Symbol systems such as numbers and language are of paramount importance to human cognition. In number theory, numbers are symbolic signs embedded in a system of higher-order sign-sign relations. During ontogeny, numerical competence passes through different referential sign relations with increasing complexity, from an iconic to an indexical and finally symbolic stage. Animals such as nonhuman primates are constrained to indexical reference. However, because symbolic reference emerges from indexical reference, behavioral and neuronal representations of semantic sign-numerosity associations in animals can elucidate the precursors of symbol systems. A neurobiological explanation of how numerical signs take their meaning is proposed by suggesting that neurons in the granular prefrontal cortex, a novel brain structure evolved in primates, enable high-order associations and establish links between nonsymbolic numerosities and arbitrary signs.

Throughout the history of mathematics, concepts of number and space have been tightly intertwined. We tested the hypothesis that cortical circuits for spatial attention contribute to mental arithmetic. We trained a multivariate classifier to infer the direction of an eye movement, left or right, from the brain activation measured in posterior parietal cortex. Without further training, the classifier then generalized to an arithmetic task. Its left versus right classification could be used to sort out subtraction versus addition trials, whether performed with symbols or with sets of dots. These findings are consistent with the suggestion that mental arithmetic co-opts parietal circuitry associated with spatial coding.

Although the concept of whole numbers is intuitive and well suited for counting and ordering, it is with the invention of fractions that the number system gained precision and flexibility. Absolute magnitude is encoded by single neurons that discharge maximally to specific numbers. However, it is unknown how the ratio of two numbers is represented, whether by processing numerator and denominator in separation, or by extending the analog magnitude code to relative quantity. Using functional MRI adaptation, we now show that populations of neurons in human fronto-parietal cortex are tuned to preferred fractions, generalizing across the format of presentation. After blood oxygen level-dependent signal adaptation to constant fractions, signal recovery to deviant fractions was modulated parametrically as a function of numerical distance between the deviant and adaptation fraction. The distance effect was invariant to changes in notation from number to word fractions and strongest in the anterior intraparietal sulcus, a key region for the processing of whole numbers. These findings demonstrate that the human brain uses the same analog magnitude code to represent both absolute and relative quantity. Our results have implications for mathematical education, which may be tailored to better harness our ability to access automatically a composite quantitative measure.

We review evidence that in the course of reading, the visual system computes abstract letter identities (ALIs): a representation of letters that encodes their identity but that abstracts away from their visual appearance. How could the visual system learn such a seemingly nonvisual representation? We propose that different forms of the same letter tend to appear in similar distributions of contexts (in the same words written in different ways) and that this environmental correlation interacts with correlation-based learning mechanisms in the brain to lead to the formation of ALIs. We review a neural network model that demonstrates the feasibility of this common contexts hypothesis and present two experiments confirming some novel predictions:(a) repeatedly presenting arbitrary visual stimuli in common contexts leads those stimuli to be confusable with each other, and (b) different forms of the same letter are more confusable with each other in word-like contexts than in nonword-like contexts. We then extend the model to use real pictures of letters as input and simulate some of the novel empirical findings from the experiments.

Mathematicians frequently evoke their "intuition" when they are able to quickly and automatically solve a problem, with little introspection into their insight. Cognitive neuroscience research shows that mathematical intuition is a valid concept that can be studied in the laboratory in reduced paradigms, and that relates to the availability of "core knowledge" associated with evolutionarily ancient and specialized cerebral subsystems. As an illustration, I discuss the case of elementary arithmetic. Intuitions of numbers and their elementary transformations by addition and subtraction are present in all human cultures. They relate to a brain system, located in the intraparietal sulcus of both hemispheres, which extracts numerosity of sets and, in educated adults, maps back and forth between numerical symbols and the corresponding quantities. This system is available to animal species and to preverbal human infants. Its neuronal organization is increasingly being uncovered, leading to a precise mathematical theory of how we perform tasks of number comparison or number naming. The next challenge will be to understand how education changes our core intuitions of number.

