Numerous studies have identified the intraparietal sulcus (IPS) as an area critically involved in numerical processing. IPS neurons in macaques are tuned to a preferred numerosity, hence neurally coding numerosity in a number-selective way. Neuroimaging studies in humans have demonstrated number-selective processing in the anterior parts of the IPS. Nevertheless, the processes that convert visual input into a number-selective neural code remain unknown. Computational studies have suggested that a neural coding stage that is sensitive, but not selective to number, precedes number-selective coding when processing nonsymbolic quantities but not when processing symbolic quantities. In Experiment 1, we used functional magnetic resonance imaging to localize number-sensitive areas in the human brain by searching for areas exhibiting increasing activation with increasing number, carefully controlling for nonnumerical parameters. An area in posterior superior parietal cortex was identified as a substrate for the intermediate number-sensitive steps required for processing nonsymbolic quantities. In Experiment 2, the interpretation of Experiment 1 was confirmed with a connectivity analysis showing that a shared number-selective representation in IPS is reached through different pathways for symbolic versus nonsymbolic quantities. The preferred pathway for processing nonsymbolic quantities included the number-sensitive area in superior parietal cortex, whereas the pathway for processing symbolic quantities did not.

How is higher cognitive function organized in the human parietal cortex? A century of neuropsychology and 30 years of functional neuroimaging has implicated the parietal lobe in many different verbal and nonverbal cognitive domains. There is little clarity, however, on how these functions are organized, that is, where do these functions coalesce (implying a shared, underpinning neurocomputation) and where do they divide (indicating different underlying neural functions). Until now, there has been no multi-domain synthesis in order to reveal where there is fusion or fission of functions in the parietal cortex. This aim was achieved through a large-scale activation likelihood estimation (ALE) analysis of 386 studies (3952 activation peaks) covering 8 cognitive domains. A tripartite, domain-general neuroanatomical division and 5 principles of cognitive organization were established, and these are discussed with respect to a unified theory of parietal functional organization.

The dexterous control of our grasping actions relies on the cooperative activation of many brain areas. In the parietal lobe, 2 grasp-related areas collaborate to orchestrate an accurate grasping action: dorsolateral area AIP and dorsomedial area V6A. Single-cell recordings in monkeys and fMRI studies in humans have suggested that both these areas specify grip aperture and wrist orientation, but encode these grasping parameters differently, depending on the context. To elucidate the causal role of phAIP and hV6A, we stimulated these areas, while participants were performing grasping actions (unperturbed grasping). rTMS over phAIP impaired the wrist orientation process, whereas stimulation over hV6A impaired grip aperture encoding. In a small percentage of trials, an unexpected reprogramming of grip aperture or wrist orientation was required (perturbed grasping). In these cases, rTMS over hV6A or over phAIP impaired reprogramming of both grip aperture and wrist orientation. These results represent the first direct demonstration of a different encoding of grasping parameters by 2 grasp-related parietal areas.

Short-term (STM) and long-term memory (LTM) have largely been considered as separate brain systems reflecting fronto-parietal and medial temporal lobe (MTL) functions, respectively. This functional dichotomy has been called into question by evidence of deficits on aspects of working memory in patients with MTL damage, suggesting a potentially direct hippocampal contribution to STM. As the hippocampus has direct anatomical connections with the thalamus, we tested the hypothesis that damage to thalamic nuclei regulating cortico-cortical interactions may contribute to STM deficits in patients with hippocampal dysfunction. We used diffusion-weighted magnetic resonance imaging-based tractography to identify anatomical subdivisions in patients with MTL epilepsy. From these, we measured resting-state functional connectivity with detailed cortical divisions of the frontal, temporal, and parietal lobes. Whereas thalamo-temporal functional connectivity reflected LTM performance, thalamo-prefrontal functional connectivity specifically predicted STM performance. Notably, patients with hippocampal volume loss showed thalamic volume loss, most prominent in the pulvinar region, not detected in patients with normal hippocampal volumes. Aberrant thalamo-cortical connectivity in the epileptic hemisphere was mirrored in a loss of behavioral association with STM performance specifically in patients with hippocampal atrophy. These findings identify thalamo-cortical disruption as a potential mechanism contributing to STM deficits in the context of MTL damage.

