Action video games and posterior parietal cortex neuromodulation enhance both attention and reading in adults with developmental dyslexia.

The impact of action video games on reading performance has been already demonstrated in individuals with and without neurodevelopmental disorders. The combination of action video games and posterior parietal cortex neuromodulation by a transcranial random noise stimulation could enhance brain plasticity, improving attentional control and reading skills also in adults with developmental dyslexia. In a double blind randomized controlled trial, 20 young adult nonaction video game players with developmental dyslexia were trained for 15 h with action video games. Half of the participants were stimulated with bilateral transcranial random noise stimulation on the posterior parietal cortex during the action video game training, whereas the others were in the placebo (i.e. sham) condition. Word text reading, pseudowords decoding, and temporal attention (attentional blink), as well as electroencephalographic activity during the attentional blink, were measured before and after the training. The action video game + transcranial random noise stimulation group showed temporal attention, word text reading, and pseudoword decoding enhancements and P300 amplitude brain potential changes. The enhancement in temporal attention performance was related with the efficiency in pseudoword decoding improvement. Our results demonstrate that the combination of action video game training with parietal neuromodulation increases the efficiency of visual attention deployment, probably reshaping goal-directed and stimulus-driven fronto-parietal attentional networks interplay in young adults with neurodevelopmental conditions.

Action video games normalise the phonemic awareness in pre-readers at risk for developmental dyslexia.

Action video-games (AVGs) could improve reading efficiency, enhancing not only visual attention but also phonological processing. Here we tested the AVG effects upon three consolidated language-based predictors of reading development in a sample of 79 pre-readers at-risk and 41 non-at-risk for developmental dyslexia. At-risk children were impaired in either phonemic awareness (i.e., phoneme discrimination task), phonological working memory (i.e., pseudoword repetition task) or rapid automatized naming (i.e., RAN of colours task). At-risk children were assigned to different groups by using an unequal allocation randomization: (1) AVG (n = 43), (2) Serious Non-Action Video Game (n = 11), (3) treatment-as-usual (i.e., speech therapy, n = 11), and (4) waiting list (n = 14). Pre- and post-training comparisons show that only phonemic awareness has a significantly higher improvement in the AVG group compared to the waiting list, the non-AVG, and the treatment-as-usual groups, as well as the combined active groups (n = 22). This cross-modal plastic change: (i) leads to a recovery in phonemic awareness when compared to the not-at-risk pre-readers; (ii) is present in more than 80% of AVG at-risk pre-readers, and; (iii) is maintained at a 6-months follow-up. The present findings indicate that this specific multisensory attentional training positively affects how phonemic awareness develops in pre-readers at risk for developmental dyslexia, paving the way for innovative prevention programs.

Prolonged neural encoding of visual information in autism.

Autism spectrum disorder (ASD) is associated with a hyper-focused visual attentional style, impacting higher-order social and affective domains. The understanding of such peculiarity can benefit from the use of multivariate pattern analysis (MVPA) of high-resolution electroencephalography (EEG) data, which has proved to be a powerful technique to investigate the hidden neural dynamics orchestrating sensory and cognitive processes. Here, we recorded EEG in typically developing (TD) children and in children with ASD during a visuo-spatial attentional task where attention was exogenously captured by a small (zoom-in) or large (zoom-out) cue in the visual field before the appearance of a target at different eccentricities. MVPA was performed both in the cue-locked period, to reveal potential differences in the modulation of the attentional focus, and in the target-locked period, to reveal potential cascade effects on stimulus processing. Cue-locked MVPA revealed that while in the TD group the pattern of neural activity contained information about the cue mainly before the target appearance, the ASD group showed a temporally sustained and topographically diffuse significant decoding of the cue neural response even after the target onset, suggesting a delayed extinction of cue-related neural activity. Crucially, this delayed extinction positively correlated with behavioral measures of attentional hyperfocusing. Results of target-locked MVPA were coherent with a hyper-focused attentional profile, highlighting an earlier and stronger decoding of target neural responses in small cue trials in the ASD group. The present findings document a spatially and temporally overrepresented encoding of visual information in ASD, which can constitute one of the main reasons behind their peculiar cognitive style.

