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Introduction: Recent research has explored the effectiveness of interactive virtual experiences in managing pain and anxiety in children during routine medical procedures, compared to conventional care methods. However, the influence of the specific technology used as an interface, 3-dimensions (D) immersive virtual reality (VR) vs. 2D touch screens, during pediatric venipuncture, remains unexamined. This study aimed to determine if immersive VR is more effective than a tablet in reducing pain and anxiety during short procedures., Methods: An interactive game was designed by clinicians and psychologists, expert in pain theory, hypnosis, and procedural pain and anxiety relief, and was tailored for both VR and tablet use. Fifty patients were randomly assigned to either the Tablet or VR group. The primary outcome measures were pain and anxiety levels during the procedure. Secondary outcome measures included the need for physical restraint, duration of the procedure, enjoyment levels, and satisfaction ratings from both parents and nurses., Results: Participants, in both groups, had low levels of pain and anxiety. Physical restraint was infrequently used, procedures were brief, and high satisfaction levels were reported by patients, parents, and nurses., Discussion: This study suggests that the type of technology used as a support for the game has a minimal effect on the child's experience, with both groups reporting low pain and anxiety levels, minimal physical restraint, and high enjoyment. Despite immersive VR's technological advancements, this study underscores the value of traditional tablets with well-designed interactive games in enhancing children's wellbeing during medical procedures., Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT05065307]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Zavlanou, Savary, Mermet, Sander, Corradi-Dell'Acqua, Rudrauf, Tisserand and Sahyoun.)

Consciousness has been described as acting as a global workspace that integrates perception, imagination, emotion and action programming for adaptive decision making. The mechanisms of this workspace and their relationships to the phenomenology of consciousness need to be further specified. Much research in this area has focused on the neural correlates of consciousness, but, arguably, computational modeling can better be used toward this aim. According to the Projective Consciousness Model (PCM), consciousness is structured as a viewpoint-organized, internal space, relying on 3D projective geometry and governed by the action of the Projective Group as part of a process of active inference. The geometry induces a group-structured subjective perspective on an encoded world model, enabling adaptive perspective taking in agents. Here, we review and discuss the PCM. We emphasize the role of projective mechanisms in perception and the appraisal of affective and epistemic values as tied to the motivation of action, under an optimization process of Free Energy minimization, or more generally stochastic optimal control. We discuss how these mechanisms enable us to model and simulate group-structured drives in the context of social cognition and to understand the mechanisms underpinning empathy, emotion expression and regulation, and approach-avoidance behaviors. We review previous results, drawing on applications in robotics and virtual humans. We briefly discuss future axes of research relating to applications of the model to simulation- and model-based behavioral science, geometrically structured artificial neural networks, the relevance of the approach for explainable AI and human-machine interactions, and the study of the neural correlates of consciousness.

In our response to a truly diverse set of commentaries, we first summarize the principal topical themes around which they cluster, then address two "outlier" positions (the problem of consciousness has been solved vs. is intractable). Next, we address ways in which commentaries by non-integrated information theory (IIT) authors engage with the specifics of our IIT critique, turning finally to the four commentaries by IIT authors.

Giulio Tononi's integrated information theory (IIT) proposes explaining consciousness by directly identifying it with integrated information. We examine the construct validity of IIT's measure of consciousness, phi (Φ), by analyzing its formal properties, its relation to key aspects of consciousness, and its co-variation with relevant empirical circumstances. Our analysis shows that IIT's identification of consciousness with the causal efficacy with which differentiated networks accomplish global information transfer (which is what Φ in fact measures) is mistaken. This misidentification has the consequence of requiring the attribution of consciousness to a range of natural systems and artifacts that include, but are not limited to, large-scale electrical power grids, gene-regulation networks, some electronic circuit boards, and social networks. Instead of treating this consequence of the theory as a disconfirmation, IIT embraces it. By regarding these systems as bearers of consciousness ex hypothesi, IIT is led toward the orbit of panpsychist ideation. This departure from science as we know it can be avoided by recognizing the functional misattribution at the heart of IIT's identity claim. We show, for example, what function is actually performed, at least in the human case, by the cortical combination of differentiation with integration that IIT identifies with consciousness. Finally, we examine what lessons may be drawn from IIT's failure to provide a credible account of consciousness for progress in the very active field of research concerned with exploring the phenomenon from formal and neural points of view.

