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The purpose of this review is to summarize how our perspective about the neuroscience of brain plasticity, informed by perceptual, experimental, and cognitive psychology, has led to the designs of a new class of therapeutic tools developed to drive functionally distorted and damaged brains in corrective directions. How does neuroplasticity science inform us about optimal therapeutic program designs? How do we apply that science, using modern technology, to drive neurological changes that address both the neurobehavioral distortions and the resulting behavioral deficits that are expressed in specific neurological and psychiatric disorders? By what strategies can we achieve the strongest and most complete rehabilitative corrections? These are questions that we have extensively explored in our efforts to establish new medical applications of neuroplasticity-based therapeutics. Here, we summarize the state of this rapidly emerging area of translational neuroscience, beginning with an explanation of the scientific premises and strategies, then describing their implementation in therapeutic software to address two human illnesses: the treatment of social cognition deficits in chronic schizophrenia and in autism; and the amelioration of age-related functional decline using strategies designed to delay the onset of--and potentially prevent--Alzheimer's Disease and related causes of dementia in aging.
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PMID:Principles of neuroplasticity-based rehabilitation. 2430 54

Neuronal Per-Arnt-Sim homology (PAS) Factor 4 (NPAS4) is a neuronal activity-dependent transcription factor which heterodimerises with ARNT2 to regulate genes involved in inhibitory synapse formation. NPAS4 functions to maintain excitatory/inhibitory balance in neurons, while mouse models have shown it to play roles in memory formation, social interaction and neurodegeneration. NPAS4 has therefore been implicated in a number of neuropsychiatric or neurodegenerative diseases which are underpinned by defects in excitatory/inhibitory balance. Here we have explored a broad set of non-synonymous human variants in NPAS4 and ARNT2 for disruption of NPAS4 function. We found two variants in NPAS4 (F147S and E257K) and two variants in ARNT2 (R46W and R107H) which significantly reduced transcriptional activity of the heterodimer on a luciferase reporter gene. Furthermore, we found that NPAS4.F147S was unable to activate expression of the NPAS4 target gene BDNF due to reduced dimerisation with ARNT2. Homology modelling predicts F147 in NPAS4 to lie at the dimer interface, where it appears to directly contribute to protein/protein interaction. We also found that reduced transcriptional activation by ARNT2 R46W was due to disruption of nuclear localisation. These results provide insight into the mechanisms of NPAS4/ARNT dimerisation and transcriptional activation and have potential implications for cognitive phenotypic variation and diseases such as autism, schizophrenia and dementia.
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PMID:Human variants in the neuronal basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) transcription factor complex NPAS4/ARNT2 disrupt function. 2446 93

von Economo's neurons (VENs) are large, spindle-shaped projection neurons in layer V of the frontoinsular (FI) cortex, and the anterior cingulate cortex. During human ontogenesis, the VENs can first be differentiated at late stages of gestation, and increase in number during the first eight postnatal months. VENs have been identified in humans, chimpanzee, bonobos, gorillas, orangutan and, more recently, in the macaque. Their distribution in great apes seems to correlate with human-like social cognitive abilities and self-awareness. VENs are also found in whales, in a number of different cetaceans, and in the elephant. This phylogenetic distribution may suggest a correlation among the VENs, brain size and the "social brain." VENs may be involved in the pathogenesis of specific neurological and psychiatric diseases, such as autism, callosal agenesis and schizophrenia. VENs are selectively affected in a behavioral variant of frontotemporal dementia in which empathy, social awareness and self-control are seriously compromised, thus associating VENs with the social brain. However, the presence of VENs has also been related to special functions such as mirror self-recognition. Areas containing VENs have been related to motor awareness or sense-of-knowing, discrimination between self and other, and between self and the external environment. Along this line, VENs have been related to the "global Workspace" architecture: in accordance the VENs have been correlated to emotional and interoceptive signals by providing fast connections (large axons = fast communication) between salience-related insular and cingulate and other widely separated brain areas. Nevertheless, the lack of a characterization of their physiology and anatomical connectivity allowed only to infer their functional role based on their location and on the functional magnetic resonance imaging data. The recent finding of VENs in the anterior insula of the macaque opens the way to new insights and experimental investigations.
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PMID:Evolutionary appearance of von Economo's neurons in the mammalian cerebral cortex. 2467 57

