Enhancing attention in children using an integrated cognitive-physical videogame: A pilot study.

Inattention can negatively impact several aspects of a child's life, including at home and school. Cognitive and physical interventions are two promising non-pharmaceutical approaches used to enhance attention abilities, with combined approaches often being marketed to teachers, therapists, and parents typically without research validation. Here, we assessed the feasibility of incorporating an integrated, cognitive-physical, closed-loop video game (body-brain trainer or 'BBT') as an after-school program, and also evaluated if there were attention benefits following its use. Twenty-two children (7-12 years of age) with a range of attention abilities were recruited to participate in this proof of concept, single-arm, longitudinal study (24 sessions over 8 weeks, ~30 min/day). We interrogated attention abilities through a parent survey of their child's behaviors, in addition to objective performance-based and neural measures of attention. Here we observed 95% compliance as well as, significant improvements on the parent-based reports of inattention and on cognitive tests and neural measures of attention that were comparable in scale to previous work. Exploratory measures of other cognitive control abilities and physical fitness also showed similar improvement, with exploratory evaluation of retained benefits on the primary attention-related outcomes being present 1-year later. Lastly, there was no correlation between the baseline parent-rated inattention score and the improvement on the primary task-based measures of attention, suggesting that intervention-based benefits were not solely attained by those who stood the most to gain. These pilot findings warrant future research to replicate and extend these findings.

Canalization and plasticity in psychopathology.

This theoretical article revives a classical bridging construct, canalization, to describe a new model of a general factor of psychopathology. To achieve this, we have distinguished between two types of plasticity, an early one that we call 'TEMP' for 'Temperature or Entropy Mediated Plasticity', and another, we call 'canalization', which is close to Hebbian plasticity. These two forms of plasticity can be most easily distinguished by their relationship to 'precision' or inverse variance; TEMP relates to increased model variance or decreased precision, whereas the opposite is true for canalization. TEMP also subsumes increased learning rate, (Ising) temperature and entropy. Dictionary definitions of 'plasticity' describe it as the property of being easily shaped or molded; TEMP is the better match for this. Importantly, we propose that 'pathological' phenotypes develop via mechanisms of canalization or increased model precision, as a defensive response to adversity and associated distress or dysphoria. Our model states that canalization entrenches in psychopathology, narrowing the phenotypic state-space as the agent develops expertise in their pathology. We suggest that TEMP - combined with gently guiding psychological support - can counter canalization. We address questions of whether and when canalization is adaptive versus maladaptive, furnish our model with references to basic and human neuroscience, and offer concrete experiments and measures to test its main hypotheses and implications. This article is part of the Special Issue on "National Institutes of Health Psilocybin Research Speaker Series".

Training sensory signal-to-noise resolution in children with ADHD in a global mental health setting.

Children with attention deficit/hyperactivity disorder (ADHD) have impaired focus on goal-relevant signals and fail to suppress goal-irrelevant distractions. To address both these issues, we developed a novel neuroplasticity-based training program that adaptively trains the resolution of challenging sensory signals and the suppression of progressively more challenging distractions. We evaluated this sensory signal-to-noise resolution training in a small sample, global mental health study in Indian children with ADHD. The children trained for 30 h over 6 months in a double-blind, randomized controlled trial. Training completers showed steady and significant improvements in ADHD-associated behaviors from baseline to post training relative to controls, and benefits sustained in a 6-month follow-up. Post-training cognitive assessments showed significant positive results for response inhibition and Stroop interference tests in training completers vs controls, while measures of sustained attention and short-term memory showed nonsignificant improvement trends. Further, training-driven improvements in distractor suppression correlated with the improved ADHD symptoms. This initial study suggests utility of signal-to-noise resolution training for children with ADHD; it emphasizes the need for further research on this intervention and substantially informs the design of a larger trial.

Expectations of Task Demands Dissociate Working Memory and Long-Term Memory Systems.

Many aspects of the complex relationship between working memory (WM) and long-term memory (LTM) remain unclear. Here, we manipulated task demands on a brief delayed-recognition paradigm to reveal behavioral and neural dissociations between these systems. Variations from a Baseline task included 3 challenges: increased delay duration, distraction during maintenance, and more closely matched memory probes, which were presented in behavioral experiments and during functional magnetic resonance imaging. Each of the challenges resulted in a significant decline in WM accuracy, and interestingly, a concurrent improvement in incidental LTM. Neural data revealed that, in task blocks, when participants anticipated, and then experienced, increased demands, they engaged medial temporal lobe (MTL) regions more during both the encoding and delay periods. Overall, these results indicate that distinct memory systems are recruited based on anticipated demands of a memory task, and MTL involvement underlies the observed dissociation between WM and LTM performance.