Functional neuroimaging research has consistently associated brain structures within the default mode network (DMN) and frontoparietal network (FPN) with mind-wandering. Targeted lesion research has documented impairments in mind-wandering after damage to the medial prefrontal cortex (mPFC) and hippocampal regions associated with the DMN. However, no lesion studies to date have applied lesion network mapping to identify common networks associated with deficits in mind-wandering. In lesion network mapping, resting-state functional connectivity data from healthy participants are used to infer which brain regions are functionally connected to each lesion location from a sample with brain injury. In the current study, we conducted a lesion network mapping analysis to test the hypothesis that lesions affecting the DMN and FPN would be associated with diminished mind-wandering. We assessed mind-wandering frequency on the Imaginal Processes Inventory (IPI) in participants with brain injury (n = 29) and healthy comparison participants without brain injury (n = 19). Lesion network mapping analyses showed the strongest association of reduced mind-wandering with the left inferior parietal lobule within the DMN. In addition, traditional lesion symptom mapping results revealed that reduced mind-wandering was associated with lesions of the dorsal, ventral, and anterior sectors of mPFC, parietal lobule, and inferior frontal gyrus in the DMN (p < 0.05 uncorrected). These findings provide novel lesion support for the role of the DMN in mind-wandering and contribute to a burgeoning literature on the neural correlates of spontaneous cognition., (© 2020 Wiley Periodicals, LLC.)

Models of consciousness should account for the phenomenology of subjective experience, including perceptual illusions. The Moon Illusion is a paradigmatic example that has yet to be accounted for. The Moon often appears larger near the perceptual horizon and smaller high in the sky, though the visual angle subtended is invariant. We show how this illusion can result from the optimization of a 3D projective geometrical frame through free energy minimization, following the principles of the Projective Consciousness Model. The model accounts for all documented modulations of the illusion without anomalies (e.g., the "size-distance paradox"), surpasses other theories in explanatory power, makes sense of inter- and intra-subjective variability vis-à-vis the illusion, and yields new quantitative and qualitative predictions. Empirical data from a virtual reality experiment support the predictions of the model. We also discuss how the model suggests explanations for other relevant illusions, concerning objects both at far and nearer distances, including the sky dome illusion, illusions of perceived size observed in the context of crowding experiments, and the Ames Room illusion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Meditation is commonly assumed to be associated with enhanced interoceptive accuracy. We previously found that experienced meditators did not exhibit a greater ability than nonmeditators to detect heartbeat sensations at rest, despite the meditators' reported subjective ratings of higher accuracy and lower difficulty. Here, attempting to overcome previous methodological limitations, we assessed interoceptive awareness of heartbeat and breathing sensations across physiological arousal levels using infusions of isoproterenol, a beta-adrenergic agonist similar to adrenaline. We hypothesized that meditators would display greater interoceptive awareness than nonmeditators, as evidenced by higher interoceptive detection rates, increased interoceptive accuracy, and differences in localization of heartbeat sensations. We studied 15 meditators and 15 nonmeditators, individually matched on age, gender, and body mass index, using randomized, double-blinded, and placebo-controlled bolus infusions of isoproterenol. Participants reported their experience of heartbeat and breathing sensations using a dial during infusions and the location of heartbeat sensations on a two-dimensional manikin afterward. There was no evidence of higher detection rates or increased accuracy across any dose, although meditators showed a tendency to report cardiorespiratory sensation changes sooner at higher doses. Relative to nonmeditators, meditators exhibited prominent geographical differences in heartbeat localization, disproportionally reporting sensations throughout central regions of the chest, abdomen, neck, back, and head. To further assess indications of potential differences in cardiac interoceptive accuracy between meditators and nonmeditators, we conducted a meta-analysis including 724 participants and found little evidence for such differences. We conclude that the practice of meditation is not associated with improved cardiac interoceptive awareness., (© 2019 Society for Psychophysiological Research.)

We summarize our recently introduced Projective Consciousness Model (PCM) (Rudrauf et al., 2017) and relate it to outstanding conceptual issues in the theory of consciousness. The PCM combines a projective geometrical model of the perspectival phenomenological structure of the field of consciousness with a variational Free Energy minimization model of active inference, yielding an account of the cybernetic function of consciousness, viz., the modulation of the field's cognitive and affective dynamics for the effective control of embodied agents. The geometrical and active inference components are linked via the concept of projective transformation, which is crucial to understanding how conscious organisms integrate perception, emotion, memory, reasoning, and perspectival imagination in order to control behavior, enhance resilience, and optimize preference satisfaction. The PCM makes substantive empirical predictions and fits well into a (neuro)computationalist framework. It also helps us to account for aspects of subjective character that are sometimes ignored or conflated: pre-reflective self-consciousness, the first-person point of view, the sense of minenness or ownership, and social self-consciousness. We argue that the PCM, though still in development, offers us the most complete theory to date of what Thomas Metzinger has called "phenomenal selfhood."

