Dysfunctions of cellular context-sensitivity in neurodevelopmental learning disabilities.

Pyramidal neurons have a pivotal role in the cognitive capabilities of neocortex. Though they have been predominantly modeled as integrate-and-fire point processors, many of them have another point of input integration in their apical dendrites that is central to mechanisms endowing them with the sensitivity to context that underlies basic cognitive capabilities. Here we review evidence implicating impairments of those mechanisms in three major neurodevelopmental disabilities, fragile X, Down syndrome, and fetal alcohol spectrum disorders. Multiple dysfunctions of the mechanisms by which pyramidal cells are sensitive to context are found to be implicated in all three syndromes. Further deciphering of these cellular mechanisms would lead to the understanding of and therapies for learning disabilities beyond any that are currently available.

Funções executivas em crianças que apresentam dificuldades de aprendizagem / Executive functions in children with learning disabilities

As Funções Executivas (FE) podem ser definidas como um grupo complexo e integrado de recursos cognitivos que permitem ao sujeito efetuar comportamentos voltados a fins previamente decididos. Alterações nessas habilidades, preditoras de uma boa prática acadêmica, podem desencadear dificuldades no processo de aprendizagem de crianças. Logo, objetivou-se apurar a relação entre FE e dificuldades de aprendizagem em crianças com idades entre 7 e 11 anos de ambos os sexos, atendidas em um centro especializado nessa demanda para o público infantil. Foram utilizadas as ferramentas Five Digit Test(FDT) e um questionário sociodemográfico para a coleta de dados. Foram feitos estudos estatísticos descritivos e correlacionais por meio do software SPSS para Windows, a partir dos quais descrevemos correlações significativas entre os componentes executivos 'Controle Inibitório' e 'Flexibilidade Cognitiva' e as dificuldades de aprendizagem, o que nos indica a importância destes para a execução acadêmica, bem como a relevância de métodos de avaliação das FE na primeira fase escolar, para assim prevenir/minimizar o impacto dessas dificuldades no curso do aprendizado. Pontua-se que foram descobertos impasses normativos para correção de erros no teste aplicado, criando limitações na pesquisa, assim, propõe-se uma ampliação de normatizações.

Executive Functions (FE) can be defined as a complex and integrated group of cognitive resources that allow the subject to perform behaviors aimed at previously decided ends. Changes in these skills, predictors of good academic practice, can trigger difficulties inthe learning process of children. Thus, the objective was to investigate the relationship between EF and learning difficulties in children aged between 7 to 11 years of both sexes, attended at a specialized center in this demand for children. Five Digit Test (FDT) tools and a sociodemographic questionnaire were used for data collection. Descriptive and correlational statistical studies were carried out using PSS for Windows software, from which we describe significant correlations between the executive components 'Inhibitory Control' and 'Cognitive Flexibility' and the learning disabilities, which indicates the importance of these for academic performance, as well as the relevance of EF assessment methods in the first school phase, in order to prevent/minimize the impact of these difficulties on the learning course. It is pointed out that normative impasses were found to correct errors in the applied test, creating limitations in the research, thus, an expansion of norms is proposed.

Agency rescues competition for credit assignment among predictive cues from adverse learning conditions.

A fundamental assumption of learning theories is that the credit assigned to predictive cues is not simply determined by their probability of reinforcement, but by their ability to compete with other cues present during learning. This assumption has guided behavioral and neural science research for decades, and tremendous empirical and theoretical advances have been made identifying the mechanisms of cue competition. However, when learning conditions are not optimal (e.g., when training is massed), cue competition is attenuated. This failure of the learning system exposes the individual's vulnerability to form spurious associations in the real world. Here, we uncover that cue competition in rats can be rescued when conditions are suboptimal provided that the individual has agency over the learning experience. Our findings reveal a new effect of agency over learning on credit assignment among predictive cues, and open new avenues of investigation into the underlying mechanisms.

Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin.

Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin-a selective inhibitor of mTORC1, Torin-2-a non-selective mTORC1/mTORC2 inhibitor, and FK-506-a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4-9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.

5q11.2 deletion syndrome revisited-Further narrowing of the smallest region of overlap for the main clinical characteristics of the syndrome.