We show that the neurological condition of synaesthesia-which causes fundamental differences in perception and cognition throughout a lifetime-is significantly represented within the childhood population, and that it manifests behavioural markers as young as age 6 years. Synaesthesia gives rise to a merging of cognitive and/or sensory functions (e.g. in grapheme-colour synaesthesia, reading letters triggers coloured visual photisms) and adult synaesthesia is characterized by a fixed pattern of paired associations for each synaesthete (e.g. if a is carmine red, it is always carmine red). We demonstrate that the onset of this systematicity can be detected in young grapheme-colour synaesthetes, but is an acquired trait with a protracted development. We show that grapheme-colour synaesthesia develops in a way that supersedes the cognitive growth of non-synaesthetic children (with both average and superior abilities) in a comparable paired association task. With methodology based on random sampling and behavioural tests of genuineness, we reveal the prevalence of grapheme-colour synaesthesia in children (over 170 000 grapheme-colour synaesthetes ages 0-17 in the UK, and over 930 000 in the US), the progression of the condition in longitudinal testing, and the developmental differences between synaesthetes and non-synaesthetes in matched tasks. We tested 615 children age 6-7 years from 21 primary schools in the UK. Each child was individually assessed with a behavioural test for grapheme-colour synaesthesia, which first detects differences between synaesthetes and non-synaesthetes, and then tracks the development of each group across 12 months (from ages 6/7 to 7/8 years). We show that the average UK primary school has 2-3 grapheme-colour synaesthetes at any time (and the average US primary school has five) and that synaesthetic associations (e.g. a = carmine red) develop from chaotic pairings into a system of fixed, consistent cogno-sensory responses over time. Our study represents the first assessment of synaesthesia in a randomly sampled childhood population demonstrating the real-time development of the condition. We discuss the complex profile of benefits and costs associated with synaesthesia, and our research calls for a dialogue between researchers, clinicians and educators to highlight the prevalence and characteristics of this unusual condition.

Until only a few decades ago, researchers still considered sensory cortices to be fixed or "hardwired," with specific cortical regions solely dedicated to the processing of selective sensory inputs. But recent evidences have shown that the brain can rewire itself, showing an impressive range of cross-modal plasticity. Visual deprivation is one of the rare human models that allow us to explore the role of experience-dependent plasticity of a sensory cortex deprived of its natural inputs. The objective of this paper is to describe recent results regarding the spatial processing of sounds in blind subjects. These studies suggest that blind individuals may demonstrate exceptional abilities in auditory spatial processing and that such enhanced performances may be intrinsically linked to the recruitment of occipital areas deprived of their normal visual inputs. Such results highlight the brain's remarkable ability to rewire its components to compensate for the challenging neurological condition that is visual deprivation. Moreover, we shall discuss that such cross-modal recruitment may, to some extent, follow organizational principles similar to the functional topography of the region observed in the sighted. Even if such recruitment is especially present in individuals having lost their sight in early infancy, occipital regions also show impressive plastic properties when vision is lost at a later age. This observation will be related to recent results demonstrating that occipital regions play a more important role than previously expected in the spatial processing of sounds, even in sighted subjects. Putative physiological mechanisms underlying such cross-modal recruitment will then be discussed. All these results have important implications for understanding the role of visual experience in shaping the development of occipital regions and may guide the implementation of rehabilitative methods such as sensory substitution or neural implants.

Synaesthesia is a heritable condition of involuntary sensory cross-activation whereby the presentation of a particular stimulus elicits a secondary sensory-perceptual experience. It is thought to be caused by aberrant cross-activation of one cortical area by another, but models differ as to whether this reflects functional or structural differences in the brains of synaesthetes. Here we consider these models in light of recent experimental findings and argue for structural differences in the brains of synaesthetes, which might be more widespread than expected. We also discuss several plausible developmental mechanisms that could link a putative genetic variant to altered cortical connectivity and illustrate how synaesthesia could be an informative model to investigate how patterns of connectivity between cortical areas are established.