In patients with pharmaco-resistant focal epilepsies investigated with intracranial electroencephalography (iEEG), direct electrical stimulations of a cortical region induce cortico-cortical evoked potentials (CCEP) in distant cerebral cortex, which properties can be used to infer large scale brain connectivity. In 2013, we proposed a new probabilistic functional tractography methodology to study human brain connectivity. We have now been revisiting this method in the F-TRACT project (f-tract.eu) by developing a large multicenter CCEP database of several thousand stimulation runs performed in several hundred patients, and associated processing tools to create a probabilistic atlas of human cortico-cortical connections. Here, we wish to present a snapshot of the methods and data of F-TRACT using a pool of 213 epilepsy patients, all studied by stereo-encephalography with intracerebral depth electrodes. The CCEPs were processed using an automated pipeline with the following consecutive steps: detection of each stimulation run from stimulation artifacts in raw intracranial EEG (iEEG) files, bad channels detection with a machine learning approach, model-based stimulation artifact correction, robust averaging over stimulation pulses. Effective connectivity between the stimulated and recording areas is then inferred from the properties of the first CCEP component, i.e. onset and peak latency, amplitude, duration and integral of the significant part. Finally, group statistics of CCEP features are implemented for each brain parcel explored by iEEG electrodes. The localization (coordinates, white/gray matter relative positioning) of electrode contacts were obtained from imaging data (anatomical MRI or CT scans before and after electrodes implantation). The iEEG contacts were repositioned in different brain parcellations from the segmentation of patients' anatomical MRI or from templates in the MNI coordinate system. The F-TRACT database using the first pool of 213 patients provided connectivity probability values for 95% of possible intrahemispheric and 56% of interhemispheric connections and CCEP features for 78% of intrahemisheric and 14% of interhemispheric connections. In this report, we show some examples of anatomo-functional connectivity matrices, and associated directional maps. We also indicate how CCEP features, especially latencies, are related to spatial distances, and allow estimating the velocity distribution of neuronal signals at a large scale. Finally, we describe the impact on the estimated connectivity of the stimulation charge and of the contact localization according to the white or gray matter. The most relevant maps for the scientific community are available for download on f-tract. eu (David et al., 2017) and will be regularly updated during the following months with the addition of more data in the F-TRACT database. This will provide an unprecedented knowledge on the dynamical properties of large fiber tracts in human., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The mirror-gazing task (MGT) experimentally induces illusions, ranging from simple color changes in the specular image of oneself, to depersonalization-like anomalous self-experiences (ASE) as in experiencing one's specular image as someone else. The objective was to characterize how connectivity in resting-state networks (RSNs) differed in adolescents reporting such depersonalization-like ASEs during the MGT, in a cross-sectional (Y1) and in a longitudinal manner (a year after). 75 adolescents were recruited; for the cross-sectional analysis, participants were split into 2 groups: those who reported depersonalization-like ASEs on the MGT (ASE), and those who did not (NoASE). For the longitudinal analysis, participants were split into 3 groups whether they experienced MGT depersonalization-like ASEs: only at Y1 (Remitters), both times (Persisters), or never (Controls). Participants also filled out self-reports assessing schizotypal personality (Schizotypal Personality Questionnaire [SPQ]), and underwent resting-state functional MRI procedure (rs-fMRI). A group level Independent Component Analysis (ICA) was conducted and voxel-wise inter-group differences within RSNs were examined. The rs-fMRI analysis revealed lower connectivity of specific visual areas within the primary visual network (PVN), and higher connectivity of regions within the Default Mode Network (DMN) when contrasting the ASE and NoASE groups. The areas that were atypically connected within the PVN further presented differential pattern of connectivity in the longitudinal analysis. Atypical connectivity of visual area within the DMN at Y1 was associated with higher scores on the disorganized dimension of schizotypy at the second evaluation. The present study uncovers a subtle signature in the RSNs of non-clinical adolescents who experienced task-induced ASEs.

