Greek language processing in naive and skilled readers: Functional properties of the VWFA investigated with ERPs

Neuroimaging studies have provided evidence that the orthographic properties of linguistic stimuli are processed within the visual word form area (VWFA) localised in the left inferotemporal cortex (Cohen & Dehaene, 2004). It is not, however, clear in the literature whether this region responds preferentially to words, distinguishing them from pseudowords, or whether the pseudowords are distinguished from letter-strings on the basis of their orthographic regularity, or again, whether the VWFA distinguishes letters from numbers or from visual stimuli such as chequerboards. Very recently, it has been claimed that there is no evidence that the ill-named VWFA changes its responsiveness during or after reading acquisition (Price & Devlin, 2004). In order to simulate a condition of pre-reading ability in adult readers, we performed this study, in which we compared processing of Greek words and legal pseudowords in mother-tongue Greeks (skilled readers) and monolingual Italian individuals (naive readers) who had no familiarity with the Greek alphabet. ERPs were recorded while volunteers were engaged in a task involving the identification and response to target letters contained within Greek words or pseudowords. The response speed was identical in the two groups (550 vs. 557 ms). ERP data showed that at 165 ms post-stimulus (N1 component) the left lateral-occipital scalp area, probably corresponding to the left ventral occipitotemporal sulcus, discriminates letters of a familiar alphabet, while an unknown alphabet also activates the homologous right-hemispheric region more than 100 ms later. This suggests that the VWFA discriminates nonalphabetic symbols from letter-strings. An analysis of the N2 component showed an increase in the activation of the same region at about 285 ms post-stimulus during the processing of words rather than pseudowords in skilled readers, thus supporting the view that the VWFA discriminates words on the basis of their familiarity. The data seem to suggest that the VWFA is alphabet-specific and that it is based on the shaping of visual area activity during acquisition of the ability to read a given symbolic code.     

Control of mucocutaneous leishmaniasis, a neglected disease: results of a control programme in Satipo Province, Peru

Mucocutaneous leishmaniasis (MCL) is an important health problem in many rural areas of Latin America, but there are few data on the results of programmatic approaches to control the disease. We report the results of a control programme in San Martin de Pangoa District, which reports one of the highest prevalences of MCL in Peru. For 2 years (2001--2002), the technicians at the health post were trained in patient case management, received medical support and were supplied with antimonials. An evaluation after 2 years showed the following main achievements: better diagnosis of patients, who were confirmed by microscopy in 34% (82/240) of the cases in 2001 and 60% of the cases (153/254) in 2002; improved follow-up during treatment: 237 of 263 (90%) patients who initiated an antimonial therapy ended the full treatment course; improved follow-up after treatment: 143 of 237 (60%) patients who ended their full treatment were correctly monitored during the required period of 6 (cutaneous cases) or 12 (mucosal cases) months after the end of treatment. These achievements were largely due to the human and logistical resources made available, the constant availability of medications and the close collaboration between the Ministry of Health, a national research institute and an international non-governmental organization. At the end of this period, the health authorities decided to register a generic brand of sodium stibogluconate, which is now in use. This should allow the treatment of a significant number of additional patients, while saving money to invest in other facets of the case management.     

Language switching mechanisms in simultaneous interpreters: an ERP study

Recent event-related potential (ERP) and neuroimaging studies suggest that bilingual individuals are able to inhibit the processing of a non-target language while speaking or reading in another language. The neural mechanisms subserving code switching still remain matter of debate. The aim of the present study was to shed some light on the neurofunctional bases of such mechanisms. ERPs were recorded in native Italian simultaneous interpreters and monolingual controls during a semantic processing task in which the subjects had to evaluate the sensibleness of final words of incomplete sentences. All participants were strictly right-handed. Interpreters knew at least four languages (from four to eight) at a professional level, from among 11 European and Asian languages, and had an excellent command of English (L2). Four hundred short sentences were presented visually; half of them had an unexpected final word, producing a semantic incongruence. Sentences could be entirely in Italian or in English (unmixed); alternatively, the body of the sentence could be in English and the final word in Italian or vice versa (mixed). ERPs were time locked to the onset of the final word. Both reaction times (RTs) and electrophysiological data indicated a lesser degree of hemispheric lateralization for linguistic function during L2 rather than L1 processing in interpreters. The first effect of lexical switching and code switching was recorded in the time window between 140 and 200 ms at left anterior sites. At N400 level, ERPs were significantly larger to L2 than to L1 words only in the mixed and not in the unmixed condition. No effect of language was observed in the unmixed condition, thus suggesting that the difference in L1/L2 processing was not related to a difference in proficiency, but rather to a different functional organization of semantic integration systems due to the later age of acquisition of L2 compared to L1. Interpreters were faster at reading and comprehending sentences in English ending with an Italian word than vice versa (L2 --> L1 switch).     