A striking way in which humans differ from non-human primates is in their ability to represent numerical quantity using abstract symbols and to use these 'mental tools' to perform skills such as exact calculations. How do functional brain circuits for the symbolic representation of numerical magnitude emerge? Do neural representations of numerical magnitude change as a function of development and the learning of mental arithmetic? Current theories suggest that cultural number symbols acquire their meaning by being mapped onto non-symbolic representations of numerical magnitude. This Review provides an evaluation of this contention and proposes hypotheses to guide investigations into the neural mechanisms that constrain the acquisition of cultural representations of numerical magnitude.

Expert readers exhibit a remarkable ability to recognize handwriting, in spite of enormous variability in character shape-a competence whose cerebral underpinnings are unknown. Subliminal priming, combined with neuroimaging, can reveal which brain areas automatically compute an invariant representation of visual stimuli. Here, we used behavioral and fMRI priming to study the areas involved in invariant handwritten word recognition. Compared to printed words, easily readable handwritten words caused additional activity in ventral occipitotemporal cortex, particularly in the right hemisphere, while difficult handwriting also mobilized an attentional parietofrontal network. Remarkably, however, subliminal repetition effects were observed across printed and handwritten styles, whether easy or difficult to read, both behaviorally and in the activation of the left visual word form area (VWFA). These results indicate that the left inferotemporal VWFA possesses an unsuspected degree of fast and automatic visual invariance for handwritten words, although surprisingly this invariance can be reflected both as repetition suppression and as repetition enhancement.

Young children often make mirror errors when learning to read and write, for instance writing their first name from right to left in English. This competence vanishes in most adult readers, who typically cannot read mirror words but retain a strong competence for mirror recognition of images. We used fast behavioral and fMRI repetition priming to probe the brain mechanisms underlying mirror generalization and its absence for words in adult readers. In two groups of French and Japanese readers, we show that the left fusiform visual word form area, a major site of learning during reading acquisition, simultaneously shows a maximal effect of mirror priming for pictures and an absence of mirror priming for words. Thus, learning to read recruits an area which possesses a property of mirror invariance, seemingly present in all primates, which is deleterious for letter recognition and may explain children's transient mirror errors.

We compared conscious and nonconscious processing of briefly flashed words using a visual masking procedure while recording intracranial electroencephalogram (iEEG) in ten patients. Nonconscious processing of masked words was observed in multiple cortical areas, mostly within an early time window (<300 ms), accompanied by induced gamma-band activity, but without coherent long-distance neural activity, suggesting a quickly dissipating feedforward wave. In contrast, conscious processing of unmasked words was characterized by the convergence of four distinct neurophysiological markers: sustained voltage changes, particularly in prefrontal cortex, large increases in spectral power in the gamma band, increases in long-distance phase synchrony in the beta range, and increases in long-range Granger causality. We argue that all of those measures provide distinct windows into the same distributed state of conscious processing. These results have a direct impact on current theoretical discussions concerning the neural correlates of conscious access.

Object recognition relies heavily on invariant visual features such as the manner in which lines meet at vertices to form viewpoint-invariant junctions (e.g. T, L). We wondered whether these features also underlie readers' competence for fast recognition of printed words. Since reading is far too recent to have exerted any evolutionary pressure on brain evolution, visual word recognition might be based on pre-existing mechanisms common to all visual object recognition. In a naming task, we presented partially deleted pictures of objects and printed words in which either the vertices or the line midsegments were preserved. Subjects showed an identical pattern of behavior with both objects and words: they made fewer errors and were faster to respond when vertices were preserved. Our results suggest that vertex invariants are used for object recognition and that this evolutionarily ancient mechanism is being co-opted for reading.

Can conscious processing be inferred from neurophysiological measurements? Some models stipulate that the active maintenance of perceptual representations across time requires consciousness. Capitalizing on this assumption, we designed an auditory paradigm that evaluates cerebral responses to violations of temporal regularities that are either local in time or global across several seconds. Local violations led to an early response in auditory cortex, independent of attention or the presence of a concurrent visual task, whereas global violations led to a late and spatially distributed response that was only present when subjects were attentive and aware of the violations. We could detect the global effect in individual subjects using functional MRI and both scalp and intracerebral event-related potentials. Recordings from 8 noncommunicating patients with disorders of consciousness confirmed that only conscious individuals presented a global effect. Taken together these observations suggest that the presence of the global effect is a signature of conscious processing, although it can be absent in conscious subjects who are not aware of the global auditory regularities. This simple electrophysiological marker could thus serve as a useful clinical tool.

