what aspects of predictive processing are affected in autism spectrum disorder. In this study, we tested autistic adults on a task in which participants acquire probability-based regularities (that is, a statistical learning task). Twenty neurotypical and 22 autistic adults learned a probabilistic, temporally distributed regularity for about 40 min. Using frequentist and Bayesian methods, we found that autistic adults performed comparably to neurotypical adults, and the dynamics of learning did not differ between groups either. Thus, our study provides evidence for intact statistical learning in autistic adults. Furthermore, we discuss potential ways this result can extend the scope of the predictive processing framework, noting that atypical processing might not always mean a deficit in performance.

The role of insulin/IGF1 signalling in neurodevelopmental and neuropsychiatric disorders - Evidence from human neuronal cell models.

Insulin and insulin-like growth factor 1 (IGF1) signalling play a central role in the development and maintenance of neurons in the brain, and human neurodevelopmental as well as neuropsychiatric disorders have been linked to impaired insulin and IGF1 signalling. This review focuses on the impairments of the insulin and IGF1 signalling cascade in the context of neurodevelopmental and neuropsychiatric disorders, based on evidence from human neuronal cell models. Clear evidence was obtained for impaired insulin and IGF1 receptor downstream signalling in neurodevelopmental disorders, while the evidence for its role in neuropsychiatric disorders was less substantial. Human neuronal model systems can greatly add to our knowledge about insulin/IGF1 signalling in the brain, its role in restoring dendritic maturity, and complement results from clinical studies and animal models. Moreover, they represent a useful model for the development of new therapeutic strategies. Further research is needed to systematically investigate the exact role of the insulin/IGF1 signalling cascades in neurodevelopmental and neuropsychiatric disorders, and to elucidate the respective therapeutic implications.

Specific nasopharyngeal Corynebacterium strains serve as gatekeepers against SARS-CoV-2 infection.

The SARS-CoV-2 virus is still causing a worldwide problem. The virus settles primarily on the nasal mucosa, and the infection and its course depend on individual susceptibility. Our aim was to investigate the nasopharynx composition's role in the individual susceptibility. During the first phase of SARS-CoV-2 pandemic, nasopharyngeal microbiome samples of close contact unvaccinated patients were investigated by 16S rRNA analysis and by culturing. The whole genome of cultured Corynebacteria was sequenced. The relative expression of ACE2, TMPRSS2, and cathepsin L on Caco-2 cells and the strength of S1-ACE2 binding were determined in the presence of Corynebacteria. From 55 close contacts exposed to identical SARS-CoV-2 exposure, 26 patients became infected and 29 remained uninfected. The nasopharyngeal microbiome analysis showed significantly higher abundance of Corynebacteria in uninfected group. Corynebacterium accolens could be cultivated only from uninfected individuals and Corynebacterium propinquum from both infected and uninfected. Corynebacteria from uninfected patient significantly reduced the ACE2 and cathepsin L expression. C. accolens significantly reduced the TMPRSS2 expression compared to other Corynebacteria. Furthermore, Corynebacterium spp. weakened the binding of the S1-ACE2. Most C. accolens isolates harbored the TAG lipase LipS1 gene. Based on these results, the presence of Corynebacterium spp. in the nasopharyngeal microbiota, especially C. accolens strains, could reduce the individual susceptibility to SARS-CoV-2 infection by several mechanisms: by downregulation the ACE2, the TMPRSS2 receptors, and cathepsin L in the host; through the inhibition of S1-ACE2 binding; and lipase production. These results suggest the use of C. accolens strains as probiotics in the nasopharynx in the future.

Concurrent and Prospective Associations of Reward Response with Affective and Alcohol Problems: ADHD-Related Differential Vulnerability.