Microdeletions at 5q11.2 are rare. Subjects show a phenotypic spectrum that overlaps CHARGE syndrome and 22q11.2 deletion syndrome. A growing number of subjects present with learning difficulty and/or intellectual disability, immune deficiency, congenital heart malformation, and dysmorphism. DHX29 and IL6ST have been proposed as candidate genes for the development of the major clinical manifestations. We present a new case and narrow down the shortest region of overlap to evaluate possible candidate genes. Our case does not present developmental delay or immune deficiency indicating a reduced penetrance for some of the main clinical manifestations. The shortest region of overlap between subjects with deletions at 5q11.2 is approximately 450 kb (position 54.3-54.7 Mb). The narrowed region comprises 10 protein coding genes, including DHX29. DHX29 is a strong candidate gene for the main features of 5q11.2-microdeletion syndrome; however, our findings suggest a joined impact of several genes as the cause of the syndrome.

Protective Effect of Hydroxysafflor Yellow A against Chronic Mild Stress-induced Memory Impairments by Suppressing Tau Phosphorylation in Mice.

Chronic stress plays a critical role in the etiology of sporadic Alzheimer's disease (AD). However, there are currently no effective drugs that can target chronic stress to prevent AD. In this study, we explored the neuroprotective effect of hydroxysafflor yellow A (HSYA) against chronic mild stress (CMS)-induced memory impairments in mice and the underlying mechanism. The Morris water maze test showed that HSYA significantly reduced CMS-induced learning and memory impairments in mice. HSYA increased the expression of brain-derived neurotrophic factor (BDNF) and activated downstream tropomyosin-related kinase B (TrkB) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B(Akt)/mammalian target of rapamycin (mTOR) signaling. HSYA decreased the expression of regulator of calcineurin 1-1L (RCAN1-1L) that could promote the activity of glycogen synthase kinase-3ß (GSK-3ß). HSYA also attenuated tau phosphorylation by inhibiting the activity of GSK-3ß and cyclin-dependent kinase-5 (Cdk5). Our data indicated that HSYA has protective effects against CMS-induced BDNF downregulation, tau phosphorylation and memory impairments. HSYA may be a promising therapeutic candidate for AD by targeting chronic stress.

Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons.

mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.

Disruption of neonatal Purkinje cell function underlies injury-related learning deficits.

It is hypothesized that perinatal cerebellar injury leads to long-term functional deficits due to circuit dysmaturation. Using a novel integration of GCaMP6f fiber photometry with automated measurement of cerebellar behavior using the ErasmusLadder, we causally link cerebellar injury to altered Purkinje cell responses during maladaptive behavior. Chemogenetic inhibition of neonatal Purkinje cells is sufficient to phenocopy the effects of perinatal cerebellar injury. Our results uncover a direct link between perinatal cerebellar injury and activity-dependent maturation of cerebellar cortex.

Neurocognitive, adaptive, and psychosocial functioning in individuals with Robinow syndrome.

It has been estimated that 10-15% of people with Robinow syndrome (RS) show delayed development, but no studies have formally assessed developmental domains. The objective of this study is to provide the first description of cognitive, adaptive, and psychological functioning in RS. Thirteen participants (10 males) aged 4-51 years were seen for neuropsychological screening. Eight had autosomal-dominant RS (DVL1, n = 5; WNT5A, n = 3), four had autosomal-recessive RS (NXN, n = 2; ROR2, n = 2), and one had a mutation on an RS candidate gene (GPC4). Participants completed measures of intellectual, fine-motor, adaptive, executive, and psychological functioning. Findings indicated generally average intellectual functioning and low-average visuomotor skills. Adaptive functioning was average in autosomal-recessive RS (RRS) but low average in autosomal-dominant RS (DRS). Parent-report indicated executive dysfunction and attention problems in 4/8 children, 3/4 of whom had a DVL1 variant; adult self-report did not indicate similar difficulties. Learning disabilities were also reported in 4/8 individuals with DRS, 3/4 of whom had a DVL1 variant. Peer problems were reported for a majority of participants, many of whom also reported emotional concerns. Altogether, the findings indicate average neurocognitive functioning in RRS. In contrast, DRS, especially DVL1 pathogenic alleles, may confer specific risk for neurodevelopmental disability.

Cognitive and non-cognitive factors in educational and occupational outcomes-Specific to reading disability?

