Reading in many alphabetic writing systems depends on both item-specific knowledge used to read irregular words (sew, yacht) and generative spelling-sound knowledge used to read pseudowords (tew, yash). Research into the neural basis of these abilities has been directed largely by cognitive accounts proposed by the dual-route cascaded and triangle models of reading. We develop a framework that enables predictions for neural activity to be derived from cognitive models of reading using 2 principles: (a) the extent to which a model component or brain region is engaged by a stimulus and (b) how much effort is exerted in processing that stimulus. To evaluate the derived predictions, we conducted a meta-analysis of 36 neuroimaging studies of reading using the quantitative activation likelihood estimation technique. Reliable clusters of activity are localized during word versus pseudoword and irregular versus regular word reading and demonstrate a great deal of convergence between the functional organization of the reading system put forward by cognitive models and the neural systems activated during reading tasks. Specifically, left-hemisphere activation clusters are revealed reflecting orthographic analysis (occipitotemporal cortex), lexical and/or semantic processing (anterior fusiform, middle temporal gyrus), spelling-sound conversion (inferior parietal cortex), and phonological output resolution (inferior frontal gyrus). Our framework and results establish that cognitive models of reading are relevant for interpreting neuroimaging studies and that neuroscientific studies can provide data relevant for advancing cognitive models. This article thus provides a firm empirical foundation from which to improve integration between cognitive and neural accounts of the reading process.

L1 function is necessary for the guidance of corticospinal axons across the pyramidal decussation in mice. Some of the defects in the corticospinal tract of humans with mutations in L1 could be due to errors in axon guidance at the pyramidal decussation.

Children identified as poor comprehenders at 8 years showed the same reading profile throughout earlier development. Their difficulties with the non-phonological aspects of oral language were present at school entry and persisted through childhood, showing that the oral language weaknesses seen in poor comprehenders in mid-childhood are not a simple consequence of their reading comprehension impairment.

Parkinson's disease (PD) is a common age-related neurodegenerative disease and it is critical to develop models which recapitulate the pathogenic process including the effect of the ageing process. Although the pathogenesis of sporadic PD is unknown, the identification of the mendelian genetic factor PINK1 has provided new mechanistic insights. In order to investigate the role of PINK1 in Parkinson's disease, we studied PINK1 loss of function in human and primary mouse neurons. Using RNAi, we created stable PINK1 knockdown in human dopaminergic neurons differentiated from foetal ventral mesencephalon stem cells, as well as in an immortalised human neuroblastoma cell line. We sought to validate our findings in primary neurons derived from a transgenic PINK1 knockout mouse. For the first time we demonstrate an age dependent neurodegenerative phenotype in human and mouse neurons. PINK1 deficiency leads to reduced long-term viability in human neurons, which die via the mitochondrial apoptosis pathway. Human neurons lacking PINK1 demonstrate features of marked oxidative stress with widespread mitochondrial dysfunction and abnormal mitochondrial morphology. We report that PINK1 plays a neuroprotective role in the mitochondria of mammalian neurons, especially against stress such as staurosporine. In addition we provide evidence that cellular compensatory mechanisms such as mitochondrial biogenesis and upregulation of lysosomal degradation pathways occur in PINK1 deficiency. The phenotypic effects of PINK1 loss-of-function described here in mammalian neurons provides mechanistic insight into the age-related degeneration of nigral dopaminergic neurons seen in PD.

Janusin and tenascin are glia-derived, structurally related, extracellular matrix glycoproteins of the J1 family that are expressed in vivo at times and in locations where active neurite outgrowth occurs, but also when the formation or stabilization of cytoarchitectonic boundaries appears to be in operation. To resolve this apparent functional dichotomy, we have studied the behavioral response of growth cones, growing in culture on the permissive substrate laminin to janusin and tenascin, by video time lapse microscopy. When janusin and tenascin were offered as sharp substrate boundaries, dorsal root ganglion (DRG) and retinal ganglion neuron growth cones avoided growing on these molecules, but were not induced to collapse. On the other hand, when janusin and tenascin were offered, in a mixture with laminin, as uniform substrates, DRG growth cones displayed a collapsed morphology and were able to advance at a faster rate than on laminin alone. In contrast, the outgrowth of retinal ganglion neuron growth cones was completely inhibited under these conditions, underscoring a cell type specificity in the response of growth cones to these molecules. Using several monoclonal antibodies binding to distinct epitopes on the tenascin molecule, we have identified two domains responsible for growth cone repulsion, on epidermal growth factor (EGF)-like repeats 3-5 and fibronectin type III homologous repeats 4 and 5. These domains are different from the one previously recognized to be involved in neurite outgrowth on a uniform tenascin substrate. We conclude that both molecules may promote or retard growth cone advance, depending on the spatial expression pattern and the neuronal cell type.