New insights into name category-related effects: is the Age of Acquisition a possible factor?

The present article examines several lines of converging evidence suggesting that the slow and insidious brain changes that accumulate over the lifespan, resulting in both natural cognitive aging and Alzheimer's disease (AD), represent a metabolism reduction program. A number of such adaptive programs are known to accompany aging and are thought to have decreased energy requirements for ancestral hunter-gatherers in their 30s, 40s and 50s. Foraging ability in modern hunter-gatherers declines rapidly, more than a decade before the average terminal age of 55 years. Given this, the human brain would have been a tremendous metabolic liability that must have been advantageously tempered by the early cellular and molecular changes of AD which begin to accumulate in all humans during early adulthood. Before the recent lengthening of life span, individuals in the ancestral environment died well before this metabolism reduction program resulted in clinical AD, thus there was never any selective pressure to keep adaptive changes from progressing to a maladaptive extent. Aging foragers may not have needed the same cognitive capacities as their younger counterparts because of the benefits of accumulated learning and life experience. It is known that during both childhood and adulthood metabolic rate in the brain decreases linearly with age. This trend is thought to reflect the fact that children have more to learn. AD "pathology" may be a natural continuation of this trend. It is characterized by decreasing cerebral metabolism, selective elimination of synapses and reliance on accumulating knowledge (especially implicit and procedural) over raw brain power (working memory). Over decades of subsistence, the behaviors of aging foragers became routinized, their motor movements automated and their expertise ingrained to a point where they no longer necessitated the first-rate working memory they possessed when younger and learning actively. Alzheimer changes selectively and precisely mediate an adaptation to this major life-history transition. AD symptomatology shares close similarities with deprivation syndromes in other animals including the starvation response. Both molecular and anatomical features of AD imitate brain changes that have been conceptualized as adaptive responses to low food availability in mammals and birds. Alzheimer's patients are known to express low overall metabolic rates and are genetically inclined to exhibit physiologically thrifty traits widely thought to allow mammals to subsist under conditions of nutritional scarcity. Additionally, AD is examined here in the contexts of anthropology, comparative neuroscience, evolutionary medicine, expertise, gerontology, neural Darwinism, neuroecology and the thrifty genotype.     

Interaction Between αCaMKII and GluN2B Controls ERK-Dependent Plasticity

Understanding how brief synaptic events can lead to sustained changes in synaptic structure and strength is a necessary step in solving the rules governing learning and memory. Activation of ERK1/2 (extracellular signal regulated protein kinase 1/2) plays a key role in the control of functional and structural synaptic plasticity. One of the triggering events that activates ERK1/2 cascade is an NMDA receptor (NMDAR)-dependent rise in free intracellular Ca(2+) concentration. However the mechanism by which a short-lasting rise in Ca(2+) concentration is transduced into long-lasting ERK1/2-dependent plasticity remains unknown. Here we demonstrate that although synaptic activation in mouse cultured cortical neurons induces intracellular Ca(2+) elevation via both GluN2A and GluN2B-containing NMDARs, only GluN2B-containing NMDAR activation leads to a long-lasting ERK1/2 phosphorylation. We show that αCaMKII, but not βCaMKII, is critically involved in this GluN2B-dependent activation of ERK1/2 signaling, through a direct interaction between GluN2B and αCaMKII. We then show that interfering with GluN2B/αCaMKII interaction prevents synaptic activity from inducing ERK-dependent increases in synaptic AMPA receptors and spine volume. Thus, in a developing circuit model, the brief activity of synaptic GluN2B-containing receptors and the interaction between GluN2B and αCaMKII have a role in long-term plasticity via the control of ERK1/2 signaling. Our findings suggest that the roles that these major molecular elements have in learning and memory may operate through a common pathway.     