Low education and unemployment are common adult-age outcomes associated with childhood RD (c-RD). However, adult-age cognitive and non-cognitive factors associated with different outcomes remain unknown. We studied whether these outcomes are equally common among individuals with c-RD and controls and whether these outcomes are related to adult-age literacy skills or cognitive and non-cognitive factors or their interaction with c-RD. We examined adult participants with c-RD (n = 48) and their matched controls (n = 37). Low education was more common among c-RD than the controls, whereas long-term unemployment was equally common in both groups. Moreover, adult-age literacy skills, cognitive skills and non-cognitive factors were related to both low education and long-term unemployment. Only a few c-RD-specific associations emerged: c-RD, especially in interaction with low verbal or reading comprehension, was associated with low education, and c-RD in interaction with slow adult-age reading was associated with long-term unemployment. Avoidant coping style, emotional wellbeing and social functioning were related to education, and life-satisfaction to unemployment irrespective of c-RD. Thus, the non-cognitive factors associated with education and employment are similar in individuals with and without c-RD. Special attention should be paid to training c-RD individuals in basic academic, social and emotional skills.

Decreased investigatory head scanning during exploration in learning-impaired, aged rats.

"Head scanning" is an investigatory behavior that has been linked to spatial exploration and the one-trial formation or strengthening of place cells in the hippocampus. Previous studies have demonstrated that a subset of aged rats with normal spatial learning performance show head scanning rates during a novel, local-global cue-mismatch manipulation that are similar to those of young rats. However, these aged rats demonstrated different patterns of expression of neural activity markers in brain regions associated with spatial learning, perhaps suggesting neural mechanisms that compensate for age-related brain changes. These prior studies did not investigate the head scanning properties of aged rats that had spatial learning impairments. The present study analyzed head scanning behavior in young, aged-unimpaired, and aged-impaired Long Evans rats. Aged-impaired rats performed the head scan behavior at a lower rate than the young rats. These results suggest that decreased attention to spatial landmarks may be a contributing factor to the spatial learning deficits shown by the aged-impaired rats.

Effects of quantitative electroencephalogram normalization using 4-channel live z-score training neurofeedback for children with learning disabilities: Preliminary data / Efectos de normalización del electroencefalograma cuantitativo utilizando neurorretroalimentación de puntuaciones Z de 4 canales en tiempo real para niños con trastornos de aprendizaje: datos preliminares

Children with learning disabilities (LD) can have difficulties in reading at word level, text comprehension, writing or arithmetic. Several studies have shown the efficacy of neurofeedback (NF) in improving learning skills through brainwave operant conditioning in children with LD. The aim of this work was to show the efficacy of live z-score NF training (LZT) for quantitative electroencephalogram (QEEG) normalization in school children with LD. Twenty-eight children aged 10-15 years with LD participated. Ten 30-min sessions of QEEG-guided LZT using patient's highly preferred feedback were applied. After 10 sessions of QEEGguided LZT, participants showed statistically significant improvements in QEEG normalization and a statistically significant small to medium improvement in the Cognitive and Emotional Checklist. The results suggest that LZT-NF produces a tendency towards normalization of brain waves in children with LD, and might be advised as a therapeutic alternative or coadjuvant along with cognitive interventions

Los niños con trastornos de aprendizaje (TA) pueden manifestar dificultades en la lectura a nivel de palabra, comprensión de textos, escritura o matemáticas. Algunos estudios han mostrado la eficacia de la neurorretroalimentación (NR) en la mejora de las habilidades de aprendizaje a través del condicionamiento operante de las ondas cerebrales en niños con TA. El objetivo de este trabajo fue mostrar datos preliminares de la eficacia de la neurorretroalimentación de puntuaciones z en tiempo real (LZT) para la normalización del electroencefalograma cuantitativo (QEEG) en escolares con TA. Participaron 28 niños de entre 10-15 años de edad con TA. Se aplicaron diez sesiones de 30 minutos de LZT guiado por QEEG utilizando retroalimentación de alta preferencia de los sujetos. Tras 10 sesiones de LZT guiado por QEEG, los participantes mostraron mejoras estadísticamente significativas en la normalización del QEEG y una mejora de pequeña a media estadísticamente significativa en la "Lista de comprobación cognitiva y emocional". Los resultados sugieren que LZT-NR produce una tendencia hacia la normalización de las ondas cerebrales en niños con TA, y podría suponer una alternativa terapéutica o coadyuvante junto con la intervención cognitiva

Red light exaggerated sepsis-induced learning impairments and anxiety-like behaviors.