The mammalian optic chiasm is widely and properly regarded as a region where axons from the temporal retina take an uncrossed course and separate from axons arising in the nasal retina that take a crossed course. However, this is but a rough approximation of the adult situation, and developmental studies must take account of several distinctive stages and axon rearrangements that characterize the region of the chiasm. At the early and late stages of development of nonprimate species the axons do not segregate in accordance with a strict naso-temporal rule at all, and their behavior at the chiasm is not relevant to the formation of the naso-temporal division. As the axons pass from the eye to the chiasm they tend to lose their retinotopic order, to gain a chronotopic order, and then, in the region of the chiasm, to regain some aspects of the retinotopic order before reaching their terminal sites. Molecular or cellular cues that allow the several distinct organizational steps to occur must be expected in the retina, on the axons themselves, and also along the pathway of the axons, prechiasmatically and at the chiasm. Some of these cues will be associated with local nerve cells, some with specialized glial elements and some with the retinofugal axons themselves. Several candidate molecules have been identified in the retina and along the path of the axons, but to date no clearly defined role in the specific events of the pathway determination have been identified. The sequence of developmental processes that characterizes the formation of the optic chiasm provides an interesting and useful challenge to experimentalists, because the advancing axons can now be observed in vitro and in the living brain. The pattern of growth changes as development proceeds, it shows distinctive properties in different species and in their genetic mutants, and it can be readily modified by simple experimental procedures. These all provide opportunities for investigating the function of proposed molecular cues that act in the development of the chiasm.

ABSTRACT-Several paradigms show that responses to one event compromise responses to a second event for around 500 ms. Such effects are generally attributed to attentional capacity limitations associated with processing information in the first event. In a task in which targets could be distinguished only by their meaning, we varied the semantic relationship between distractors and targets following at different lags. Semantic relatedness alone produced a classic attentional blink. We conclude by discussing how attention theory might best accommodate these new effects.Attention mechanisms select salient events. People selectively attend to their names (Moray, 1959), and anxious individuals show increased sensitivity to threat words (MacLeod, Mathews, & Tata, 1986). Mostly, people attend to things that matter for their current goals (Duncan, 2000), and what ''matters'' in laboratory paradigms is determined by experimental instructions about how to respond to particular stimulus properties, either in static arrays or as events dynamically unfold over time.Several paradigms show that responses to one event compromise responses to a second event. These paradigms include the psychological refractory period (Pashler & Johnson, 1998), task switching during rapid word sequences (Allport, Styles, & Hseih, 1994), and the attentional blink (AB). In the latter paradigm, participants watch items presented at a rate of around 10 items/s. It is a divided-attention task, involving two targets, each requiring a different response. For example, participants might have to report a white letter (T1) embedded in a stream of black letters, and then report whether a probe (T2), such as the letter X, occurs subsequently. Given correct report of T1, detection of T2 is impaired for about 500 ms (Raymond, Shapiro, & Arnell, 1992). There are now several accounts of this effect (e.g., see Shapiro, Arnell, & Raymond, 1997). All assume that allocating attention to T1 leaves less attention for T2, although the various theories differ in the precise mechanisms, stages, or storage components proposed.Attention to meaning is also selective. When asked, ''How many animals of each type did Moses take into the Ark?'' respondents frequently answer, ''Two,'' apparently failing to access their knowledge that the agent was really Noah (Erickson & Mattson, 1981). They do not make this mistake when ''Nixon'' is substituted for ''Moses.'' The effect occurs because both Moses and Noah fit the generic schema ''male Old Testament figure with two-syllable name.'' The question focuses attention on number rather than agent identity. Because ''Moses'' is compatible with the evolving biblical schema, ''Ark'' can pass along the conveyor belt of semantic interpretation without detailed scrutiny of its antecedent. Its occurrence following ''Nixon'' requires attention.Selective attention to events and to meaning may be connected. Whatever the task, incoming information must be evaluated against some mental representation of relevant knowledge. In classic visual attenti...

Two experiments explored learning, generalization, and the influence of semantics on orthographic processing in an artificial language. In Experiment 1, 16 adults learned to read 36 novel words written in novel characters. Posttraining, participants discriminated trained from untrained items and generalized to novel items, demonstrating extraction of individual character sounds. Frequency and consistency effects in learning and generalization showed that participants were sensitive to the statistics of their learning environment. In Experiment 2, 32 participants were preexposed to the sounds of all items (lexical phonology) and to novel definitions for half of these items (semantics). Preexposure to either lexical phonology or semantics boosted the early stages of orthographic learning relative to Experiment 1. By the end of training, facilitation was restricted to the semantic condition and to items containing low-frequency inconsistent vowels. Preexposure reduced generalization, suggesting that enhanced item-specific learning was achieved at the expense of character-sound abstraction. The authors' novel paradigm provides a new tool to explore orthographic learning. Although the present findings support the idea that semantic knowledge supports word reading processes, they also suggest that item-specific phonological knowledge is important in the early stages of learning to read.