Cross-species approaches to cognitive neuroplasticity research.

Neuroplasticity studies investigate the neural mechanisms that support learning-induced changes in cognition and behavior. These studies are performed in both experimental animals and humans across development from childhood to aging. Here, we review select recent studies that have sought to combine both animal and human neuroplasticity research within the same study. In investigating the same cognitive/behavioral functions in parallel in animals and humans, these studies take advantage of complementary neuroscience research methods that have been established for each species. In animals, these methods include investigations of genetic and molecular biomarker expression and micro-scale electrophysiology in single neurons in vivo or in brain slices. In humans, these studies assess macro-scale neural network dynamics using neuroimaging methods including EEG (electroencephalography) and functional and structural MRI (magnetic resonance imaging). Thus, by combining these diverse and complementary methodologies cross-species studies have the unique ability to bridge molecular, systems and cognitive neuroscience research. Additionally, they serve a vital role in translational neuroscience, providing a direct bridge between animal models and human neuropsychiatric disorders. Comprehensive cross-species understanding of neural mechanisms at multiple scales of resolution and how these neural dynamics relate to behavioral outcomes, then serve to inform development and optimization of treatment strategies.

Network dynamics predict improvement in working memory performance following donepezil administration in healthy young adults.

Attentional selection in the context of goal-directed behavior involves top-down modulation to enhance the contrast between relevant and irrelevant stimuli via enhancement and suppression of sensory cortical activity. Acetylcholine (ACh) is believed to be involved mechanistically in such attention processes. The objective of the current study was to examine the effects of donepezil, a cholinesterase inhibitor that increases synaptic levels of ACh, on the relationship between performance and network dynamics during a visual working memory (WM) task involving relevant and irrelevant stimuli. Electroencephalogram (EEG) activity was recorded in 14 healthy young adults while they performed a selective face/scene working memory task. Each participant received either placebo or donepezil (5mg, orally) on two different visits in a double-blinded study. To investigate the effects of donepezil on brain network dynamics we utilized a novel EEG-based Brain Network Activation (BNA) analysis method that isolates location-time-frequency interrelations among event-related potential (ERP) peaks and extracts condition-specific networks. The activation level of the network modulated by donepezil, reflected in terms of the degree of its dynamical organization, was positively correlated with WM performance. Further analyses revealed that the frontal-posterior theta-alpha sub-network comprised the critical regions whose activation level correlated with beneficial effects on cognitive performance. These results indicate that condition-specific EEG network analysis could potentially serve to predict beneficial effects of therapeutic treatment in working memory.

Video game training enhances cognitive control in older adults.

Cognitive control is defined by a set of neural processes that allow us to interact with our complex environment in a goal-directed manner. Humans regularly challenge these control processes when attempting to simultaneously accomplish multiple goals (multitasking), generating interference as the result of fundamental information processing limitations. It is clear that multitasking behaviour has become ubiquitous in today's technologically dense world, and substantial evidence has accrued regarding multitasking difficulties and cognitive control deficits in our ageing population. Here we show that multitasking performance, as assessed with a custom-designed three-dimensional video game (NeuroRacer), exhibits a linear age-related decline from 20 to 79 years of age. By playing an adaptive version of NeuroRacer in multitasking training mode, older adults (60 to 85 years old) reduced multitasking costs compared to both an active control group and a no-contact control group, attaining levels beyond those achieved by untrained 20-year-old participants, with gains persisting for 6 months. Furthermore, age-related deficits in neural signatures of cognitive control, as measured with electroencephalography, were remediated by multitasking training (enhanced midline frontal theta power and frontal-posterior theta coherence). Critically, this training resulted in performance benefits that extended to untrained cognitive control abilities (enhanced sustained attention and working memory), with an increase in midline frontal theta power predicting the training-induced boost in sustained attention and preservation of multitasking improvement 6 months later. These findings highlight the robust plasticity of the prefrontal cognitive control system in the ageing brain, and provide the first evidence, to our knowledge, of how a custom-designed video game can be used to assess cognitive abilities across the lifespan, evaluate underlying neural mechanisms, and serve as a powerful tool for cognitive enhancement.

Neural indices of improved attentional modulation over middle childhood.

The ability to control the focus of attention relies on top-down modulation of cortical activity in areas involved in stimulus processing, and this ability is critical for maintaining items in working memory in the presence of distraction. Prior research demonstrates that children are less capable of focusing attention, relative to adults, and that this ability develops significantly during middle childhood. Here, using fMRI and a face/scene working memory task adapted from Gazzaley and colleagues (Gazzaley et al. 2005), we compared top-down modulation in fifteen children (aged 8-13) and fifteen young adults (aged 19-26). Replicating prior results, in young adults, attention to scenes modulated activity in the parahippocampal place area (PPA). In addition, modulation of PPA activity increased as a function of age in children. PPA activity was also related to performance in this group, on the working memory task as well on a test of subsequent memory. Dorsolateral PFC also demonstrated increasing task-specific activation, as a function of age, in children. The present findings support the idea that children's reduced ability to maintain items in working memory, especially in the presence of distraction, is driven by weaker top-down modulation of activity in areas involved in stimulus processing.