We introduce a mathematical model of embodied consciousness, the Projective Consciousness Model (PCM), which is based on the hypothesis that the spatial field of consciousness (FoC) is structured by a projective geometry and under the control of a process of active inference. The FoC in the PCM combines multisensory evidence with prior beliefs in memory and frames them by selecting points of view and perspectives according to preferences. The choice of projective frames governs how expectations are transformed by consciousness. Violations of expectation are encoded as free energy. Free energy minimization drives perspective taking, and controls the switch between perception, imagination and action. In the PCM, consciousness functions as an algorithm for the maximization of resilience, using projective perspective taking and imagination in order to escape local minima of free energy. The PCM can account for a variety of psychological phenomena: the characteristic spatial phenomenology of subjective experience, the distinctions and integral relationships between perception, imagination and action, the role of affective processes in intentionality, but also perceptual phenomena such as the dynamics of bistable figures and body swap illusions in virtual reality. It relates phenomenology to function, showing the computational advantages of consciousness. It suggests that changes of brain states from unconscious to conscious reflect the action of projective transformations and suggests specific neurophenomenological hypotheses about the brain, guidelines for designing artificial systems, and formal principles for psychology., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Deep brain stimulation (DBS) of the subgenual cingulate gyrus (area CG25) is beneficial in treatment resistant depression. Though the mechanisms of action of Cg25 DBS remain largely unknown, it is commonly believed that Cg25 DBS modulates limbic activity of large networks to achieve thymic regulation of patients. To investigate how emotional attention is influenced by Cg25 DBS, we assessed behavioral and electroencephalographic (EEG) responses to an emotional Stroop task in 5 patients during ON and OFF stimulation conditions. Using EEG source localization, we found that the main effect of DBS was a reduction of neuronal responses in limbic regions (temporal pole, medial prefrontal and posterior cingulate cortices) and in ventral visual areas involved in face processing. In the dynamic causal modeling (DCM) approach, the changes of the evoked response amplitudes are assumed to be due to changes of long range connectivity induced by Cg25 DBS. Here, using a simplified neural mass model that did not take explicitly into account the cytoarchitecture of the considered brain regions, we showed that the remote action of Cg25 DBS could be explained by a reduced top-down effective connectivity of the amygdalo-temporo-polar complex. Overall, our results thus indicate that Cg25 DBS during the emotional Stroop task causes a decrease of top-down limbic influence on the ventral visual stream itself, rather than a modulation of prefrontal cognitive processes only. Tuning down limbic excitability in relation to sensory processing might be one of the biological mechanisms through which Cg25 DBS produces positive clinical outcome in the treatment of resistant depression., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Brain computation relies on effective interactions between ensembles of neurons. In neuroimaging, measures of functional connectivity (FC) aim at statistically quantifying such interactions, often to study normal or pathological cognition. Their capacity to reflect a meaningful variety of patterns as expected from neural computation in relation to cognitive processes remains debated. The relative weights of time-varying local neurophysiological dynamics versus static structural connectivity (SC) in the generation of FC as measured remains unsettled. Empirical evidence features mixed results: from little to significant FC variability and correlation with cognitive functions, within and between participants. We used a unified approach combining multivariate analysis, bootstrap and computational modeling to characterize the potential variety of patterns of FC and SC both qualitatively and quantitatively. Empirical data and simulations from generative models with different dynamical behaviors demonstrated, largely irrespective of FC metrics, that a linear subspace with dimension one or two could explain much of the variability across patterns of FC. On the contrary, the variability across BOLD time-courses could not be reduced to such a small subspace. FC appeared to strongly reflect SC and to be partly governed by a Gaussian process. The main differences between simulated and empirical data related to limitations of DWI-based SC estimation (and SC itself could then be estimated from FC). Above and beyond the limited dynamical range of the BOLD signal itself, measures of FC may offer a degenerate representation of brain interactions, with limited access to the underlying complexity. They feature an invariant common core, reflecting the channel capacity of the network as conditioned by SC, with a limited, though perhaps meaningful residual variability., Competing Interests: The authors have declared that no competing interests exist.

Background: Effective connectivity can be explored using direct electrical stimulations in patients suffering from drug-resistant focal epilepsies and investigated with intracranial electrodes. Responses to brief electrical pulses mimic the physiological propagation of signals and manifest as cortico-cortical evoked potentials (CCEP). The first CCEP component is believed to reflect direct connectivity with the stimulated region but the stimulation artifact, a sharp deflection occurring during a few milliseconds, frequently contaminates it., New Method: In order to recover the characteristics of early CCEP responses, we developed an artifact correction method based on electrical modeling of the electrode-tissue interface. The biophysically motivated artifact templates are then regressed out of the recorded data as in any classical template-matching removal artifact methods., Results: Our approach is able to make the distinction between the physiological responses time-locked to the stimulation pulses and the non-physiological component. We tested the correction on simulated CCEP data in order to quantify its efficiency for different stimulation and recording parameters. We demonstrated the efficiency of the new correction method on simulations of single trial recordings for early responses contaminated with the stimulation artifact. The results highlight the importance of sampling frequency for an accurate analysis of CCEP. We then applied the approach to experimental data., Comparison With Existing Method: The model-based template removal was compared to a correction based on the subtraction of the averaged artifact., Conclusions: This new correction method of stimulation artifact will enable investigators to better analyze early CCEP components and infer direct effective connectivity in future CCEP studies., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Functional neuroimaging investigations of pain have discovered a reliable pattern of activation within limbic regions of a putative "pain matrix" that has been theorized to reflect the affective dimension of pain. To test this theory, we evaluated the experience of pain in a rare neurological patient with extensive bilateral lesions encompassing core limbic structures of the pain matrix, including the insula, anterior cingulate, and amygdala. Despite widespread damage to these regions, the patient's expression and experience of pain was intact, and at times excessive in nature. This finding was consistent across multiple pain measures including self-report, facial expression, vocalization, withdrawal reaction, and autonomic response. These results challenge the notion of a "pain matrix" and provide direct evidence that the insula, anterior cingulate, and amygdala are not necessary for feeling the suffering inherent to pain. The patient's heightened degree of pain affect further suggests that these regions may be more important for the regulation of pain rather than providing the decisive substrate for pain's conscious experience.