Light exerts critical non-visual effects on a multitude of physiological processes and behaviors, including sleep-wake behavior and cognitive function. In this study, we investigated the effects of continued exposure to different colors of light on cognitive function after sepsis in old mice. We found that exposure to red light, but not green light, exaggerated learning impairments and anxiety-like behaviors after sepsis. Red light also induced remarkable splenomegaly and altered the diversity and composition of the fecal microbiota. Pseudo germ-free mice transplanted with fecal bacteria from septic mice exposed to red light developed the same behavioral defects and splenomegaly as their donors. Intriguingly, splenectomy and subdiaphragmatic vagotomy reversed the learning impairments and anxiety-like behaviors resulting from red light exposure after sepsis. After subdiaphragmatic vagotomy, no differences in behavior or spleen size were observed among pseudo germ-free mice transplanted with fecal bacteria from septic mice exposed to different colors of light. Our results suggested that red light exposure after sepsis in old mice causes gut microbiota dysfunction, thus stimulating signaling through the subdiaphragmatic vagus nerve that induces splenomegaly and aggravates learning impairments and anxiety-like behaviors.

Exercise reverses learning deficits induced by hippocampal injury by promoting neurogenesis.

Hippocampal atrophy and cognitive decline are common sequelae of many neurodegenerative disorders, including stroke. To determine whether cognitive decline can be ameliorated by exercise-induced neurogenesis, C57BL/6 mice in which a unilateral hippocampal injury had been induced by injecting the vasoconstrictor endothelin-1 into their right hippocampus, were run voluntarily for 21 days on a running-wheel. We found the severe deficits in spatial learning, as detected by active place-avoidance task, following injury were almost completely restored in animals that ran whereas those that did not run showed no improvement. We show the increase in neurogenesis found in both the injured and contralateral hippocampi following running was responsible for the restoration of learning since bilateral ablation of newborn doublecortin (DCX)-positive neurons abrogated the cognitive improvement, whereas unilateral ablations of DCX-positive neurons did not prevent recovery, demonstrating that elevated neurogenesis in either the damaged or intact hippocampus is sufficient to reverse hippocampal injury-induced deficits.

Impact of COVID-19 outbreak on mental health and perceived strain among caregivers tending children with special needs.

BACKGROUND: While COVID-19 outbreak has had adverse psychological effects in children with special needs, the mental state and burden on their caregivers during this pandemic has yet to be reported. AIMS: The objectives of this study were to describe the mental health status and the change in perceived strain among caregivers during the COVID-19 outbreak. METHODS AND PROCEDURES: Two hundred sixty four caregivers completed an online survey that assessed demographics, use and perspective on tele-rehabilitation, homecare therapy, caregiver's strain and mental health. OUTCOMES AND RESULTS: The prevalence of depression, anxiety and stress symptoms were found to be 62.5 %, 20.5 % and 36.4 % respectively. A significant difference in caregiver strain (p <  0.001, effect size = 0.93) was observed during the outbreak compared to levels pre-outbreak (pre-outbreak strain was measured retrospectively). Caregivers not using tele-rehabilitation along with a perception of it being a poor medium for rehabilitation were at greater risks for poor mental health whereas a negative perception on homecare therapy were strongly associated with higher psychological symptoms and strain. CONCLUSIONS AND IMPLICATIONS: This study identified a high prevalence of depression and significant change in strain displayed by caregivers during the COVID-19 outbreak. We identified several factors associated with poor mental health and perceived strain that can be used to help safeguard caregivers.

Multimodal Protocol for Assessing Metacognition and Self-Regulation in Adults with Learning Difficulties.

Learning disabilities (LDs) encompass disorders of those who have difficulty learning and using academic skills, exhibiting performance below expectations for their chronological age in the areas of reading, writing, and/or mathematics. Each of the disorders making up the LDs involve different deficits; however, some commonalities can be found within that heterogeneity, such in terms of learning self-regulation and metacognition. Unlike in early ages and later educational levels, there are hardly any evidence-based evaluation protocols for adults with LDs. LDs influence academic performance but also have serious consequences in professional, social, and family contexts. In response to this, the current work proposes a multimodal evaluation protocol focused on metacognitive, self-regulation of learning, and emotional processes, which make up the basis of the difficulties in adults with LDs. The assessment is carried out through analysis of the on-line learning process using a variety methods, techniques, and sensors (e.g., eye tracking, facial expressions of emotion, physiological responses, concurrent verbalizations, log files, screen recordings of human-machine interactions) and off-line methods (e.g., questionnaires, interviews, and self-report measures). This theoretically-driven and empirically-based guideline aims to provide an accurate assessment of LDs in adulthood in order to design effective prevention and intervention proposals.