Dendritic spine plasticity in hippocampus.

Most excitatory input in the hippocampus and cerebral cortex impinges on dendritic spines. Alterations in dendritic spine density or shape are suspected to be morphological manifestations of changes in physiology or behavior. The links between spine plasticity and physiological responses have probably been best studied in the hippocampus in the context of changes in the circulating levels of steroid hormones or long-term potentiation. Here we review and present data which indicate that both the age of the preparation and the timing of the analysis can dramatically effect the results obtained. Collectively the data suggest that different cellular and morphological strategies may be utilized at different ages and under different circumstances to effect similar physiological responses or behaviors.

Attenuated lesion-induced N-methyl-D-aspartate receptor (NMDAR) plasticity in the dentate gyrus of aged rats following perforant path lesions.

Young animals demonstrate a significant upregulation of N-methyl-d-aspartate receptor 1 (NMDAR1) in the outer molecular layer (OML) of the dentate gyrus following a total unilateral ablation of the perforant path, and this response presumably facilitates a degree of functional recovery. Aged animals have attenuated responses to lesion-induced synaptic plasticity as compared with young subjects, and in fact display decreased synaptogenesis and sprouting following a unilateral perforant path lesion. To investigate the response of NMDAR1 in the dentate gyrus of aged animals to perforant path ablation, 24-month-old Sprague-Dawley male rats received a unilateral knife cut of the angular bundle. Our results demonstrated that aged animals displayed a blunted response to lesion-induced NMDA receptor-mediated plasticity, suggesting that aged animals have an impaired ability to respond to deafferentation through an increase in NMDA receptor levels in the deafferented zone.

Preserved number of entorhinal cortex layer II neurons in aged macaque monkeys.

The perforant path, which consists of the projection from the layer II neurons of the entorhinal cortex to the outer molecular layer of the dentate gyrus, is a critical circuit involved in learning and memory formation. Accordingly, disturbances in this circuit may contribute to age-related cognitive deficits. In a previous study, we demonstrated a decrease in N-methyl-D-aspartate receptor subunit 1 immunofluorescence intensity in the outer molecular layer of aged macaque monkeys. In this study, we used the optical fractionator, a stereological method, to determine if a loss of layer II neurons occurred in the same animals in which the N-methyl-D-aspartate receptor subunit 1 alteration was observed. Our results revealed no significant differences in the number of layer II neurons between juvenile, young adult, and aged macaque monkeys. These results suggest that the circuit-specific decrease in N-methyl-D-aspartate receptor subunit 1 reported previously occurs in the absence of structural compromise of the perforant path, and thus may be linked to an age-related change in the physiological properties of this circuit.

Differential subcellular regulation of NMDAR1 protein and mRNA in dendrites of dentate gyrus granule cells after perforant path transection.

Unilateral transection of the excitatory perforant path results in the acute deafferentation of a segregated zone on the distal dendrites of hippocampal dentate gyrus granule cells (i.e., outer molecular layer), followed by sprouting, reactive synaptogenesis, and a return of physiological and behavioral function. To investigate cellular mechanisms underlying NMDA receptor plasticity in response to such extensive synaptic reorganization, we quantitatively evaluated changes in intensity levels of NMDAR1 immunofluorescence and NMDAR1 mRNA hybridization within subcellular compartments of dentate gyrus granule cells 2, 5, and 9 d after perforant path lesions. There were no significant changes in either measure at 2 d postlesion. However, at 5 and 9 d postlesion, during the period of axonal sprouting and synaptogenesis, there was an increase in NMDAR1 immunolabeling that was restricted to the dendritic segments of the denervated outer molecular layer and the granule cell somata. In contrast, NMDAR1 mRNA levels at 5 and 9 d postlesion increased throughout the full extent of the molecular layer, including both denervated and nondenervated segments of granule cell dendrites. These findings reveal that NMDAR1 mRNA is one of a limited population of mRNAs that is transported into dendrites and further suggest that in response to terminal proliferation and sprouting, increased mRNA transport occurs throughout the full dendritic extent, whereas increased local protein synthesis is restricted to denervated regions of the dendrites whose afferent activity is perturbed. These results begin to elucidate the dynamic postsynaptic subcellular regulation of receptor subunits associated with synaptic plasticity after denervation.