Lesion-deficit studies support the hypothesis that the left anterior temporal lobe (ATL) plays a critical role in retrieving names of concrete entities. They further suggest that different regions of the left ATL process different conceptual categories. Here we test the specificity of these relationships and whether the anatomical segregation is related to the underlying organization of white matter connections. We reanalyzed data from a previous lesion study of naming and recognition across five categories of concrete entities. In voxelwise logistic regressions of lesion-deficit associations, we formally incorporated measures of disconnection of long-range association fiber tracts (FTs) and covaried for recognition and non-category-specific naming deficits. We also performed fiber tractwise analyses to assess whether damage to specific FTs was preferentially associated with category-selective naming deficits. Damage to the basolateral ATL was associated with naming deficits for both unique (famous faces) and non-unique entities, whereas the damage to the temporal pole was associated with naming deficits for unique entities only. This segregation pattern remained after accounting for comorbid recognition deficits or naming deficits in other categories. The tractwise analyses showed that damage to the uncinate fasciculus (UNC) was associated with naming impairments for unique entities, while damage to the inferior longitudinal fasciculus (ILF) was associated with naming impairments for non-unique entities. Covarying for FT transection in voxelwise analyses rendered the cortical association for unique entities more focal. These results are consistent with the partial segregation of brain system support for name retrieval of unique and non-unique entities at both the level of cortical components and underlying white matter fiber bundles. Our study reconciles theoretic accounts of the functional organization of the left ATL by revealing both category-related processing and semantic hub sectors., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Meditation is commonly thought to induce physiologically quiescent states, as evidenced by decreased autonomic parameters during the meditation practice including reduced heart rate, respiratory rate, blood pressure, skin conductance, and increased alpha activity in the electroencephalogram. Preliminary empirical support for this idea was provided in a case report by Dimsdale and Mills (2002), where it was found that meditation seemed to regulate increased levels of cardiovascular arousal induced by bolus isoproterenol infusions. In that study, while meditating, a self-taught meditator exhibited unexpected decreases in heart rate while receiving moderate intravenous doses of the beta adrenergic agonist isoproterenol. This effect was no longer observed when the individual received isoproterenol infusions while not meditating. The current study was designed to explore this phenomenon empirically in a group of formally trained meditators. A total of 15 meditators and 15 non-meditators individually matched on age, sex, and body mass index were recruited. Participants received four series of infusions in a pseudorandomized order: isoproterenol while meditating (or during a relaxation condition for the non-meditators), isoproterenol while resting, saline while meditating (or during a relaxation condition for the non-meditators), and saline while resting. Heart rate was continuously measured throughout all infusions, and several measures of heart rate were derived from the instantaneous cardiac waveform. There was no evidence at the group or individual level suggesting that meditation reduced the cardiovascular response to isoproterenol, across all measures. These results suggest that meditation is not associated with increased regulation of elevated cardiac adrenergic tone.

