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Developmental disabilities, including attention-deficit hyperactivity disorder (ADHD), intellectual disability (ID), and autism spectrum disorders (ASD), affect one in six children in the USA. Recently, gene mutations in patched domain containing 1 (PTCHD1) have been found in ~1% of patients with ID and ASD. Individuals with PTCHD1 deletion show symptoms of ADHD, sleep disruption, hypotonia, aggression, ASD, and ID. Although PTCHD1 is probably critical for normal development, the connection between its deletion and the ensuing behavioural defects is poorly understood. Here we report that during early post-natal development, mouse Ptchd1 is selectively expressed in the thalamic reticular nucleus (TRN), a group of GABAergic neurons that regulate thalamocortical transmission, sleep rhythms, and attention. Ptchd1 deletion attenuates TRN activity through mechanisms involving small conductance calcium-dependent potassium currents (SK). TRN-restricted deletion of Ptchd1 leads to attention deficits and hyperactivity, both of which are rescued by pharmacological augmentation of SK channel activity. Global Ptchd1 deletion recapitulates learning impairment, hyper-aggression, and motor defects, all of which are insensitive to SK pharmacological targeting and not found in the TRN-restricted deletion mouse. This study maps clinically relevant behavioural phenotypes onto TRN dysfunction in a human disease model, while also identifying molecular and circuit targets for intervention.

Recent research in cognitive and developmental neuroscience is providing a new approach to the understanding of dyscalculia that emphasizes a core deficit in understanding sets and their numerosities, which is fundamental to all aspects of elementary school mathematics. The neural bases of numerosity processing have been investigated in structural and functional neuroimaging studies of adults and children, and neural markers of its impairment in dyscalculia have been identified. New interventions to strengthen numerosity processing, including adaptive software, promise effective evidence-based education for dyscalculic learners.

Competency with numbers is essential in today’s society; yet, up to 20% of children exhibit moderate to severe mathematical learning disabilities (MLD). Behavioural intervention can be effective, but the neurobiological mechanisms underlying successful intervention are unknown. Here we demonstrate that eight weeks of 1:1 cognitive tutoring not only remediates poor performance in children with MLD, but also induces widespread changes in brain activity. Neuroplasticity manifests as normalization of aberrant functional responses in a distributed network of parietal, prefrontal and ventral temporal–occipital areas that support successful numerical problem solving, and is correlated with performance gains. Remarkably, machine learning algorithms show that brain activity patterns in children with MLD are significantly discriminable from neurotypical peers before, but not after, tutoring, suggesting that behavioural gains are not due to compensatory mechanisms. Our study identifies functional brain mechanisms underlying effective intervention in children with MLD and provides novel metrics for assessing response to intervention. Mathematical learning disabilities (MLD) affect up to 20% of children and are linked to poorer socioeconomic and health outcomes in adulthood. Here, Iuculano et al . show that tutoring induced functional changes in multiple brain systems underlie remediation of poor maths skills in children with MLD.

Individuals with autism spectrum disorders (ASDs) are characterized by social communication difficulties and behavioural rigidity. Difficulties in learning from others are one of the most devastating features of this group of conditions. Nevertheless, the nature of learning difficulties in ASDs is still unclear. Given the relevance of implicit learning for social and communicative functioning, a link has been hypothesized between ASDs and implicit learning deficit. However, studies that have employed formal testing of implicit learning in ASDs provided mixed results. We undertook a systematic search of studies that examined implicit learning in ASDs using serial reaction time (SRT), alternating serial reaction time (ASRT), pursuit rotor (PR), and contextual cueing (CC) tasks, and synthesized the data using meta-analysis. A total of 11 studies were identified, representing data from 407 individuals with ASDs and typically developing comparison participants. The results indicate that individuals with ASDs do not differ in any task considered [SRT and ASRT task: standardized mean difference (SMD) -0.18, 95% confidence interval (CI) -0.71 to 0.36; PR task: SMD -0.34, 95% CI -1.04 to 0.36; CC task: SMD 0.27, 95% CI -0.07 to 0.60]. Based on our synthesis of the existing literature, we conclude that individuals with ASDs can learn implicitly, supporting the hypothesis that implicit learning deficits do not represent a core feature in ASDs.

Developmental dyscalculia (DD) is a specific learning disability that affects the acquisition of mathematical skills in children with normal intelligence and age-appropriate school education (prevalence 3–6%). One essential step in the development of mathematical understanding is the formation and automated access to a spatial representation of numbers. Many children with DD show a deficient development of such a mental number line. The present study aimed to develop a computer-based training program to improve the construction and access to the mental number line. Sixteen children with DD aged 8–10years and 16 matched control children completed the 5-week computer training. All children played the game 15min a day for 5days a week. The efficiency of the training was evaluated by means of neuropsychological tests and functional magnetic resonance imaging (fMRI) during a number line task. In general, children with and without DD showed a benefit from the training indicated by (a) improved spatial representation of numbers and (b) the number of correctly solved arithmetical problems. Regarding group differences in brain activation, children with DD showed less activation in bilateral parietal regions, which reflects neuronal dysfunction in pivotal regions for number processing. Both groups showed reduced recruitment of relevant brain regions for number processing after the training which can be attributed to automatization of cognitive processes necessary for mathematical reasoning. Moreover, results point to a partial remediation of deficient brain activation in dyscalculics after consolidation of acquired and refined number representation. To conclude, the present study represents the first attempt to evaluate a custom-designed training program in a group of dyscalculic children and results indicate that the training leads to an improved spatial representation of the mental number line and a modulation of neural activation, which both facilitate processing of numerical tasks. ► Evaluation of a training program for children with developmental dyscalculia. ► Training of spatial representation of numbers. ► Improved number processing after training. ► Modulation of brain activation after training.