The effects of bilateral posterior parietal cortex tRNS on reading performance.

According to established cognitive neuroscience knowledge based on studies on disabled and typically developing readers, reading is based on a dual-stream model in which a phonological-dorsal stream (left temporo-parietal and inferior frontal areas) processes unfamiliar words and pseudowords, whereas an orthographic-ventral stream (left occipito-temporal and inferior frontal areas) processes known words. However, correlational neuroimaging, causal longitudinal, training, and pharmacological studies have suggested the critical role of visuo-spatial attention in reading development. In a double blind, crossover within-subjects experiment, we manipulated the neuromodulatory effect of a short-term bilateral stimulation of posterior parietal cortex (PPC) by using active and sham tRNS during reading tasks in a large sample of young adults. In contrast to the dual-stream model predicting either no effect or a selective effect on the stimulated phonological-dorsal stream (as well as to a general multisensory effect on both reading streams), we found that only word-reading performance improved after active bilateral PPC tRNS. These findings demonstrate a direct neural connectivity between the PPC, controlling visuo-spatial attention, and the ventral stream for visual word recognition. These results support a neurobiological model of reading where performance of the orthographic-ventral stream is boosted by an efficient deployment of visuo-spatial attention from bilateral PPC stimulation.

Visuo-spatial attention deficit in children with reading difficulties.

Although developmental reading disorders (developmental dyslexia) have been mainly associated with auditory-phonological deficits, recent longitudinal and training studies have shown a possible causal role of visuo-attentional skills in reading acquisition. Indeed, visuo-attentional mechanisms could be involved in the orthographic processing of the letter string and the graphemic parsing that precede the grapheme-to-phoneme mapping. Here, we used a simple paper-and-pencil task composed of three labyrinths to measure visuo-spatial attention in a large sample of primary school children (n = 398). In comparison to visual search tasks requiring visual working memory, our labyrinth task mainly measures distributed and focused visuo-spatial attention, also controlling for sensorimotor learning. Compared to typical readers (n = 340), children with reading difficulties (n = 58) showed clear visuo-spatial attention impairments that appear not linked to motor coordination and procedural learning skills implicated in this paper and pencil task. Since visual attention is dysfunctional in about 40% of the children with reading difficulties, an efficient reading remediation program should integrate both auditory-phonological and visuo-attentional interventions.

Beyond Reading Modulation: Temporo-Parietal tDCS Alters Visuo-Spatial Attention and Motion Perception in Dyslexia.

Dyslexia is a neurodevelopmental disorder with an atypical activation of posterior left-hemisphere brain reading networks (i.e., temporo-occipital and temporo-parietal regions) and multiple neuropsychological deficits. Transcranial direct current stimulation (tDCS) is a tool for manipulating neural activity and, in turn, neurocognitive processes. While studies have demonstrated the significant effects of tDCS on reading, neurocognitive changes beyond reading modulation have been poorly investigated. The present study aimed at examining whether tDCS on temporo-parietal regions affected not only reading, but also phonological skills, visuo-spatial working memory, visuo-spatial attention, and motion perception in a polarity-dependent way. In a within-subjects design, ten children and adolescents with dyslexia performed reading and neuropsychological tasks after 20 min of exposure to Left Anodal/Right Cathodal (LA/RC) and Right Anodal/Left Cathodal (RA/LC) tDCS. LA/RC tDCS compared to RA/LC tDCS improved text accuracy, word recognition speed, motion perception, and modified attentional focusing in our group of children and adolescents with dyslexia. Changes in text reading accuracy and word recognition speed-after LA/RC tDCS compared to RA/LC-were related to changes in motion perception and in visuo-spatial working memory, respectively. Our findings demonstrated that reading and domain-general neurocognitive functions in a group of children and adolescents with dyslexia change following tDCS and that they are polarity-dependent.

Action Video Games Enhance Attentional Control and Phonological Decoding in Children with Developmental Dyslexia.