The relationship between structural connectivity (SC) and functional connectivity (FC) in the human brain can be studied using magnetic resonance imaging (MRI). However many of the underlying physiological mechanisms and parameters cannot be directly observed with MRI. This limitation has motivated the recent use of various computational models meant to bridge the gap. However their absolute and relative explanatory power and the properties that actually drive that power remain insufficiently characterized. We performed an extensive comparison of seven mainstream computational models predicting FC from SC. We investigated the extent to which simulated FC could predict empirical FC. We also applied graph theory to the entire set of simulated and empirical FCs in order to further characterize the relationships between the models and the MRI data. The comparison was performed at three different spatial scales. We found that (i) there were significant effects of scale and model on predictive power; (ii) among all models, the simplest model, the simultaneous autoregressive (SAR) model, was found to consistently perform better than the other models; (iii) the SAR also appeared more 'central' from a graph theory perspective; and (iv) empirical FC only appeared weakly correlated with simulated FCs, and was featured as 'peripheral' in the graph analysis. We conclude that the substantial differences existing between these computational models have little impact on their predictive power for FC and that their capacity to predict FC from SC appears to be both moderate and essentially underlined by a simple core linear process embodied by the SAR model., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Functional neuroimaging studies have implicated the default mode network (DMN) in autobiographical memory (AM). Convergent evidence from a lesion approach would help clarify the role of the DMN in AM. In this study, we used a voxelwise lesion-deficit approach to test the hypothesis that regions of the DMN are necessary for AM. We also explored whether the neural correlates of semantic AM (SAM) and episodic AM (EAM) were overlapping or distinct. Using the Iowa Autobiographical Memory Questionnaire, we tested AM retrieval in 92 patients with focal, stable brain lesions. In support of our hypothesis, damage to regions within the DMN (medial prefrontal cortex, mPFC; posterior cingulate cortex, PCC; inferior parietal lobule, IPL; medial temporal lobe, MTL) was associated with AM impairments. Within areas of effective lesion coverage, the neural correlates of SAM and EAM were largely distinct, with limited areas of overlap in right IPL. Whereas SAM deficits were associated with left mPFC and MTL damage, EAM deficits were associated with right mPFC and MTL damage. These results provide novel neuropsychological evidence for the necessary role of parts of the DMN in AM. More broadly, the findings shed new light on how the DMN participates in self-referential processing., (© The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Elucidating the brain basis for psychological processes and behavior is a fundamental aim of cognitive neuroscience. The lesion method, using voxel-based statistical analysis, is an important approach to this goal, identifying neural structures that are necessary for the support of specific mental operations, and complementing the strengths of functional imaging techniques. Lesion coverage in a population is by nature spatially heterogeneous and biased, systematically affecting the ability of lesion-deficit correlation methods to detect and localize functional associations. We have developed a simulator that allows investigators to model parameters in a lesion-deficit study and characterize the statistical bias in lesion deficit detection coverage that will result from specific assumptions. We used the simulator to assess the signal detection properties and localization accuracy of standard lesion-deficit correlation methods, under a simple truth model - that a critical region of interest (CR), when damaged, gives rise to a deficit. We considered voxel-based lesion-symptom mapping (VLSM) and proportional MAP-3 (PM3). Using regression analysis, we examined if the pattern of outcome statistics can be explained by simulation parameters, factors that are inherent to anatomic parcels, and lesion coverage of the population, which consisted of a representative sample of 351 subjects drawn from the Iowa Patient Registry. We examined the effect of using nonparametric versus parametric statistics to obtain thresholded maps and the effect of correcting for multiple comparisons using false discovery rate or cluster-based correction. Our results, which are derived from samples of realistic lesions, indicate that even a simple truth model yields localization errors that are systematic and pervasive, averaging 2 cm in the standard anatomic space, and tending to be directed towards areas of greater anatomic coverage. This displacement positions the center of mass of the detected region in a different anatomical region 87% of the time. This basic result is not affected by the choice of PM3 vs VLSM as the fundamental approach, nor is localization error ameliorated by incorporation of lesion size as a covariate in the VLSM approach, or by data distribution-driven approaches to controlling multiple spatial comparisons (false discovery rate or cluster-based correction approaches). Our simulations offer a quantitative basis for interpreting lesion studies in cognitive neuroscience. We suggest ways in which lesion simulation and analysis frameworks could be productively extended.

Investigating the relationship between brain structure and function is a central endeavor for neuroscience research. Yet, the mechanisms shaping this relationship largely remain to be elucidated and are highly debated. In particular, the existence and relative contributions of anatomical constraints and dynamical physiological mechanisms of different types remain to be established. We addressed this issue by systematically comparing functional connectivity (FC) from resting-state functional magnetic resonance imaging data with simulations from increasingly complex computational models, and by manipulating anatomical connectivity obtained from fiber tractography based on diffusion-weighted imaging. We hypothesized that FC reflects the interplay of at least three types of components: (i) a backbone of anatomical connectivity, (ii) a stationary dynamical regime directly driven by the underlying anatomy, and (iii) other stationary and non-stationary dynamics not directly related to the anatomy. We showed that anatomical connectivity alone accounts for up to 15% of FC variance; that there is a stationary regime accounting for up to an additional 20% of variance and that this regime can be associated to a stationary FC; that a simple stationary model of FC better explains FC than more complex models; and that there is a large remaining variance (around 65%), which must contain the non-stationarities of FC evidenced in the literature. We also show that homotopic connections across cerebral hemispheres, which are typically improperly estimated, play a strong role in shaping all aspects of FC, notably indirect connections and the topographic organization of brain networks.

How does the brain integrate multiple sources of information to support normal sensorimotor and cognitive functions? To investigate this question we present an overall brain architecture (called "the dual intertwined rings architecture") that relates the functional specialization of cortical networks to their spatial distribution over the cerebral cortex (or "corticotopy"). Recent results suggest that the resting state networks (RSNs) are organized into two large families: 1) a sensorimotor family that includes visual, somatic, and auditory areas and 2) a large association family that comprises parietal, temporal, and frontal regions and also includes the default mode network. We used two large databases of resting state fMRI data, from which we extracted 32 robust RSNs. We estimated: (1) the RSN functional roles by using a projection of the results on task based networks (TBNs) as referenced in large databases of fMRI activation studies; and (2) relationship of the RSNs with the Brodmann Areas. In both classifications, the 32 RSNs are organized into a remarkable architecture of two intertwined rings per hemisphere and so four rings linked by homotopic connections. The first ring forms a continuous ensemble and includes visual, somatic, and auditory cortices, with interspersed bimodal cortices (auditory-visual, visual-somatic and auditory-somatic, abbreviated as VSA ring). The second ring integrates distant parietal, temporal and frontal regions (PTF ring) through a network of association fiber tracts which closes the ring anatomically and ensures a functional continuity within the ring. The PTF ring relates association cortices specialized in attention, language and working memory, to the networks involved in motivation and biological regulation and rhythms. This "dual intertwined architecture" suggests a dual integrative process: the VSA ring performs fast real-time multimodal integration of sensorimotor information whereas the PTF ring performs multi-temporal integration (i.e., relates past, present, and future representations at different temporal scales).