In the dual-stream model of language processing, the exact connectivity of the ventral stream to the anterior temporal lobe remains elusive. To investigate the connectivity between the inferior frontal gyrus (IFG) and the lateral part of the temporal and parietal lobes, we integrated spatiotemporal profiles of cortico-cortical evoked potentials (CCEPs) recorded intraoperatively in 14 patients who had undergone surgical resection for a brain tumor or epileptic focus. Four-dimensional visualization of the combined CCEP data showed that the pars opercularis (Broca's area) is connected to the posterior temporal cortices and the supramarginal gyrus, whereas the pars orbitalis is connected to the anterior lateral temporal cortices and angular gyrus. Quantitative topographical analysis of CCEP connectivity confirmed an anterior-posterior gradient of connectivity from IFG stimulus sites to the temporal response sites. Reciprocality analysis indicated that the anterior part of the IFG is bidirectionally connected to the temporal or parietal area. This study shows that each IFG subdivision has different connectivity to the temporal lobe with an anterior-posterior gradient and supports the classical connectivity concept of Dejerine; that is, the frontal lobe is connected to the temporal lobe through the arcuate fasciculus and also a double fan-shaped structure anchored at the limen insulae.

Many neuroimaging studies of the mirror neuron system (MNS) examine if certain voxels in the brain are shared between action observation and execution (shared voxels, sVx). Unfortunately, finding sVx in standard group analyses is not a guarantee that sVx exist in individual subjects. Using unsmoothed, single-subject analyses we show sVx can be reliably found in all 16 investigated participants. Beside the ventral premotor (BA6/44) and inferior parietal cortex (area PF) where mirror neurons (MNs) have been found in monkeys, sVx were reliably observed in dorsal premotor, supplementary motor, middle cingulate, somatosensory (BA3, BA2, and OP1), superior parietal, middle temporal cortex and cerebellum. For the premotor, somatosensory and parietal areas, sVx were more numerous in the left hemisphere. The hand representation of the primary motor cortex showed a reduced BOLD during hand action observation, possibly preventing undesired overt imitation. This study provides a more detailed description of the location and reliability of sVx and proposes a model that extends the original idea of the MNS to include forward and inverse internal models and motor and sensory simulation, distinguishing the MNS from a more general concept of sVx.

Age-related differences in the functional hierarchical organization of the frontal lobe remain unclear. We adopted task-related functional magnetic resonance imaging (fMRI) to investigate age differences in the functional hierarchical organization of the frontal lobe. Behavioral results report both reaction time and efficiency declined as the levels of abstraction increased in the selection of a set of stimulus-response mappings in older adults compared with young adults. fMRI findings suggest trends of the hierarchical organization along the rostro-caudal axis in both groups, and brain-behavior correlation further suggests neural dedifferentiation in older adults when performing at the highest level of control demands experiment. Behavioral performances and age difference overactivations at the highest level of control demands were both associated with working memory capacity, suggesting the working memory capacity is important for processing the highest task demands. Region-of-interest analysis revealed age differences in brain overactivation and common activation across experiments in the primary motor cortex, parietal lobule, and the fusiform gyrus may serve as shared mechanisms underlying tasks that are required for the selection of stimulus-response mapping sets. Overall, older adults reflect maladaptive overactivation in task-irrelevant regions that are detrimental to performance with the highest control demands.

The sense of agency is defined as the subjective experience that "I" am the one who is causing the action. Theoretical studies postulate that this subjective experience is developed through multistep processes extending from the sensorimotor to the cognitive level. However, it remains unclear how the brain processes such different levels of information and constitutes the neural substrates for the sense of agency. To answer this question, we combined two strategies: an experimental paradigm, in which self-agency gradually evolves according to sensorimotor experience, and a multivoxel pattern analysis. The combined strategies revealed that the sensorimotor, posterior parietal, anterior insula, and higher visual cortices contained information on self-other attribution during movement. In addition, we investigated whether the found regions showed a preference for self-other attribution or for sensorimotor information. As a result, the right supramarginal gyrus, a portion of the inferior parietal lobe (IPL), was found to be the most sensitive to self-other attribution among the found regions, while the bilateral precentral gyri and left IPL dominantly reflected sensorimotor information. Our results demonstrate that multiple brain regions are involved in the development of the sense of agency and that these show specific preferences for different levels of information.