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder. Data on the role of transdiagnostic, intermediate phenotypes in ADHD-relevant characteristics and outcomes are needed to advance conceptual understanding and approaches to precision psychiatry. Specifically, the extent to which the association between neural response to reward and ADHD-associated affective, externalizing, internalizing, and substance use problems differ depending on ADHD status is unknown. Aims were to examine, in 129 adolescents, whether concurrent and prospective associations of fMRI-measured initial response to reward attainment (relative to loss) with affectivity and externalizing, internalizing, and alcohol use problems differs between youth at-risk for (i.e., subclinical) (n = 50) and not at-risk for ADHD. Adolescents were, on average, 15.29 years old (SD = 1.00; 38% female), 50 were at-risk for (Mage = 15.18 years, SD = 1.04; 22% female) and 79 not at-risk for (Mage = 15.37 years, SD = 0.98; 48.1% female) ADHD. Both concurrent and prospective relations differed given ADHD risk: across analyses, in at-risk youth, greater superior frontal gyrus response was associated with lower concurrent depressive problems but in not at-risk youth, these characteristics were not related. Controlling for baseline use, in at-risk youth, greater putamen response was associated with greater 18-month hazardous alcohol use, whereas in not at-risk youth, greater putamen response was associated with lower use. Where in brain and for which outcomes modulate (direction of) observed relations: superior frontal gyrus response is relevant for depressive problems whereas putamen response is relevant for alcohol problems and greater neural responsivity is linked to less depressive but to more alcohol problems in adolescents at-risk for ADHD and less alcohol problems in adolescents not at-risk. Differences in neural response to reward differentially confer vulnerability for adolescent depressive and alcohol problems depending on ADHD risk.

Electrophysiological underpinnings of dysfunctional inhibitory control in adults with attention-deficit/hyperactivity disorder: evidence for reduced NoGo anteriorization.

Our aim was to delineate the electrophysiological basis of dysfunctional inhibitory control of adult ADHD via investigating the anteriorization of the P3 component of the event-related brain response associated with the NoGo task condition (i.e., NoGo anteriorization, NGA). NGA is a neurophysiological measure of brain topography for cognitive response control, which indexes an overall shift of the brain's electrical activity in anterior direction towards the prefrontal areas. While the NoGo P3 received considerable attention in the adult ADHD literature, the brain topography of this component, which reflects the inhibitory process, remains largely unaddressed. EEG recordings were obtained during a Go/NoGo task from 51 subjects (n = 26 adult patients with ADHD, n = 25 healthy controls) using a high-density, 128-channel BioSemi ActiveTwo recording system. ADHD patients had significantly lower P3 NGA response compared to controls. The decrease in NGA was related to impulsivity scores as measured by the Conners' Adult ADHD Rating Scale: patients with higher impulsivity scores had significantly lower NGA. Treatment with stimulant medication, as compared to the lack of such treatment, was associated with a correction of the lower NGA response in ADHD patients. The current study revealed a lower NGA in adult ADHD, a finding which is consistent with the inhibitory control and frontal lobe dysfunctions described in the disorder. Our finding of the inverse relationship between NGA and impulsivity suggests that clinically more severe impulsivity is linked to a more pronounced frontal dysfunction in adult ADHD subjects.

Adolescent ADHD and electrophysiological reward responsiveness: A machine learning approach to evaluate classification accuracy and prognosis.

We evaluated event-related potential (ERP) indices of reinforcement sensitivity as ADHD biomarkers by examining, in N=306 adolescents (Mage=15.78, SD=1.08), the extent to which ERP amplitude and latency variables measuring reward anticipation and response (1) differentiate, in age- and sex-matched subsamples, (i) youth with vs. without ADHD, (ii) youth at-risk for vs. not at-risk for ADHD, and, in the with ADHD subsample, (iii) youth with the inattentive vs. the hyperactive/impulsive (H/I) and combined presentations. We further examined the extent to which ERP variables (2) predict, in the ADHD subsample, substance use (i) concurrently and (ii) prospectively at 18-month follow-up. Linear support vector machine analyses indicated ERPs weakly differentiate youth with/without (65%) - and at-risk for/not at-risk for (63%) - ADHD but better differentiate ADHD presentations (78%). Regression analyses showed in adolescents with ADHD, ERPs explain a considerable proportion of variance (50%) in concurrent alcohol use and, controlling for concurrent marijuana and tobacco use, explain a considerable proportion of variance (87 and 87%) in, and predict later marijuana and tobacco use. Findings are consistent with the dual-pathway model of ADHD. Results also highlight limitations of a dichotomous, syndromic classification and indicate differences in neural reinforcement sensitivity are a promising ADHD prognostic biomarker.