Affective and cooperative social interactions modulate effective connectivity within and between the mirror and mentalizing systems

Decoding the meaning of others’ actions, a crucial step for social cognition, involves different neural mechanisms. While the “mirror” and “mentalizing” systems have been associated with, respectively, the processing of biological actions versus more abstract information, their respective contribution to intention understanding is debated. Processing social interactions seems to recruit both neural systems, with a different weight depending on cues emphasizing either shared action goals or shared mental states. We have previously shown that observing cooperative and affective social interactions elicits stronger activity in key nodes of, respectively, the mirror (left posterior superior temporal sulcus (pSTS), superior parietal cortex (SPL), and ventral/dorsal premotor cortex (vPMC/dPMC)) and mentalizing (ventromedial prefrontal cortex (vmPFC)) systems. To unveil their causal organization, we investigated the effective connectivity underlying the observation of human social interactions expressing increasing cooperativity (involving left pSTS, SPL, and vPMC) versus affectivity (vmPFC) via dynamic causal modeling in 36 healthy human subjects. We found strong evidence for a model including the pSTS and vPMC as input nodes for the observed interactions. The extrinsic connectivity of this model undergoes oppositely valenced modulations, with cooperativity promoting positive modulations of connectivity between pSTS and both SPL (forward) and vPMC (mainly backward), and affectivity promoting reciprocal positive modulations of connectivity between pSTS and vmPFC (mainly backward). Alongside fMRI data, such divergent effective connectivity suggests that different dimensions underlying the processing of social interactions recruit distinct, although strongly interconnected, neural pathways associated with, respectively, the bottom–up visuomotor processing of motor intentions, and the top–down attribution of affective/mental states.     

Progranulin expression correlates with dense‐core amyloid plaque burden in Alzheimer disease mouse models

Amyloid‐β (Aβ) plaques are pathological hallmarks of Alzheimer disease (AD). In addition, innate inflammatory responses, such as those mediated by microglia, are integral to the pathogenesis of AD. Interestingly, only dense‐core plaques and not diffuse plaques are associated with neuritic and inflammatory pathology in AD patients as well as in mouse AD models. However, the precise neuropathological changes that occur in the brain in response to amyloid deposition are largely unknown. To study the molecular mechanism(s) responsible for Aβ‐mediated neuropathology, we performed a gene expression analysis on laser‐microdissected brain tissue of Tg2576 and APPPS1 mice that are characterized by different types of amyloid plaques and genetic backgrounds. Data were validated by image and biochemical analyses on different ages of Tg2576, APPPS1, and Aβ42‐depositing BRI‐Aβ42 mice. Consistent with an important role of inflammatory responses in AD, we identified progranulin (mouse Grn; human GRN) as one of the top ten up‐regulated molecules in Tg2576 (≈8‐fold increased) and APPPS1 (≈2‐fold increased) mice compared to littermate controls, and among the eight significantly up‐regulated molecules common to both mouse models. In addition, Grn levels correlated significantly with amyloid load, especially the dense‐core plaque pathology (p < 0.001). We further showed that Grn is up‐regulated in microglia and neurons and neurites around dense‐core plaques, but not in astrocytes or oligodendrocytes, as has been shown in AD patients. Our data therefore support the ongoing use of these mouse models in drug trials, especially those with anti‐inflammatory compounds. Moreover, the correlation of Grn with increasing disease severity in AD mouse models prompts human studies exploring the viability of GRN as a disease biomarker. Because loss of GRN has recently been shown to cause frontotemporal dementia and serves as a risk factor for AD, the strong GRN reactivity around dense‐core plaques is consistent with an important role of this factor in AD pathogenesis. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.