High-functioning older adults can exhibit normal recollection when measured subjectively, via "remember" judgments, but not when measured objectively, via source judgments, whereas low-functioning older adults exhibit impairments for both measures. A potential explanation for this is that typical subjective and objective tests of recollection necessitate different processing demands, supported by distinct brain regions, and that deficits in these tests are observed according to the degree of age-related changes in these regions. Here, we used event-related functional magnetic resonance imaging to measure the effects of aging on neural correlates of subjective and objective measures of recollection, in young, high-functioning (Old-High) and low-functioning (Old-Low) older adults. Behaviorally, the Old-High group showed intact subjective ("remember" judgments) but impaired objective recollection (for 1 of 2 spatial or temporal sources), whereas the Old-Low group was impaired on both measures. Imaging data showed changes in parietal subjective recollection effects in the Old-Low group and in lateral frontal objective recollection effects in both older adult groups. Our results highlight the importance of examining performance variability in older adults and suggest that differential effects of aging on brain regions are associated with different patterns of performance on tests of subjective and objective recollection.

Previous behavioral research points to a positive relationship between maternal touch and early social development. Here, we explored the brain correlates of this relationship. The frequency of maternal touch was recorded for 43 five-year-old children during a 10 min standardized play session. Additionally, all children completed a resting-state functional magnetic resonance imaging session. Investigating the default mode network revealed a positive relation between the frequency of maternal touch and activity in the right posterior superior temporal sulcus (pSTS) extending into the temporo-parietal junction. Using this effect as a seed in a functional connectivity analysis identified a network including extended bilateral regions along the temporal lobe, bilateral frontal cortex, and left insula. Compared with children with low maternal touch, children with high maternal touch showed additional connectivity with the right dorso-medial prefrontal cortex. Together these results support the notion that childhood tactile experiences shape the developing "social brain" with a particular emphasis on a network involved in mentalizing.

Neurons, even in the earliest sensory areas of cortex, are subject to a great deal of contextual influence from both within and across modality connections. In the present work, we investigated whether the earliest regions of somatosensory cortex (S1 and S2) would contain content-specific information about visual object categories. We reasoned that this might be possible due to the associations formed through experience that link different sensory aspects of a given object. Participants were presented with visual images of different object categories in 2 fMRI experiments. Multivariate pattern analysis revealed reliable decoding of familiar visual object category in bilateral S1 (i.e., postcentral gyri) and right S2. We further show that this decoding is observed for familiar but not unfamiliar visual objects in S1. In addition, whole-brain searchlight decoding analyses revealed several areas in the parietal lobe that could mediate the observed context effects between vision and somatosensation. These results demonstrate that even the first cortical stages of somatosensory processing carry information about the category of visually presented familiar objects.

The ability to represent concepts and the relationships between them is critical to human cognition. How does the brain code relationships between items that share basic conceptual properties (e.g., dog and wolf) while simultaneously representing associative links between dissimilar items that co-occur in particular contexts (e.g., dog and bone)? To clarify the neural bases of these semantic components in neurologically intact participants, both types of semantic relationship were investigated in an fMRI study optimized for anterior temporal lobe (ATL) coverage. The clear principal finding was that the same core semantic network (ATL, superior temporal sulcus, ventral prefrontal cortex) was equivalently engaged when participants made semantic judgments on the basis of association or conceptual similarity. Direct comparisons revealed small, weaker differences for conceptual similarity > associative decisions (e.g., inferior prefrontal cortex) and associative > conceptual similarity (e.g., ventral parietal cortex) which appear to reflect graded differences in task difficulty. Indeed, once reaction time was entered as a covariate into the analysis, no associative versus category differences remained. The paper concludes with a discussion of how categorical/feature-based and associative relationships might be represented within a single, unified semantic system.

