Publications

Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery.

While most theories of consciousness posit some kind of dependence on global network activities, I consider here an alternative, localist perspective—in which localized cortical regions each underlie the emergence of a unique category of conscious experience. Under this perspective, the large-scale activation often found in the cortex is a consequence of the complexity of typical conscious experiences rather than an obligatory condition for the emergence of conscious awareness—which can flexibly shift, depending on the richness of its contents, from local to more global activation patterns. This perspective fits a massive body of human imaging, recordings, lesions and stimulation data but opens a fundamental problem: how can the information, defining each content, be derived locally in each cortical region. Here, I will discuss a solution echoing pioneering structuralist ideas in which the content of a conscious experience is defined by its relationship to all other contents within an experiential category. In neuronal terms, this relationship structure between contents is embodied by the local geometry of similarity distances between cortical activation patterns generated during each conscious experience, likely mediated via networks of local neuronal connections. Thus, in order for any conscious experience to appear in an individual’s mind, two central conditions must be met. First, a specific configural pattern (“bar-code”) of neuronal activity must appear within a local relational geometry, i.e. a cortical area. Second, the individual neurons underlying the activated pattern must be bound into a unified functional ensemble through a burst of recurrent neuronal firing: local “ignitions”.

Resting-state fluctuations are ubiquitous and widely studied phenomena of the human brain, yet we are largely in the dark regarding their function in human cognition. Here we examined the hypothesis that resting-state fluctuations underlie the generation of free and creative human behaviors. In our experiment, participants were asked to perform three voluntary verbal tasks: a verbal fluency task, a verbal creativity task, and a divergent thinking task, during functional magnetic resonance imaging scanning. Blood oxygenation level dependent (BOLD)-activity during these tasks was contrasted with a control- deterministic verbal task, in which the behavior was fully determined by external stimuli. Our results reveal that all voluntary verbal-generation responses displayed a gradual anticipatory buildup that preceded the deterministic control-related responses. Critically, the time-frequency dynamics of these anticipatory buildups were significantly correlated with resting-state fluctuations' dynamics. These correlations were not a general BOLD-related or verbal-response related result, as they were not found during the externally determined verbal control condition. Furthermore, they were located in brain regions known to be involved in language production, specifically the left inferior frontal gyrus. These results suggest a common function of resting-state fluctuations as the neural mechanism underlying the generation of free and creative behaviors in the human cortex.

A major limitation of conventional human brain research has been its basis in highly artificial laboratory experiments. Due to technical constraints, little is known about the nature of cortical activations during ecological real life. We have previously proposed the "spontaneous trait reactivation (STR)" hypothesis arguing that resting-state patterns, which emerge spontaneously in the absence of external stimulus, reflect the statistics of habitual cortical activations during real life. Therefore, these patterns can serve as a window into daily life cortical activity. A straightforward prediction of this hypothesis is that spontaneous patterns should preferentially correlate to patterns generated by naturalistic stimuli compared with artificial ones. Here we targeted high-level category-selective visual areas and tested this prediction by comparing BOLD functional connectivity patterns formed during rest to patterns formed in response to naturalistic stimuli, as well as to more artificial category-selective, dynamic stimuli. Our results revealed a significant correlation between the resting-state patterns and functional connectivity patterns generated by naturalistic stimuli. Furthermore, the correlations to naturalistic stimuli were significantly higher than those found between resting-state patterns and those generated by artificial control stimuli. These findings provide evidence of a stringent link between spontaneous patterns and the activation patterns during natural vision.

Hippocampal sharp-wave ripples (SWRs) constitute one of the most synchronized activation events in the brain and play a critical role in offline memory consolidation. Yet their cognitive content and function during awake, conscious behavior remains unclear. We directly examined this question using intracranial recordings in human patients engaged in episodic free recall of previously viewed photographs. Our results reveal a content-selective increase in hippocampal ripple rate emerging 1 to 2 seconds prior to recall events. During recollection, high-order visual areas showed pronounced SWR-coupled reemergence of activation patterns associated with recalled content. Finally, the SWR rate during encoding predicted subsequent free-recall performance. These results point to a role for hippocampal SWRs in triggering spontaneous recollections and orchestrating the reinstatement of cortical representations during free episodic memory retrieval.

In the absence of a task, the human brain enters a mode of slow spontaneous fluctuations. A fundamental, unresolved question is whether these fluctuations are ongoing and thus persist during task engagement, or alternatively, are quenched and replaced by task-related activations. Here, we examined this issue in the human visual cortex, using fMRI. Participants were asked to either perform a recognition task of randomly appearing face and non-face targets (attended condition) or watch them passively (unattended condition). Importantly, in approximately half of the trials, all sensory stimuli were absent. Our results show that even in the absence of stimuli, spontaneous fluctuations were suppressed by attention. The effect occurred in early visual cortex as well as in fronto-parietal attention network regions. During unattended trials, the activity fluctuations were negatively linked to pupil diameter, arguing against attentional fluctuations as underlying the effect. The results demonstrate that spontaneous fluctuations do not remain unchanged with task performance, but are rather modulated according to behavioral and cognitive demands.