A considerable body of previous research on the prefrontal cortex (PFC) has helped characterize the regional specificity of various cognitive functions, such as cognitive control and decision making. Here we provide definitive findings on this topic, using a neuropsychological approach that takes advantage of a unique dataset accrued over several decades. We applied voxel-based lesion-symptom mapping in 344 individuals with focal lesions (165 involving the PFC) who had been tested on a comprehensive battery of neuropsychological tasks. Two distinct functional-anatomical networks were revealed within the PFC: one associated with cognitive control (response inhibition, conflict monitoring, and switching), which included the dorsolateral prefrontal cortex and anterior cingulate cortex and a second associated with value-based decision-making, which included the orbitofrontal, ventromedial, and frontopolar cortex. Furthermore, cognitive control tasks shared a common performance factor related to set shifting that was linked to the rostral anterior cingulate cortex. By contrast, regions in the ventral PFC were required for decision-making. These findings provide detailed causal evidence for a remarkable functional-anatomical specificity in the human PFC.

To further investigate the neural substrates of lexical and conceptual knowledge of actions, we administered a battery of six tasks to 226 brain-damaged patients with widely distributed lesions in the left and right cerebral hemispheres. The tasks probed lexical and conceptual knowledge of actions in a variety of verbal and non-verbal ways, including naming, word-picture matching, attribute judgments involving both words and pictures, and associative comparisons involving both words and pictures. Of the 226 patients who were studied, 61 failed one or more of the six tasks, with four patients being impaired on the entire battery, and varied numbers of patients being impaired on varied combinations of tasks. Overall, the 61 patients manifested a complex array of associations and dissociations across the six tasks. The lesion sites of 147 of the 226 patients were also investigated, using formal methods for lesion-deficit statistical mapping and power analysis of lesion overlap maps. Significant effects for all six tasks were found in the following left-hemisphere regions: the inferior frontal gyrus; the ventral precentral gyrus, extending superiorly into what are likely to be hand-related primary motor and premotor areas; and the anterior insula. In addition, significant effects for 4-5 tasks were found in not only the regions just mentioned, but also in several other left-hemisphere areas: the ventral postcentral gyrus; the supramarginal gyrus; and the posterior middle temporal gyrus. These results converge with previous research on the neural underpinnings of action words and concepts. However, the current study goes considerably beyond most previous investigations by providing extensive behavioral and lesion data for an unusually large and diverse sample of brain-damaged patients, and by incorporating multiple measures of verb comprehension. Regarding theoretical implications, the study provides new support for the Embodied Cognition Framework, which maintains that conceptual knowledge is grounded in sensorimotor systems., (Copyright © 2010 Elsevier Srl. All rights reserved.)

The amygdala's contribution to emotion, cognition and behavior depends on its interactions with subcortical and cortical regions. Amygdala lesions result in altered functional activity in connected regions, but it is not known whether there might be long-term structural sequelae as well. We hypothesized that developmental bilateral amygdala lesions would be associated with specific gray matter morphometric abnormalities in the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC) and the ventral visual stream. We conducted regions of interest and vertex-based analyses of structural MRI data acquired in two patients with long-standing focal bilateral amygdala lesions (S.M. and A.P.), compared to gender- and age-matched healthy comparison subjects. Both patients showed significant proportional increases in gray matter volume of the vmPFC. Cortical thickness was increased in the vmPFC and ACC and decreased in the ventral visual stream. There were no morphometric changes in dorsolateral prefrontal cortex or dorsal visual stream cortices. These findings support the hypothesis that cortical regions strongly connected with the amygdala undergo morphometric changes with long-standing amygdala damage. This is the first evidence in humans of the remote alteration of brain morphology in association with amygdala lesions, and will help in interpreting the structural and functional consequences of amygdala pathology in neuropsychiatric disorders.