Reading acquisition is extremely difficult for about 5% of children because they are affected by a heritable neurobiological disorder called developmental dyslexia (DD). Intervention studies can be used to investigate the causal role of neurocognitive deficits in DD. Recently, it has been proposed that action video games (AVGs)-enhancing attentional control-could improve perception and working memory as well as reading skills. In a partial crossover intervention study, we investigated the effect of AVG and non-AVG training on attentional control using a conjunction visual search task in children with DD. We also measured the non-alphanumeric rapid automatized naming (RAN), phonological decoding and word reading before and after AVG and non-AVG training. After both video game training sessions no effect was found in non-alphanumeric RAN and in word reading performance. However, after only 12 h of AVG training the attentional control was improved (i.e., the set-size slopes were flatter in visual search) and phonological decoding speed was accelerated. Crucially, attentional control and phonological decoding speed were increased only in DD children whose video game score was highly efficient after the AVG training. We demonstrated that only an efficient AVG training induces a plasticity of the fronto-parietal attentional control linked to a selective phonological decoding improvement in children with DD.

Manual dexterity predicts phonological decoding speed in typical reading adults.

Manual dexterity and phonological decoding involve the posterior parietal cortex, which controls location coding for visually guided actions, as well as a large fronto-cerebellar network. We studied the relationship between manual dexterity and reading ability in adult typical readers. Two measurements of manual dexterity were collected to index the procedural learning effect. A linear regression model demonstrated that phonological short-term memory, manual dexterity at time 1 and procedural learning of manual dexterity predicted phonological decoding speed. Similar results were found when left-hand dexterity at time 1 and procedural learning dexterity were entered last. The better one's phonological decoding skill was, the less fluent their manual dexterity was, suggesting a recycle from object-location to letter-location coding. However, the greater the procedural learning, the faster phonological decoding was, suggesting that larger plasticity of object-location coding was linked to better letter-location coding. An independent role of the interhemispheric connections or of the right posterior parietal cortex is also suggested.

Local perception impairs the lexical reading route.

Human perception of a visual scene is hierarchically organized. Such rapid, albeit coarse, global processing allows people to create a useful context in which local details can be successively allocated. Lack of the typical hierarchical global-to-local visual processing is longitudinally predictive of future reading difficulties in pre-readers, which suggests that an atypical local perception can interfere with reading skill acquisition. Global and local Navon tasks were used to induce a transient perceptual priming before a reading-aloud task. We tested the effect of an atypical local perception on lexical and sublexical reading routes in typical adult readers. Local (vs. global) priming resulted in a slower phonological access to irregular, relative to regular, words. By contrast, pseudoword reading was not affected by local (vs. global) perceptual priming. Our findings demonstrate that, in typical adult readers, local priming impairs the fast processing of the letter string useful for lexical reading.

Caffeine improves text reading and global perception.

BACKGROUND: Reading is a unique human skill. Several brain networks involved in this complex skill mainly involve the left hemisphere language areas. Nevertheless, nonlinguistic networks found in the right hemisphere also seem to be involved in sentence and text reading. These areas do not deal with phonological information, but are involved in verbal and nonverbal pattern information processing. The right hemisphere is responsible for global processing of a scene, which is needed for developing reading skills. AIMS: Caffeine seems to affect global pattern processing specifically. Consequently, our aim was to discover if it could enhance text reading skill. METHODS: In two mechanistic studies (n=24 and n=53), we tested several reading skills, global and local perception, alerting, spatial attention and executive functions, as well as rapid automatised naming and phonological memory, using a double-blind, within-subjects, repeated-measures design in typical young adult readers. RESULTS: A single dose of 200 mg caffeine improved global processing, without any effect on local information processing, alerting, spatial attention and executive or phonological functions. This improvement in global processing was accompanied by faster text reading speed of meaningful sentences, whereas single word/pseudoword or pseudoword text reading abilities were not affected. These effects of caffeine on reading ability were enhanced by mild sleep deprivation. CONCLUSIONS: These findings show that a small quantity of caffeine could improve global processing and text reading skills in adults.