The idea that abstract words are grounded in our sensorimotor experience is gaining support and popularity, as observed in the increasing number of studies dealing with "neurosemantics." Therefore, it is important to form models that explain how to bridge the gap between basic bodily experiences and abstract language. This paper focuses on the embodiment of connotations, such as "sweet" in "sweet baby," where the adjective has been abstracted from its concrete and embodied sense. We summarize several findings from recent studies in neuroscience and the cognitive sciences suggesting that emotion, body, and language are three factors required for understanding the emergence of abstract words, and (1) propose a model explaining how these factors contribute to the emergence of connotations, (2) formulate a computational model instantiating our theoretical model, and (3) test our model in a task involving the automatic identification of connotations. The results support our model pointing to the role of embodiment in the formation of connotations.

The fusiform gyrus (FG) is an important node in the face processing network, but knowledge of its causal role in face perception is currently limited. Recent work demonstrated that high frequency stimulation applied to the FG distorts the perception of faces in human subjects (Parvizi et al. [2012]: J Neurosci 32: 14915-14920). However, the timing of this process in the FG relative to stimulus onset and the spatial extent of FG's role in face perception are unknown. Here, we investigate the causal role of the FG in face perception by applying precise, event-related electrical stimulation (ES) to higher order visual areas including the FG in six human subjects undergoing intracranial monitoring for epilepsy. We compared the effects of single brief (100 ls) electrical pulses to the FG and non-face-selective visual areas on the speed and accuracy of detecting distorted faces. Brief ES applied to face-selective sites did not affect accuracy but significantly increased the reaction time (RT) of detecting face distortions. Importantly, RT was altered only when ES was applied 100ms after visual onset and in face-selective but not place-selective sites. Furthermore, ES applied to face-selective areas decreased the amplitude of visual evoked potentials and high gamma power over this time window. Together, these results suggest that ES of face-selective regions within a critical time window induces a delay in face perception. These findings support a temporally and spatially specific causal role of face-selective areas and signify an important link between electrophysiology and behavior in face perception. (C) 2017 Wiley Periodicals, Inc.

An inherent limitation of human visual system research stems from its reliance on highly controlled laboratory conditions. Visual processing in the real world differs substantially from such controlled conditions. In particular, during natural vision, we continuously sample the dynamic environment by variable eye movements that lead to inherent instability of the optical image. The neuronal mechanism by which human perception remains stable under these natural conditions remains unknown. Here, we examined a neural mechanism that may contribute to such stability, i.e., the extent to which neuronal responses remain invariant to oculomotor parameters and viewing conditions. To this end, we introduce an experimental paradigm in which intracranial brain activity, a video of the real-life visual scene, and free oculomotor behavior were simultaneously recorded in human patients. Our results reveal, in high-order visual areas, a remarkable level of neural invariance to the length of eye fixations and lack of evidence for a saccade related neuronal signature. Thus, neuronal responses, while showing high selectivity to the category of visual images, manifested stable "iconic" dynamics. This property of invariance to fixation onset and duration emerged only in high-order visual representations. In early visual cortex, the fixation onset was accompanied with suppressive neural signal, and duration of neuronal responses was largely determined by the fixation times. These results uncover unique neuronal dynamics in high-order ventral stream visual areas that could play an important role in achieving perceptual stability, despite the drastic changes introduced by oculomotor behavior in real life.

We hardly notice our eye blinks, yet an externally generated retinal interruption of a similar duration is perceptually salient. We examined the neural correlates of this perceptual distinction using intracranially measured ECoG signals from the human visual cortex in 14 patients. In early visual areas (V1 and V2), the disappearance of the stimulus due to either invisible blinks or salient blank video frames ('gaps') led to a similar drop in activity level, followed by a positive overshoot beyond baseline, triggered by stimulus reappearance. Ascending the visual hierarchy, the reappearance-related overshoot gradually subsided for blinks but not for gaps. By contrast, the disappearance-related drop did not follow the perceptual distinction it was actually slightly more pronounced for blinks than for gaps. These findings suggest that blinks' limited visibility compared with gaps is correlated with suppression of blink-related visual activity transients, rather than with "filling-in" of the occluded content during blinks.

Natural sleep provides a powerful model system for studying the neuronal correlates of awareness and state changes in the human brain. To quantitatively map the nature of sleep-induced modulations in sensory responses we presented participants with auditory stimuli possessing different levels of linguistic complexity. Ten participants were scanned using functional magnetic resonance imaging (fMRI) during the waking state and after falling asleep. Sleep staging was based on heart rate measures validated independently on 20 participants using concurrent EEG and heart rate measurements and the results were confirmed using permutation analysis. Participants were exposed to three types of auditory stimuli: scrambled sounds, meaningless word sentences and comprehensible sentences. During non-rapid eye movement (NREM) sleep, we found diminishing brain activation along the hierarchy of language processing, more pronounced in higher processing regions. Specifically, the auditory thalamus showed similar activation levels during sleep and waking states, primary auditory cortex remained activated but showed a significant reduction in auditory responses during sleep, and the high order language-related representation in inferior frontal gyrus (IFG) cortex showed a complete abolishment of responses during NREM sleep. In addition to an overall activation decrease in language processing regions in superior temporal gyrus and IFG, those areas manifested a loss of semantic selectivity during NREM sleep. Our results suggest that the decreased awareness to linguistic auditory stimuli during NREM sleep is linked to diminished activity in high order processing stations.