Pediatric Obstructive Sleep Apnea and Neurocognition.

Pediatric obstructive sleep apnea affects a large number of children and has multiple end-organ sequelae. Although many of these have been demonstrated to be reversible, the effects on some of the organ systems, including the brain, have not shown easy reversibility. Progress in this area has been hampered by lack of a preclinical model to study the disease. Therefore, perioperative and sleep physicians are tasked with making a number of difficult decisions, including optimal surgical timing to prevent disease evolution, but also to keep the perioperative morbidity in a safe range for these patients.

Effects of neonatal isoflurane anesthesia exposure on learning-specific and sensory systems in adults.

Millions of children undergo general anesthesia each year, and animal and human studies have indicated that exposure to anesthesia at an early age can impact neuronal development, leading to behavioral and learning impairments that manifest later in childhood and adolescence. Here, we examined the effects of isoflurane, a commonly-used general anesthetic, which was delivered to newborn rabbits. Trace eyeblink classical conditioning was used to assess the impact of neonatal anesthesia exposure on behavioral learning in adolescent subjects, and a variety of MRI techniques including fMRI, MR volumetry, spectroscopy and DTI captured functional, metabolic, and structural changes in key regions of the learning and sensory systems associated with anesthesia-induced learning impairment. Our results demonstrated a wide array of changes that were specific to anesthesia-exposed subjects, which supports previous studies that have pointed to a link between early anesthesia exposure and the development of learning and behavioral deficiencies. These findings point to the need for caution in avoiding excessive use of general anesthesia in young children and neonates.

Learning difficulties in Japanese schoolchildren with focal epilepsy.

BACKGROUND: Children with epilepsy often show some degree of cognitive impairment. In this study, we investigated their learning skills to clarify the characteristics of the difficulties related to learning in Japanese-speaking children with focal epilepsy. METHODS: The study included 13 boys and 17 girls of mean age 9.7 years (standard deviation 2.61; range 6-14 years) with focal epilepsy and a normal magnetic resonance brain scan. None of the patients had any other neurological disorder. RESULTS: Twenty-two children had "learning difficulties", i.e., an intellectual disability or low scores on a learning abilities task. Significant differences were found in age (P = 0.030), age at onset of epilepsy (P = 0.033), and electroencephalographic findings, as well as between bilateral vs. unilateral (P = 0.028) and right-localized vs. left-localized or bilateral (P = 0.014) involvement between subjects with and without learning difficulties. Seven (88%) of eight children with low scores on a learning abilities task showed abnormalities in reading speed. DISCUSSION: More than half of Japanese-speaking children with focal epilepsy need learning assistance. This finding points to a need for learning support in children with focal epilepsy regardless of language. Measurement of reading speed is useful in children with learning difficulties to identify those who require early intervention.

Diagnostic Associations of Processing Speed in a Transdiagnostic, Pediatric Sample.

INTRODUCTION: The present study examines the relationships between processing speed (PS), mental health disorders, and learning disorders. Prior work has tended to explore relationships between PS deficits and specific diagnoses in isolation of one another. Here, we simultaneously investigated PS associations with five diagnoses (i.e., anxiety, autism, ADHD, depressive, specific learning) in a large-scale, transdiagnostic, community self-referred sample. METHOD: 843 children, ages 8-16 were included from the Healthy Brain Network (HBN) Biobank. Principal component analysis (PCA) was employed to create a composite measure of four PS tasks, referred to as PC1. Intraclass correlation coefficient (ICC) between the four PS measures, as well as PC1, were calculated to assess reliability. RESULTS: ICCs were moderate between WISC-V tasks (0.663), and relatively modest between NIH Toolbox Pattern Comparison and other PS scales (0.14-0.27). Regression analyses revealed specific significant relationships between PS and reading and math disabilities, ADHD-inattentive presentation (ADHD-I), and ADHD-combined presentation (ADHD-C). After accounting for inattention, the present study did not find a significant relationship with Autism Spectrum Disorder. DISCUSSION: Our examination of PS in a large, transdiagnostic sample suggested more specific associations with ADHD and learning disorders than the literature currently suggests. Implications for understanding how PS interacts with a highly heterogeneous childhood sample are discussed.