Is excessive visual crowding causally linked to developmental dyslexia?

For about 10% of children reading acquisition is extremely difficult because they are affected by a heritable neurobiological disorder called developmental dyslexia (DD), mainly associated to an auditory-phonological disorder. Visual crowding is a universal phenomenon that impairs the recognition of stimuli in clutter, such as a letter in a word or a word in a text. Several studies have shown an excessive crowding in individuals with DD, but the causal link between excessive crowding and DD is not yet clearly established. An excessive crowding might be, indeed, a simple effect of DD due to reduced reading experience. The results of five experiments in 181 children reveal that: (i) an excessive crowding only at unattended locations characterizes an unselected group of children with DD (Experiment 1); (ii) an extra-large spaced text increases reading accuracy by reducing crowding in an unselected group of children with DD (Experiment 2); (iii) efficient attentional action video game trainings reduce crowding and accelerate reading speed in two unselected groups of children with DD (Experiment 3 and 4), and; (iv) pre-reading crowding longitudinally predicts future poor readers (Experiment 5). Our results show multiple causal links between visual crowding and learning to read. These findings provide new insights for a more efficient remediation and prevention for DD.

Improving action video games abilities increases the phonological decoding speed and phonological short-term memory in children with developmental dyslexia.

Learning to read is extremely difficult for about 10% of the children because they are affected by a heritable neurobiological disorder called developmental dyslexia (DD). The causal role of cognitive deficits typically associated to DD can be investigated through intervention studies. It has been demonstrated that visual-attention and reading speed could be simultaneously improved by using action video game (AVG) training both in shallow and deep alphabetic orthographies. Here, in a clinical study we showed that after this general-domain behavioral intervention both the phonological decoding speed and phonological short-term memory were increased only in DD children in which their video game score was improved. These findings confirm that an AVG training enhances the efficiency of both visual and auditory processing. The plasticity of the multi-sensory attentional network could explain the reading and reading-related improvements induced by the AVG training in children with DD.

A different vision of dyslexia: Local precedence on global perception.

Individuals perceive the wor(l)d hierarchically. Firsty, the global visual scene is processed by the right hemisphere, and later, the local features are perceived by the left hemisphere. Based on this hierarchical analysis, humans evolved unique communication ability: reading. However, for about 10% of people reading acquisition is extremely difficult, they are affected by a heritable neurodevelopmental disorder called dyslexia. Differences in perceiving the wor(l)d might be one of the causes of reading disabilities. Here we show multiple causal links between the global before local perception and learning to read. Five behavioral experiments in 353 children reveal that: (i) a local before global perception characterizes three independent groups of unselected children with dyslexia; (ii) two global before local perception trainings improve reading skills in children with dyslexia; and stringently (iii) pre-reading local before global perception longitudinally predicts future poor readers. Challenging the uni-causal and left-lateralized phonological explanation of dyslexia, our results demonstrate that learning to read depends also on an efficient right neural network for the global analysis of the visual scene. These results provide new insights in learning strategies and pave the way for early identification and possible prevention programs.

Action video games improve reading abilities and visual-to-auditory attentional shifting in English-speaking children with dyslexia.

Dyslexia is characterized by difficulties in learning to read and there is some evidence that action video games (AVG), without any direct phonological or orthographic stimulation, improve reading efficiency in Italian children with dyslexia. However, the cognitive mechanism underlying this improvement and the extent to which the benefits of AVG training would generalize to deep English orthography, remain two critical questions. During reading acquisition, children have to integrate written letters with speech sounds, rapidly shifting their attention from visual to auditory modality. In our study, we tested reading skills and phonological working memory, visuo-spatial attention, auditory, visual and audio-visual stimuli localization, and cross-sensory attentional shifting in two matched groups of English-speaking children with dyslexia before and after they played AVG or non-action video games. The speed of words recognition and phonological decoding increased after playing AVG, but not non-action video games. Furthermore, focused visuo-spatial attention and visual-to-auditory attentional shifting also improved only after AVG training. This unconventional reading remediation program also increased phonological short-term memory and phoneme blending skills. Our report shows that an enhancement of visuo-spatial attention and phonological working memory, and an acceleration of visual-to-auditory attentional shifting can directly translate into better reading in English-speaking children with dyslexia.