Cognitive dysfunction and memory loss are common features of Alzheimer's disease (AD). Abnormalities in the expression profile of immediate early genes that play a critical role in memory formation, such as the cAMP-response element binding protein (CREB), have been reported in the brains of AD patients. Here we show that amyloid-β (Aβ) accumulation, which plays a primary role in the cognitive deficits of AD, interferes with CREB activity. We further show that restoring CREB function via brain viral delivery of the CREB-binding protein (CBP) improves learning and memory deficits in an animal model of AD. Notably, such improvements occur without changes in Aβ and tau pathology, and instead are linked to an increased level of brain-derived neurotrophic factor. The resulting data suggest that Aβ-induced learning and memory deficits are mediated by alterations in CREB function, based on the finding that restoring CREB activity by directly modulating CBP levels in the brains of adult mice is sufficient to ameliorate learning and memory. Therefore, increasing CBP expression in adult brains may be a valid therapeutic approach not only for AD, but also for various brain disorders characterized by alterations in immediate early genes, further supporting the concept that viral vector delivery may be a viable therapeutic approach in neurodegenerative diseases.

The limited success of genetic studies of major depression has raised questions concerning the definition of genetically relevant phenotypes. This paper presents strategies to improve the phenotypic definition of major depression by proposing endophenotypes at two levels: First, dissecting the depressive phenotype into key components results in narrow definitions of putative psychopathological endophenotypes: mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. A review of the recent literature on neurobiological and genetic findings associated with these components is given. Second, the most consistent heritable biological markers of major depression are proposed as biological endophenotypes for genetic studies: REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical axis, and CRH systems, and intracellular signal transduction endophenotypes. The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiality, and clinical and biological plausibility. Finally, the case is made for the development of a new classification system in order to reduce the heterogeneity of depression representing a major impediment to elucidating the genetic and neurobiological basis of this common, severe, and often life-threatening illness.

Synaptic plasticity is the ability of synapses to modulate the strength of neuronal connections; however, the molecular factors that regulate this feature are incompletely understood. Here, we demonstrated that mice lacking brain-specific angiogenesis inhibitor 1 (BAI1) have severe deficits in hippocampus-dependent spatial learning and memory that are accompanied by enhanced long-term potentiation (LTP), impaired long-term depression (LTD), and a thinning of the postsynaptic density (PSD) at hippocampal synapses. We showed that compared with WT animals, mice lacking Bai1 exhibit reduced protein levels of the canonical PSD component PSD-95 in the brain, which stems from protein destabilization. We determined that BAI1 prevents PSD-95 polyubiquitination and degradation through an interaction with murine double minute 2 (MDM2), the E3 ubiquitin ligase that regulates PSD-95 stability. Restoration of PSD-95 expression in hippocampal neurons in BAI1-deficient mice by viral gene therapy was sufficient to compensate for Bai1 loss and rescued deficits in synaptic plasticity. Together, our results reveal that interaction of BAI1 with MDM2 in the brain modulates PSD-95 levels and thereby regulates synaptic plasticity. Moreover, these results suggest that targeting this pathway has therapeutic potential for a variety of neurological disorders.

Patients with Parkinson's disease (PD) and freezing of gait (FOG) suffer from more impaired motor and cognitive functioning than their non-freezing counterparts. This underlies an even higher need for targeted rehabilitation programs in this group. However, so far it is unclear whether FOG affects the ability for consolidation and generalization of motor learning and thus the efficacy of rehabilitation. To investigate the hallmarks of motor learning in people with FOG compared to those without by comparing the effects of an intensive motor learning program to improve handwriting. Thirty five patients with PD, including 19 without and 16 with FOG received six weeks of handwriting training consisting of exercises provided on paper and on a touch-sensitive writing tablet. Writing training was based on single- and dual-task writing and was supported by means of visual target zones. To investigate automatization, generalization and retention of learning, writing performance was assessed before and after training in the presence and absence of cues and dual tasking and after a six-week retention period. Writing amplitude was measured as primary outcome measure and variability of writing and dual-task accuracy as secondary outcomes. Significant learning effects were present on all outcome measures in both groups, both for writing under single- and dual-task conditions. However, the gains in writing amplitude were not retained after a retention period of six weeks without training in the patient group without FOG. Furthermore, patients with FOG were highly dependent on the visual target zones, reflecting reduced generalization of learning in this group. Although short-term learning effects were present in both groups, generalization and retention of motor learning were specifically impaired in patients with PD and FOG. The results of this study underscore the importance of individualized rehabilitation protocols.

We review current knowledge about reading development and the origins of difficulties in learning to read. We distinguish between the processes involved in learning to decode print, and the processes involved in reading for meaning (reading comprehension). At a cognitive level, difficulties in learning to read appear to be predominantly caused by deficits in underlying oral language skills. The development of decoding skills appears to depend critically upon phonological language skills, and variations in phoneme awareness, letter–sound knowledge and rapid automatized naming each appear to be causally related to problems in learning to read. Reading comprehension difficulties in contrast appear to be critically dependent on a range of oral language comprehension skills (including vocabulary knowledge and grammatical, morphological and pragmatic skills).