A close association between early-life experience and cognitive and emotional outcomes is found in humans. In experimental models, early-life experience can directly influence a number of brain functions long-term. Specifically, and often in concert with genetic background, experience regulates structural and functional maturation of brain circuits and alters individual neuronal function via large-scale changes in gene expression. Because adverse experience during sensitive developmental periods is often associated with neuropsychiatric disease, there is an impetus to create realistic models of distinct early-life experiences. These can then be used to study causality between early-life experiential factors and cognitive and emotional outcomes, and to probe the underlying mechanisms. Although chronic early-life stress has been linked to the emergence of emotional and cognitive disorders later in life, most commonly used rodent models of involve daily maternal separation and hence intermittent early-life stress. We describe here a naturalistic and robust chronic early-life stress model that potently influences cognitive and emotional outcomes. Mice and rats undergoing this stress develop structural and functional deficits in a number of limbic-cortical circuits. Whereas overt pathological memory impairments appear during adulthood, emotional and cognitive vulnerabilities emerge already during adolescence. This naturalistic paradigm, widely adopted around the world, significantly enriches the repertoire of experimental tools available for the study of normal brain maturation and of cognitive and stress-related disorders including depression, autism, post-traumatic stress disorder, and dementia.
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PMID:Naturalistic rodent models of chronic early-life stress. 2491 Jan 69

Creativity is commonly thought of as a positive advance for society that transcends the status quo knowledge. Humans display an inordinate capacity for it in a broad range of activities, with art being only one. Most work on creativity's neural substrates measures general creativity, and that is done with laboratory tasks, whereas specific creativity in art is gleaned from acquired brain damage, largely in observing established visual artists, and some in visual de novo artists (became artists after the damage). The verb "to create" has been erroneously equated with creativity; creativity, in the classic sense, does not appear to be enhanced following brain damage, regardless of etiology. The turning to communication through art in lieu of language deficits reflects a biological survival strategy. Creativity in art, and in other domains, is most likely dependent on intact and healthy knowledge and semantic conceptual systems, which are represented in several pathways in the cortex. It is adversely affected when these systems are dysfunctional, for congenital reasons (savant autism) or because of acquired brain damage (stroke, dementia, Parkinson's), whereas inherent artistic talent and skill appear less affected. Clues to the neural substrates of general creativity and specific art creativity can be gleaned from considering that art is produced spontaneously mainly by humans, that there are unique neuroanatomical and neurofunctional organizations in the human brain, and that there are biological antecedents of innovation in animals.
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PMID:Creativity, brain, and art: biological and neurological considerations. 2491 7

A growing body of evidence suggests that the amygdala is central to handling the demands of complex social life in primates. In this paper, we synthesize extant anatomical and functional data from rodents, monkeys, and humans to describe the topography of three partially distinct large-scale brain networks anchored in the amygdala that each support unique functions for effectively managing social interactions and maintaining social relationships. These findings provide a powerful componential framework for parsing social behavior into partially distinct neural underpinnings that differ among healthy people and disintegrate or fail to develop in neuropsychiatric populations marked by social impairment, such as autism, antisocial personality disorder, and frontotemporal dementia.
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PMID:The amygdala as a hub in brain networks that support social life. 2515 30