Global neuronal workspace theory predicts that damage to long-distance white matter (WM) tracts should impair access to consciousness during the perception of brief stimuli. To address this issue, we studied visual backward masking in 18 patients at the very first clinical stage of multiple sclerosis (MS), a neurological disease characterized by extensive WM damage, and in 18 matched healthy subjects. In our masking paradigm, the visibility of a digit stimulus increases non-linearly as a function of the interval duration between this target and a subsequent mask. In order to characterize quantitatively, for each subject, the transition between non-conscious and conscious perception of the stimulus, we used non-linear regression to fit a sigmoid curve to objective performance and subjective visibility reports as a function of target-mask delay. The delay corresponding to the inflexion point of the sigmoid, where visibility suddenly increases, was termed the "non-linear transition threshold" and used as a summary measure of masking efficiency. Objective and subjective non-linear transition thresholds were highly correlated across subjects in both groups, and were higher in patients compared to controls. In patients, variations in the non-linear transition threshold were inversely correlated to the MTR values inside the right dorsolateral prefrontal WM, the right occipito-frontal fasciculus and in the left cerebellum. This study provides clinical evidence of a relationship between impairments of conscious access and integrity of large WM bundles, particularly involving prefrontal cortex, as predicted by global neuronal workspace theory.

Functional neuroimaging and studies of brain-damaged patients made it possible to delineate the main components of the cerebral system for word reading. However, the anatomical connections subtending the flow of information within this network are still poorly defined. Here we study the connectivity of the Visual Word Form Area (VWFA), a pivotal component of the reading network achieving the invariant identification of letter strings, and reproducibly located in the left lateral occipitotemporal sulcus. Diffusion images and functional imaging data were gathered in a patient who developed pure alexia following a small surgical lesion in the vicinity of his VWFA. We had a unique opportunity to compare images obtained before, early after, and late after surgery. Analysis of diffusion images with white matter tractography and voxel-based morphometry showed that the VWFA was mainly linked to the occipital cortex through the inferior longitudinal fasciculus (ILF), and to perisylvian language areas (supramarginal gyrus) through the arcuate fasciculus. After surgery, we observed the progressive and selective degeneration of the ILF, while the VWFA was anatomically intact. This allowed us to establish the critical causal role of this fiber tract in normal reading, and to show that its disruption is one pathophysiological mechanism of pure alexia, thus clarifying a long-standing debate on the role of disconnection in neurocognitive disorders.

Subitizing is the rapid and accurate enumeration of small sets (up to 3-4 items). Although subitizing has been studied extensively since its first description about 100 years ago, its underlying mechanisms remain debated. One hypothesis proposes that subitizing results from numerical estimation mechanisms that, according to Weber's law, operate with high precision for small numbers. Alternatively, subitizing might rely on a distinct process dedicated to small numerosities. In this study, we tested the hypothesis that there is a shared estimation system for small and large quantities in human adults, using a masked forced-choice paradigm in which participants named the numerosity of displays taken from sets matched for discrimination difficulty; one set ranged from 1 through 8 items, and the other ranged from 10 through 80 items. Results showed a clear violation of Weber's law (much higher precision over numerosities 1-4 than over numerosities 10-40), thus refuting the single-estimation-system hypothesis and supporting the notion of a dedicated mechanism for apprehending small numerosities.