Altered interpersonal distance regulation in autism spectrum disorder.

Interpersonal distance regulation is an essential element of social communication. Its impairment in autism spectrum disorder (ASD) is widely acknowledged among practitioners, but only a handful of studies reported empirical research in real-life settings, focusing mainly on children. Interpersonal distance in adults with ASD and related autonomic functions received less attention. Here, we measured interpersonal distance along with heart rate variability (HRV) in adults with ASD, and tested the modulatory effects of eye-contact and attribution. Twenty-two adults diagnosed with ASD and 21 matched neurotypical controls participated in our study from October 2019 to February 2020. Our experimental design combined the modified version of the stop distance paradigm with HRV measurement controlling for eye contact between the experimenter and the participant to measure interpersonal distance. Still, we did not detect significant modulatory effect of eye contact and attribution. Our results showed a greater preferred distance in ASD. Moreover, we found lower baseline HRV and reduced HRV reactivity in ASD; however, these autonomic measurements could not predict preferred interpersonal distance. Our study highlights the importance of interpersonal space regulation in ASD: it might be considered that people with ASD need individually variable, presumably greater interpersonal distance. In addition, regardless of the distance they may have reduced autonomic regulatory capacity in social situations. Our results could help shape future experiments with sophisticated designs to grasp the complexity and underlying factors of distance regulation in typical and atypical populations.

Microglia modulate proliferation, neurite generation and differentiation of human neural progenitor cells.

Microglia, the primary immune cells of the brain, significantly influence the fate of neurons after neural damage. Depending on the local environment, they exhibit a wide range of phenotypes, including patrolling (naïve), proinflammatory, and anti-inflammatory characteristics, which greatly affects neurotoxicity. Despite the fact that neural progenitor cells (NPCs) and hippocampal neurons represent cell populations, which play pivotal role in neural regeneration, interaction between microglia and these cell types is poorly studied. In the present work, we investigated how microglial cells affect the proliferation and neurite outgrowth of human stem cell-derived NPCs, and how microglia stimulation with proinflammatory or anti-inflammatory agents modulates this interaction. We found that naïve microglia slightly diminish NPC proliferation and have no effect on neurite outgrowth. In contrast, proinflammatory stimulated microglia promote both proliferation and neurite generation, whereas microglia stimulated with anti-inflammatory cytokines augment neurite outgrowth leaving NPC proliferation unaffected. We also studied how microglia influence neurite development and differentiation of hippocampal dentate gyrus granule cells differentiated from NPCs. We found that proinflammatory stimulated microglia inhibit axonal development but facilitate dendrite generation in these differentiating neurons. Our results elucidate a fine-tuned modulatory effect of microglial cells on cell types crucial for neural regeneration, opening perspectives for novel regenerative therapeutic interventions.

Potential Role of the Antidepressants Fluoxetine and Fluvoxamine in the Treatment of COVID-19.

Mapping non-canonical cellular pathways affected by approved medications can accelerate drug repurposing efforts, which are crucial in situations with a global impact such as the COVID-19 pandemic. Fluoxetine and fluvoxamine are well-established and widely-used antidepressive agents that act as serotonin reuptake inhibitors (SSRI-s). Interestingly, these drugs have been reported earlier to act as lysosomotropic agents, inhibitors of acid sphingomyelinase in the lysosomes, and as ligands of sigma-1 receptors, mechanisms that might be used to fight severe outcomes of COVID-19. In certain cases, these drugs were administered for selected COVID-19 patients because of their antidepressive effects, while in other cases, clinical studies were performed to assess the effect of these drugs on treating COVID-19 patients. Clinical studies produced promising data that encourage the further investigation of fluoxetine and fluvoxamine regarding their use in COVID-19. In this review, we summarize experimental data and the results of the performed clinical studies. We also provide an overview of previous knowledge on the tissue distribution of these drugs and by integrating this information with the published experimental results, we highlight the real opportunity of using these drugs in our fight against COVID-19.