The neural origins of visual crowding as revealed by event-related potentials and oscillatory dynamics.

Visual crowding is the difficulty in perceiving a target in the presence of nearby flankers. Most neurophysiological studies of crowding employed functional neuroimaging, but because of its low temporal resolution, no definitive answer can be given to the question: is crowding arising at the earliest or at later stages of visual processing? Here, we used a classic letters crowding paradigm in combination with electroencephalography (EEG). We manipulated the critical space between peripheral target and flankers, while ensuring a proper control of basic stimulus characteristics. Analyses were focused on event-related potentials (ERPs) and oscillatory activity in the alpha (8-12 Hz), beta (15-30 Hz) and gamma (30-80 Hz) bands. At the ERP level, we found that the first sign of a crowding-induced modulation of EEG activity was a suppression of the N1 component. Oscillatory analysis revealed an early stimulus-evoked gamma enhancement and a later alpha reduction that, however, were not influenced by the amount of crowding. Importantly, reduction in the beta band reflected the amount of crowding (i.e., stronger reduction for strong relative to mid crowding condition) and correlated with individual behavioral performance. Collectively, these findings show that crowding for complex objects emerges at later stages of visual processing, possibly as a result of large-scale network interaction.

Carbonic Anhydrase 9 mRNA/microRNA34a Interplay in Hypoxic Human Mammospheres.

The hypoxic environment is a crucial component of the cancer stem cell niche and it is capable of eliciting stem cell features in cancer cells. We previously reported that SNAI2 up-regulates the expression of Carbonic Anhydrase iso-enzyme 9 (CA9) in hypoxic MCF7 cells. Here we show that SNAI2 down-regulates miR34a expression in hypoxic MCF7 cell-derived mammospheres. Next, we report on the capability of miR34a to decrease CA9 mRNA stability and CA9 protein expression. We also convey that the over-expression of cloned CA9-mRNA-3'UTR increases the mRNA half-life and protein levels of two miR34a targets JAGGED1 and NOTCH3. The data here reported shows that the SNAI2-dependent down-regulation of miR34a substantially contributes to the post-transcriptional up-regulation of CA9, and that CA9-mRNA-3'UTR acts as an endogenous microRNA sponge. We conclude that CA9/miR34 interplay shares in the hypoxic regulation of mammospheres and therefore, may play a relevant role in the hypoxic breast cancer stem cell niche.

Towards a unitary perspective between post-traumatic stress disorder and substance use disorder. Heroin use disorder as case study.

BACKGROUND: Genetic, neurobiological, environmental and psychosocial mechanisms have received considerable attention in exploring the mechanisms that underlie comorbid PTSD and SUD. PTSD and SUD are not necessarily linked by a causal relationship, as the self-medication hypothesis had supposed. They might, in fact, both be caused by a third factor that predisposes these subjects to develop the two disorders (so allowing a unitary perspective). METHODS: Using a conceptualization of the PTSD spectrum, we studied the PTSD-SUD unitary perspective by testing the correlation between severity of heroin addiction, dose of opioid medication and severity of PTSD spectrum in 82 methadone-treated, heroin-dependent patients. RESULTS: Canonical correlation analysis (Wilks Lambda=0.125F=1.41 p=0.014), univariate and multivariate comparisons between subgroups, identified on the basis of addiction severity, showed a highly positive correlation between the PTSD spectrum and the severity of heroin addiction. In addition, negative correlations were found between PTSD spectrum severity and methadone dose (r=0.225; p=0.042). CONCLUSIONS: This strength and breadth of the correlations encourage us to move towards a unified vision of the two disorders.

PPARγ and RXR ligands disrupt the inflammatory cross-talk in the hypoxic breast cancer stem cells niche.