Social cognition-the basis of all communicative and otherwise interpersonal relationships-is embedded in specific contextual circumstances which shape intrinsic meanings. This domain is compromised in the autism spectrum disorders (ASDs), including Asperger's syndrome (AS) (DSM-V). However, the few available reports of social cognition skills in adults with AS have largely neglected the effects of contextual factors. Moreover, previous studies on this population have also failed to simultaneously (a) assess multiple social cognition domains, (b) examine executive functions, (c) follow strict sample selection criteria, and (d) acknowledge the cognitive heterogeneity typical of the disorder. The study presently reviewed (Baez et al., 2012), addressed all these aspects in order to establish the basis of social cognition deficits in adult AS patients. Specifically, we assessed the performance of AS adults in multiple social cognition tasks with different context-processing requirements. The results suggest that social cognition deficits in AS imply a reduced ability to implicitly encode and integrate contextual cues needed to access social meaning. Nevertheless, the patients' performance was normal when explicit social information was presented or when the situation could be navigated with abstract rules. Here, we review the results of our study and other relevant data, and discuss their implications for the diagnosis and treatment of AS and other neuropsychiatric conditions (e.g., schizophrenia, bipolar disorder, frontotemporal dementia). Finally, we analyze previous results in the light of a current neurocognitive model of social-context processing.
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PMID:The effects of context processing on social cognition impairments in adults with Asperger's syndrome. 2523 1

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine.
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PMID:Consensus paper: radiological biomarkers of cerebellar diseases. 2538 14

The release of smartphones and tablets, which offer more advanced communication and computing capabilities, has led to the strong emergence of mHealth on the market. mHealth systems are being used to improve patients' lives and their health, in addition to facilitating communication between doctors and patients. Researchers are now proposing mHealth applications for many health conditions such as dementia, autism, dysarthria, Parkinson's disease, and so on. Usability becomes a key factor in the adoption of these applications, which are often used by people who have problems when using mobile devices and who have a limited experience of technology. The aim of this paper is to investigate the empirical usability evaluation processes described in a total of 22 selected studies related to mHealth applications by means of a Systematic Literature Review. Our results show that the empirical evaluation methods employed as regards usability could be improved by the adoption of automated mechanisms. The evaluation processes should also be revised to combine more than one method. This paper will help researchers and developers to create more usable applications. Our study demonstrates the importance of adapting health applications to users' need.
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PMID:Empirical studies on usability of mHealth apps: a systematic literature review. 2560 Jan 93

Human empathic experience is a multifaceted psychological construct which arises from functional integration of multiple neural networks. Despite accumulating knowledge about the cortical circuitry of empathy, almost nothing is known about the connectivity that may be concerned in conveying empathy-related neural information. To bridge this gap in knowledge, we studied dispositional empathy in a large-sized cohort of 107 patients who had undergone surgery for a diffuse low-grade glioma. The self-report questionnaire used enabled us to obtain a global measure of subjective empathy but also, importantly, to assess the two main components of empathy (cognitive and emotional). Data were processed by combining voxelwise and tractwise lesion-symptom analyses. Several major findings emerged from our analyses. First of all, topological voxelwise analyses were inconclusive. Conversely, tractwise multiple regression analyses, including all major associative white matter pathways as potential predictors, yielded to significant models explaining substantial part of the behavioural variance. Among the main results, we found that disconnection of the left cingulum bundle was a strong predictor of a low cognitive empathy (p<0.0005 Bonferroni-corrected). Similarly, we found that disconnection of the right uncinate fasciculus and the right inferior fronto-occipital fasciculus predicted, respectively, a low (p<0.05 Bonferroni-corrected) and a high (p<0.05 Bonferroni-corrected) subjective empathy. Finally, although we failed to relate emotional empathy to disruption of a specific tract, correlation analyses indicated a positive association between this component of empathy and the volumes of residual lesion infiltration in the right hemisphere (p<0.01). Taken as a whole, these findings provide key fundamental insights into the anatomical connectivity of empathy. They may help to better understand the pathophysiology of empathy impairments in pathological conditions characterized by abnormalities of long-range anatomical connectivity, such as autism spectrum disorders, schizophrenia and fronto-temporal dementia.
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PMID:A disconnection account of subjective empathy impairments in diffuse low-grade glioma patients. 2568 31


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