While neglected stimuli can still be processed, few studies have directly addressed the issue of the unconscious access to semantics. In order to clarify this issue, we engaged four patients with unilateral left spatial neglect in a number comparison task. Each target number was preceded by a lateralized number prime, either in the intact or neglected hemifield (HF). Both group analyses and the intensive study of a single patient show that left (neglected) as well as right (consciously perceived) number primes affect performance: primes representing quantities that fall on the same side of the reference as the target lead to faster categorization. This congruency effect is highly suggestive of numerical semantic processing of neglected stimuli. Absence of conscious perception of neglected primes was evaluated using a combination of subjective and objective measures of performance in forced-choice tasks.

Fast, parallel word recognition, in expert readers, relies on sectors of the left ventral occipito-temporal pathway collectively known as the visual word form area. This expertise is thought to arise from perceptual learning mechanisms that extract informative features from the input strings. The perceptual expertise hypothesis leads to two predictions:(1) parallel word recognition, based on the ventral visual system, should be limited to words displayed in a familiar format (foveal horizontal words with normally spaced letters);(2) words displayed in formats outside this field of expertise should be read serially, under supervision of dorsal parietal attention systems. We presented adult readers with words that were progressively degraded in three different ways (word rotation, letter spacing, and displacement to the visual periphery). Behaviorally, we identified degradation thresholds above which reading difficulty increased non-linearly, with the concomitant emergence of a word length effect on reading latencies reflecting serial reading strategies. fMRI activations were correlated with reading difficulty in bilateral occipito-temporal and parietal regions, reflecting the strategies required to identify degraded words. A core region of the intraparietal cortex was engaged in all modes of degradation. Furthermore, in the ventral pathway, word degradation led to an amplification of activation in the posterior visual word form area, at a level thought to encode single letters. We also found an effect of word length restricted to highly degraded words in bilateral occipitoparietal regions. Those results clarify when and how the ventral parallel visual word form system needs to be supplemented by the deployment of dorsal serial reading strategies.

Recent functional neuroimaging studies have indicated that culture may contribute to differential representation of Arabic numbers in the brain of Chinese and English speakers. The brain networks underlying even very simple arithmetic operation differ among these groups. To what extent do different cultures lead to differences in functional connectivity among the distributed brain areas that constitute the network supporting numerical and arithmetic processes? Key cultural differences are educational system, learning strategy, reading experience, and even genetic background; which ones are important? This review addresses these questions and summarizes findings from recent research on number/arithmetic cognition as well related studies in other cognitive domains. Future directions are also addressed.

OBJECTIVE: Magnetic resonance imaging method opened up the possibility for in vivo examination of the anatomy of human brain. For this reason it is interesting and relevant to compare the knowledge accumulated over a number of years during the examination of the composition of dead brain to that obtained from magnetic resonance images. The aim of this study was to determine and compare the thickness of cerebral cortex in human of different age and sex, measured in different sites of the hemispheres when applying anatomical mesoscopic imaging and magnetic resonance imaging. MATERIAL AND METHODS: The thickness of cerebral cortex was measured in symmetrical Brodmann's areas of both hemispheres. The anatomical mesoscopic imaging technique was used for the examination of 2x2-cm cortex samples obtained during autopsy and fixed for 4 weeks in 10% paraformaldehyde. In these samples, cortex thickness was measured in sections perpendicular to the convolution, using an operative microscope, in a mesoscopic image at x16 magnification and with an accuracy of 0.01 mm. Using cerebral magnetic resonance imaging, the thickness of cerebral cortex in live subjects was measured on T1-weighted images of patients examined at the Clinic of Radiology, Kaunas University of Medicine Hospital. The measured cortical field image was magnified to the smallest element of digital image - the pixel - and measured with an accuracy of 0.01 mm. Each of the two techniques was applied for the examination of 20 men and women who were divided into age groups of 20-60 years (n=10) and older than 60 years (n=10). RESULTS AND CONCLUSIONS: Both examination methods yielded a statistically significant difference in the thickness of cerebral cortex between Brodmann's areas 1, 4, and 19. No significant difference in cortex thickness was found between different age and sex groups; however, the findings showed that the difference in cortex thickness between the different age male groups was 4.6% and female - 1.6%. No significant difference using different techniques was found, but the cortex thickness in the fixed samples was reduced by 0.5 cm on average.