Synaptic distribution of the AMPA-GluR2 subunit and its colocalization with calcium-binding proteins in rat cerebral cortex: an immunohistochemical study using a GluR2-specific monoclonal antibody.

Due to its role as the dominant AMPA receptor subunit in respect to regulation of calcium permeability, information on the neuronal localization of GluR2 is of particular importance, yet has been hampered by the lack of a GluR2-specific antibody. Monoclonal antibodies were raised against the putative N-terminal portion (amino acids 175--430) of GluR2, using the fusion protein linked to trpE as an antigen. Western blot analysis and immunocytochemistry of transiently transfected human embryonic kidney 293 cells unambiguously confirmed the specificity of monoclonal antibody 6C4 for GluR2, which did not recognize or cross-react with any other AMPA/Kainate GluR subunits expressed. 6C4 was used in immunohistochemical studies to characterize the regional, cellular, and subcellular distribution of the GluR2 subunit at the light and electron microscopic levels in rat hippocampus and somatosensory cortex and in colocalization studies with the three calcium-binding proteins: parvalbumin, calbindin, and calretinin. GluR2 was widely distributed in both pyramidal cells and interneurons. Asymmetric synapses were labeled on both spines and small dendritic shafts. In contrast to previous reports, our double labeling studies using monoclonal antibody 6C4 with polyclonal antisera against calcium-binding proteins demonstrated that 84--97% of parvalbumin and calbindin-immunoreactive and 45--66% of the calretinin-immunoreactive interneurons in CA1 and somatosensory cortex also contain GluR2. These data have important implications regarding heterogeneity in calcium permeability of AMPA receptors across cell types in neocortex and hippocampus, as well as for differential vulnerability to excitotoxic injury.

Differential regulation of NMDAR1 mRNA and protein by estradiol in the rat hippocampus.

Estradiol treatment increases the number of NMDA receptor binding sites, and changes evoked synaptic currents in a manner consistent with a steroid-induced functional enhancement of NMDA receptors in rat hippocampus. In this study, we investigate the cellular mechanisms of estradiol-induced NMDA receptor regulation at the protein and mRNA levels in ovariectomized rats treated with ovarian steroids using immunocytochemical and in situ hybridization techniques. Confocal laser scanning microscopy was used to quantify alterations in immunofluorescence intensity levels of NMDAR1 subunit proteins within neuronal somata and dendrites of discrete hippocampal fields, whereas in parallel, in situ hybridization was used to examine NMDAR1 mRNA levels in corresponding hippocampal regions. The data indicate that estradiol treatment in ovariectomized rats significantly increases immunofluorescence intensity levels in comparison with nonsteroid treated ovariectomized rats within the somata and dendrites of CA1 pyramidal cells and, to a lesser extent, within the granule cell somata of the dentate gyrus. In contrast, such alterations in immunofluorescence intensity occur without concomitant changes in mRNA hybridization levels. Thus, these data suggest that estradiol modulates NMDA receptor function via post-transcriptional regulation of the NMDAR1 subunit protein. The increase in immunofluorescence intensity may reflect an increase in the concentration of the subunit protein, which could account for estrogen-induced changes in pharmacological and physiological properties of the NMDA receptor.

Circuit-specific alterations of N-methyl-D-aspartate receptor subunit 1 in the dentate gyrus of aged monkeys.

Age-associated memory impairment occurs frequently in primates. Based on the established importance of both the perforant path and N-methyl-D-aspartate (NMDA) receptors in memory formation, we investigated the glutamate receptor distribution and immunofluorescence intensity within the dentate gyrus of juvenile, adult, and aged macaque monkeys with the combined use of subunit-specific antibodies and quantitative confocal laser scanning microscopy. Here we demonstrate that aged monkeys, compared to adult monkeys, exhibit a 30.6% decrease in the ratio of NMDA receptor subunit 1 (NMDAR1) immunofluorescence intensity within the distal dendrites of the dentate gyrus granule cells, which receive the perforant path input from the entorhinal cortex, relative to the proximal dendrites, which receive an intrinsic excitatory input from the dentate hilus. The intradendritic alteration in NMDAR1 immunofluorescence occurs without a similar alteration of non-NMDA receptor subunits. Further analyses using synaptophysin as a reflection of total synaptic density and microtubule-associated protein 2 as a dendritic structural marker demonstrated no significant difference in staining intensity or area across the molecular layer in aged animals compared to the younger animals. These findings suggest that, in aged monkeys, a circuit-specific alteration in the intradendritic concentration of NMDAR1 occurs without concomitant gross structural changes in dendritic morphology or a significant change in the total synaptic density across the molecular layer. This alteration in the NMDA receptor-mediated input to the hippocampus from the entorhinal cortex may represent a molecular/cellular substrate for age-associated memory impairments.