In the following article we present a view that social cognition and social neuroscience, as shaped by the current research paradigms, are not sufficient to improve our understanding of psychopathological phenomena. We hold that the self, self-awareness, and inter-subjectivity are integral to social perception and actions. In addition, we emphasize that the self and self-awareness are, by their very nature and function, involved over the entire lifespan with the way the individual is perceived in the social environment. Likewise, the modes of operation and identification of the self and self-awareness receive strong developmental contributions from social interactions with parental figures, siblings, peers, and significant others. These contributions are framed by a competitive and cooperative struggle for love and recognition. We suggest that in humans social cognitive neuroscience should be informed by a thoughtful appreciation of the equal significance of the struggle for "life" and that for love and recognition. In order to be better positioned to improve the research agenda and practice of clinical psychiatry, we propose that cognitive and social neurosciences explicitly incorporate in their models phenomena relative to the self, self-awareness, and inter-subjectivity.

Functional neuroimaging studies suggest that the medial PFC (mPFC) is a key component of a large-scale neural system supporting a variety of self-related processes. However, it remains unknown whether the mPFC is critical for such processes. In this study, we used a human lesion approach to examine this question. We administered a standard trait judgment paradigm [Kelley, W. M., Macrae, C. N., Wyland, C. L., Caglar, S., Inati, S., & Heatherton, T. F. Finding the self? An event-related fMRI study. Journal of Cognitive Neuroscience, 14, 785-794, 2002] to patients with focal brain damage to the mPFC. The self-reference effect (SRE), a memory advantage conferred by self-related processing, served as a measure of intact self-processing ability. We found that damage to the mPFC abolished the SRE. The results demonstrate that the mPFC is necessary for the SRE and suggest that this structure is important for self-referential processing and the neural representation of self.

It has been proposed that self-awareness (SA), a multifaceted phenomenon central to human consciousness, depends critically on specific brain regions, namely the insular cortex, the anterior cingulate cortex (ACC), and the medial prefrontal cortex (mPFC). Such a proposal predicts that damage to these regions should disrupt or even abolish SA. We tested this prediction in a rare neurological patient with extensive bilateral brain damage encompassing the insula, ACC, mPFC, and the medial temporal lobes. In spite of severe amnesia, which partially affected his "autobiographical self", the patient's SA remained fundamentally intact. His Core SA, including basic self-recognition and sense of self-agency, was preserved. His Extended SA and Introspective SA were also largely intact, as he has a stable self-concept and intact higher-order metacognitive abilities. The results suggest that the insular cortex, ACC and mPFC are not required for most aspects of SA. Our findings are compatible with the hypothesis that SA is likely to emerge from more distributed interactions among brain networks including those in the brainstem, thalamus, and posteromedial cortices.

We report here a case study of a rare neurological patient with bilateral brain damage encompassing a substantial portion of the so-called "limbic system." The patient, Roger, has been studied in our laboratory for over 14 years, and the current article presents his complete neuroanatomical and neuropsychological profiles. The brain damage occurred in 1980 following an episode of herpes simplex encephalitis. The amount of destroyed neural tissue is extensive and includes bilateral damage to core limbic and paralimbic regions, including the hippocampus, amygdala, parahippocampal gyrus, temporal poles, orbitofrontal cortex, basal forebrain, anterior cingulate cortex, and insular cortex. The right hemisphere is more extensively affected than the left, although the lesions are largely bilateral. Despite the magnitude of his brain damage, Roger has a normal IQ, average to above-average attention, working memory, and executive functioning skills, and very good speech and language abilities. In fact, his only obvious presenting deficits are a dense global amnesia and a severe anosmia and ageusia. Roger's case presents a rare opportunity to advance our understanding of the critical functions underlying the human limbic system, and the neuropsychological and neuroanatomical data presented here provide a critical foundation for such investigations.

An array of cortical and subcortical structures have been implicated in the recognition of emotion from facial expressions. It remains unknown how these regions communicate as parts of a system to achieve recognition, but white matter tracts are likely critical to this process. We hypothesized that (1) damage to white matter tracts would be associated with recognition impairment and (2) the degree of disconnection of association fiber tracts [inferior longitudinal fasciculus (ILF) and/or inferior fronto-occipital fasciculus (IFOF)] connecting the visual cortex with emotion-related regions would negatively correlate with recognition performance. One hundred three patients with focal, stable brain lesions mapped onto a reference brain were tested on their recognition of six basic emotional facial expressions. Association fiber tracts from a probabilistic atlas were coregistered to the reference brain. Parameters estimating disconnection were entered in a general linear model to predict emotion recognition impairments, accounting for lesion size and cortical damage. Damage associated with the right IFOF significantly predicted an overall facial emotion recognition impairment and specific impairments for sadness, anger, and fear. One subject had a pure white matter lesion in the location of the right IFOF and ILF. He presented specific, unequivocal emotion recognition impairments. Additional analysis suggested that impairment in fear recognition can result from damage to the IFOF and not the amygdala. Our findings demonstrate the key role of white matter association tracts in the recognition of the facial expression of emotion and identify specific tracts that may be most critical.