Two important theories in cognitive neuroscience are predictive coding (PC) and the global workspace (GW) theory. A key research task is to understand how these two theories relate to one another, and particularly, how the brain transitions from a predictive early state to the eventual engagement of a brain-scale state (the GW). To address this question, we present a source-localization of EEG responses evoked by the local-global task-an experimental paradigm that engages a predictive hierarchy, which encompasses the GW. The results of our source reconstruction suggest three phases of processing. The first phase involves the sensory (here auditory) regions of the superior temporal lobe and predicts sensory regularities over a short timeframe (as per the local effect). The third phase is brain-scale, involving inferior frontal, as well as inferior and superior parietal regions, consistent with a global neuronal workspace (GNW; as per the global effect). Crucially, our analysis suggests that there is an intermediate (second) phase, involving modulatory interactions between inferior frontal and superior temporal regions. Furthermore, sedation with propofol reduces modulatory interactions in the second phase. This selective effect is consistent with a PC explanation of sedation, with propofol acting on descending predictions of the precision of prediction errors; thereby constraining access to the GNW.

Humans are especially good at taking another's perspective-representing what others might be thinking or experiencing. This "mentalizing" capacity is apparent in everyday human interactions and conversations. We investigated its neural basis using magnetoencephalography. We focused on whether mentalizing was engaged spontaneously and routinely to understand an utterance's meaning or largely on-demand, to restore "common ground" when expectations were violated. Participants conversed with 1 of 2 confederate speakers and established tacit agreements about objects' names. In a subsequent "test" phase, some of these agreements were violated by either the same or a different speaker. Our analysis of the neural processing of test phase utterances revealed recruitment of neural circuits associated with language (temporal cortex), episodic memory (e.g., medial temporal lobe), and mentalizing (temporo-parietal junction and ventromedial prefrontal cortex). Theta oscillations (3-7 Hz) were modulated most prominently, and we observed phase coupling between functionally distinct neural circuits. The episodic memory and language circuits were recruited in anticipation of upcoming referring expressions, suggesting that context-sensitive predictions were spontaneously generated. In contrast, the mentalizing areas were recruited on-demand, as a means for detecting and resolving perceived pragmatic anomalies, with little evidence they were activated to make partner-specific predictions about upcoming linguistic utterances.

During linguistic processing, a set of brain regions on the lateral surfaces of the left frontal, temporal, and parietal cortices exhibit robust responses. These areas display highly correlated activity while a subject rests or performs a naturalistic language comprehension task, suggesting that they form an integrated functional system. Evidence suggests that this system is spatially and functionally distinct from other systems that support high-level cognition in humans. Yet, how different regions within this system might be recruited dynamically during task performance is not well understood. Here we use network methods, applied to fMRI data collected from 22 human subjects performing a language comprehension task, to reveal the dynamic nature of the language system. We observe the presence of a stable core of brain regions, predominantly located in the left hemisphere, that consistently coactivate with one another. We also observe the presence of a more flexible periphery of brain regions, predominantly located in the right hemisphere, that coactivate with different regions at different times. However, the language functional ROIs in the angular gyrus and the anterior temporal lobe were notable exceptions to this trend. By highlighting the temporal dimension of language processing, these results suggest a trade-off between a region's specialization and its capacity for flexible network reconfiguration.

Preterm birth is a leading cause of cognitive impairment in childhood and is associated with cerebral gray and white matter abnormalities. Using multimodal image analysis, we tested the hypothesis that altered thalamic development is an important component of preterm brain injury and is associated with other macro- and microstructural alterations. T(1)- and T(2)-weighted magnetic resonance images and 15-direction diffusion tensor images were acquired from 71 preterm infants at term-equivalent age. Deformation-based morphometry, Tract-Based Spatial Statistics, and tissue segmentation were combined for a nonsubjective whole-brain survey of the effect of prematurity on regional tissue volume and microstructure. Increasing prematurity was related to volume reduction in the thalamus, hippocampus, orbitofrontal lobe, posterior cingulate cortex, and centrum semiovale. After controlling for prematurity, reduced thalamic volume predicted: lower cortical volume; decreased volume in frontal and temporal lobes, including hippocampus, and to a lesser extent, parietal and occipital lobes; and reduced fractional anisotropy in the corticospinal tracts and corpus callosum. In the thalamus, reduced volume was associated with increased diffusivity. This demonstrates a significant effect of prematurity on thalamic development that is related to abnormalities in allied brain structures. This suggests that preterm delivery disrupts specific aspects of cerebral development, such as the thalamocortical system.