Presurgical functional MR imaging (fMRI) is discussed as a possible replacement of intraoperative electrocortical stimulation (ES) in the mapping of language function. On the basis of a literature study and illustrated by our own preliminary clinical experience, it is concluded that at present fMRI does offer valuable information by identifying the language-dominant hemisphere preoperatively and estimating the distance between the tumour and functional language areas. However, it is not a reliable alternative to ES because of technical and conceptual problems.

The aim of this research was to detect the major cytoarchitectonical features of individual variability in anterior limbic area 24 in the left and right hemispheres of human brain, using the modern morphometric analysis methods. With the aid of DiaMorph (Russia) software-hardware complex, the neuron profile field area was measured, the percentage of neurons of each dimensional class was calculated, and the total fraction of neurons in layers III and V of subarea 24 in the anterior limbic region of human cortex was defined. A considerable individual variability of these characteristics and the asymmetry of their values between the left and right brain hemispheres were detected. It was found that the largest value and greatest scattering of individual differences of these characteristics took place in the associative layer III of the right hemisphere.

Part of human cortex is specialized for cultural domains such as reading and arithmetic, whose invention is too recent to have influenced the evolution of our species. Representations of letter strings and of numbers occupy reproducible locations within large-scale macromaps, respectively in the left occipito-temporal and bilateral intraparietal cortex. Furthermore, recent fMRI studies reveal a systematic architecture within these areas. To explain this paradoxical cerebral invariance of cultural maps, we propose a neuronal recycling hypothesis, according to which cultural inventions invade evolutionarily older brain circuits and inherit many of their structural constraints.

Previous functional neuroimaging studies have described shape-selectivity for haptic stimuli in many cerebral cortical regions, of which some are also visually shape-selective. However, the literature is equivocal on the existence of haptic or visuo-haptic texture-selectivity. We report here on a human functional magnetic resonance imaging (fMRI) study in which shape and texture perception were contrasted using haptic stimuli presented to the right hand, and visual stimuli presented centrally. Bilateral selectivity for shape, with overlap between modalities, was found in a dorsal set of parietal areas: the postcentral sulcus and anterior, posterior and ventral parts of the intraparietal sulcus (IPS); as well as ventrally in the lateral occipital complex. The magnitude of visually- and haptically-evoked activity was significantly correlated across subjects in the left posterior IPS and right lateral occipital complex, suggesting that these areas specifically house representations of object shape. Haptic shape-selectivity was also found in the left postcentral gyrus, the left lingual gyrus, and a number of frontal cortical sites. Haptic texture-selectivity was found in ventral somatosensory areas: the parietal operculum and posterior insula bilaterally, as well as in the right medial occipital cortex, overlapping with a medial occipital cortical region, which was texture-selective for visual stimuli. The present report corroborates and elaborates previous suggestions of specialized visuo-haptic processing of texture and shape. Hum Brain Mapp 2007.(c) 2007 Wiley-Liss, Inc.

The cerebral cortex, with its conserved 6-layer structure, has inspired many unifying models of function. However, recent comparative studies of primary visual cortex have revealed considerable structural diversity, raising doubts about the possibility of an all-encompassing theory. This review examines similarities and differences in V1 across mammals. Gross laminar interconnections are relatively conserved. Major functional response classes are found universally or nearly universally. Orientation and spatial frequency tuning bandwidths are quite similar despite an enormous range of visual resolution across species, and orientation tuning is contrast-invariant. Nevertheless, there is considerable diversity in the abundance of different cell classes, laminar organization, functional architecture, and functional connectivity. Orientation-selective responses arise in different layers in different species. Some mammals have elaborate columnar architecture like orientation maps and ocular dominance bands, but others lack this organization with no apparent impact on single cell properties. Finally, local functional connectivity varies according to map structure: similar cells are connected in smooth map regions but dissimilar cells are linked in animals without maps. If there is a single structure/function relation for cortex, it must accommodate significant variations in cortical circuitry. Alternatively, natural selection may craft unique circuits that function differently in each species. DOI: 10.1177/1073858407306597.