Cancer stem cells (CSCs) are affected by the local micro-environment, the niche, in which inflammatory stimuli and hypoxia act as steering factors. Here, two nuclear receptors (NRs) agonists, i.e. pioglitazone (PGZ), a ligand of peroxisome proliferator activated receptor-γ, and 6-OH-11-O-hydroxyphenanthrene (IIF), a ligand of retinoid X receptors, were investigated for their capability to interference with the cross-talk between breast CSCs and the niche compartment. We found that IIF potentiates the ability of PGZ to hamper the mammospheres-forming capability of human breast tumours and MCF7 cancer cells, reducing the expression of CSCs regulatory genes (Notch3, Jagged1, SLUG, Interleukin-6, Apolipoprotein E, Hypoxia inducible factor-1α and Carbonic anhydrase IX). Notably, these effects are not observed in normal-MS obtained from human breast tissue. Importantly, NRs agonists abolish the capability of hypoxic MCF7 derived exosomes to induce a pro-inflammatory phenotype in mammary glands fibroblasts. Moreover, NRs agonist also directly acts on breast tumour associated fibroblasts to downregulate nuclear factor-κB pathway and metalloproteinases (MMP2 and MMP9) expression and activity. In conclusion, NRs agonists disrupt the inflammatory cross-talk of the hypoxic breast CSCs niche.

Glutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation.

Busulfan liver metabolism depends on glutathione, a crucial mediator of cellular and systemic stress. Here we investigated 40 polymorphisms at 27 loci involved in hepatic glutathione homeostasis, with the aim of testing their impact on the clinical outcome of 185 busulfan-conditioned allogeneic transplants. GSTA2 S112T serine allele homozygosity is an independent prognostic factor for poorer survival (RR=2.388), for increased any time- and 100-day transplant-related mortality (RR=4.912 and RR=5.185, respectively). The genotype also predicts a wider busulfan area under the concentration-time curve (1214.36 ± 570.06 vs. 838.10 ± 282.40 mMol*min) and higher post-transplant bilirubin serum levels (3.280 ± 0.422 vs. 1.874+0.197 mg/dL). In vitro, busulfan elicits pro-inflammatory activation (increased NF-KappaB activity and interleukin-8 expression) in human hepatoma cells. At the same time, the drug down-regulates a variety of genes involved in bilirubin liver clearance: constitutive androstane receptor, multidrug resistance-associated protein, solute carrier organic anion transporters, and even GSTA2. It is worthy of note that GSTA2 also acts as an intra-hepatic bilirubin binding protein. These data underline the prognostic value of GSTA2 genetic variability in busulfan-conditioned allotransplants and suggest a patho-physiological model in which busulfan-induced inflammation leads to the impairment of post-transplant bilirubin metabolism.

Beta-catenin/HuR post-transcriptional machinery governs cancer stem cell features in response to hypoxia.

Hypoxia has been long-time acknowledged as major cancer-promoting microenvironment. In such an energy-restrictive condition, post-transcriptional mechanisms gain importance over the energy-expensive gene transcription machinery. Here we show that the onset of hypoxia-induced cancer stem cell features requires the beta-catenin-dependent post-transcriptional up-regulation of CA9 and SNAI2 gene expression. In response to hypoxia, beta-catenin moves from the plasma membrane to the cytoplasm where it binds and stabilizes SNAI2 and CA9 mRNAs, in cooperation with the mRNA stabilizing protein HuR. We also provide evidence that the post-transcriptional activity of cytoplasmic beta-catenin operates under normoxia in basal-like/triple-negative breast cancer cells, where the beta-catenin knockdown suppresses the stem cell phenotype in vitro and tumor growth in vivo. In such cells, we unravel the generalized involvement of the beta-catenin-driven machinery in the stabilization of EGF-induced mRNAs, including the cancer stem cell regulator IL6. Our study highlights the crucial role of post-transcriptional mechanisms in the maintenance/acquisition of cancer stem cell features and suggests that the hindrance of cytoplasmic beta-catenin function may represent an unprecedented strategy for targeting breast cancer stem/basal-like cells.