To control our actions efficiently, our brain represents our body based on a combination of visual and proprioceptive cues, weighted according to how (un)reliable-how precise-each respective modality is in a given context. However, perceptual experiments in other modalities suggest that the weights assigned to sensory cues are also modulated "top-down" by attention. Here, we asked whether during action, attention can likewise modulate the weights (i.e., precision) assigned to visual versus proprioceptive information about body position. Participants controlled a virtual hand (VH) via a data glove, matching either the VH or their (unseen) real hand (RH) movements to a target, and thus adopting a ``visual'' or ``proprioceptive'' attentional set, under varying levels of visuo-proprioceptive congruence and visibility. Functional magnetic resonance imaging (fMRI) revealed increased activation of the multisensory superior parietal lobe (SPL) during the VH task and increased activation of the secondary somatosensory cortex (S2) during the RH task. Dynamic causal modeling (DCM) showed that these activity changes were the result of selective, diametrical gain modulations in the primary visual cortex (V1) and the S2. These results suggest that endogenous attention can balance the gain of visual versus proprioceptive brain areas, thus contextualizing their influence on multisensory areas representing the body for action.

The multiple-demand (MD) network is sensitive to many aspects of cognitive demand, showing increased activation with more difficult tasks. However, it is currently unknown whether the MD network is modulated by the context in which task difficulty is experienced. Using functional magnetic resonance imaging, we examined MD network responses to low, medium, and high difficulty arithmetic problems within 2 cued contexts, an easy versus a hard set. The results showed that MD activity varied reliably with the absolute difficulty of a problem, independent of the context in which the problem was presented. Similarly, MD activity during task execution was independent of the difficulty of the previous trial. Representational similarity analysis further supported that representational distances in the MD network were consistent with a context-independent code. Finally, we identified several regions outside the MD network that showed context-dependent coding, including the inferior parietal lobule, paracentral lobule, posterior insula, and large areas of the visual cortex. In sum, a cognitive effort is processed by the MD network in a context-independent manner. We suggest that this absolute coding of cognitive demand in the MD network reflects the limited range of task difficulty that can be supported by the cognitive apparatus.

It is often assumed that neural activity in face-responsive regions of primate cortex correlates with conscious perception of faces. However, whether such activity occurs without awareness is still debated. Using functional magnetic resonance imaging (fMRI) in conjunction with a novel masked face priming paradigm, we observed neural modulations that could not be attributed to perceptual awareness. More specifically, we found reduced activity in several classic face-processing regions, including the "fusiform face area," "occipital face area," and superior temporal sulcus, when a face was preceded by a briefly flashed image of the same face, relative to a different face, even when 2 images of the same face differed. Importantly, unlike most previous studies, which have minimized awareness by using conditions of inattention, the present results occurred when the stimuli (the primes) were attended. By contrast, when primes were perceived consciously, in a long-lag priming paradigm, we found repetition-related activity increases in additional frontal and parietal regions. These data not only demonstrate that fMRI activity in face-responsive regions can be modulated independently of perceptual awareness, but also document where such subliminal face-processing occurs (i.e., restricted to face-responsive regions of occipital and temporal cortex) and to what extent (i.e., independent of the specific image).

To understand the relationship between the structure and function of primate neocortical areas at a molecular level, we have been screening for genes differentially expressed across macaque neocortical areas by restriction landmark cDNA scanning (RLCS). Here, we report enriched expression of the paraneoplastic antigen-like 5 gene (PNMA5) in association areas but not in primary sensory areas, with the lowest expression level in primary visual cortex. In situ hybridization in the primary sensory areas revealed PNMA5 mRNA expression restricted to layer II. Along the ventral visual pathway, the expression gradually increased in the excitatory neurons from the primary to higher visual areas. This differential expression pattern was very similar to that of retinol-binding protein (RBP) mRNA, another association-area-enriched gene that we reported previously. Additional expression analysis for comparison of other genes in the PNMA gene family, PNMA1, PNMA2, PNMA3, and MOAP1 (PNMA4), showed that they were widely expressed across areas and layers but without the differentiated pattern of PNMA5. In mouse brains, PNMA1 was only faintly expressed and PNMA5 was not detected. Sequence analysis showed divergence of PNMA5 sequences among mammals. These findings suggest that PNMA5 acquired a certain specialized role in the association areas of the neocortex during primate evolution.