Copyright 2016 Elsevier Inc. All rights reserved.Recently we proposed that the information contained in spontaneously emerging (resting-state) fluctuations may reflect individually unique neuro-cognitive traits. One prediction of this conjecture, termed the "spontaneous trait reactivation" (STR) hypothesis, is that resting-state activity patterns could be diagnostic of unique personalities, talents and life-styles of individuals. Long-term meditators could provide a unique experimental group to test this hypothesis. Using fMRI we found that, during resting-state, the amplitude of spontaneous fluctuations in long-term mindfulness meditation (MM) practitioners was enhanced in the visual cortex and significantly reduced in the DMN compared to naive controls. Importantly, during a visual recognition memory task, the MM group showed heightened visual cortex responsivity, concomitant with weaker negative responses in Default Mode Network (DMN) areas. This effect was also reflected in the behavioral performance, where MM practitioners performed significantly faster than the control group. Thus, our results uncover opposite changes in the visual and default mode systems in long-term meditators which are revealed during both rest and task. The results support the STR hypothesis and extend it to the domain of local changes in the magnitude of the spontaneous fluctuations.

Electrophysiological mass potentials show complex spectral changes upon neuronal activation. However, it is unknown to what extent these complex band-limited changes are interrelated or, alternatively, reflect separate neuronal processes. To address this question, intracranial electrocorticograms (ECoG) responses were recorded in patients engaged in visuomotor tasks. We found that in the 10- to 100-Hz frequency range there was a significant reduction in the exponent chi of the 1/f(chi) component of the spectrum associated with neuronal activation. In a minority of electrodes showing particularly high activations the exponent reduction was associated with specific band-limited power modulations: emergence of a high gamma (80-100 Hz) and a decrease in the alpha (9-12 Hz) peaks. Importantly, the peaks' height was correlated with the 1/f(chi) exponent on activation. Control simulation ruled out the possibility that the change in 1/f(chi) exponent was a consequence of the analysis procedure. These results reveal a new global, cross-frequency (10-100 Hz) neuronal process reflected in a significant reduction of the power spectrum slope of the ECoG signal.

Autism spectrum disorder (ASD) has been associated with a reduction in resting state functional connectivity, though this assertion has recently been challenged by reports of increased connectivity in ASD. To address these contradictory findings, we examined both inter- and intrahemispheric functional connectivity in several resting state data sets acquired from adults with high-functioning ASD and matched control participants. Our results reveal areas of both increased and decreased connectivity in multiple ASD groups as compared to control groups. We propose that this heterogeneity stems from a previously unrecognized ASD characteristic: idiosyncratic distortions of the functional connectivity pattern relative to the typical, canonical template. The magnitude of an individual's pattern distortion in homotopic interhemispheric connectivity correlated significantly with behavioral symptoms of ASD. We propose that individualized alterations in functional connectivity organization are a core characteristic of high-functioning ASD, and that this may account for previous discrepant findings.

Previous advances in magnetic resonance imaging allow the analysis of blood oxygen level-dependent signals in real time, thus opening the possibility of feeding an index of these signals back to scanned human participants. However, it is still not known to what extent different cortical networks may differ in their sensitivity to such internally generated neurofeedback (NF). Here, we compare NF efficacy across six cortical regions including: early and high-order visual areas and the posterior parietal lobe, a prominent node of the default mode network (DMN). Our results reveal a consistent difference in NF activation across these areas. Sham controls ruled out a role of attention/arousal in these effects. These differences are suggestive of a relationship to the relative reliance on intrinsic information, moving from early visual cortex (lowest) to the DMN (highest). Interestingly, the visual parahippocampal place area showed NF activation closer to the DMN node. The results are compatible with the notion of the DMN as an intrinsically oriented system.

Objective. We have developed a brain-computer interface (BCI) system based on real-time functional magnetic resonance imaging (fMRI) with virtual reality feedback. The advantage of fMRI is the relatively high spatial resolution and the coverage of the whole brain; thus we expect that it may be used to explore novel BCI strategies, based on new types of mental activities. However, fMRI suffers from a low temporal resolution and an inherent delay, since it is based on a hemodynamic response rather than electrical signals. Thus, our objective in this paper was to explore whether subjects could perform a BCI task in a virtual environment using our system, and how their performance was affected by the delay. Approach. The subjects controlled an avatar by left-hand, right-hand and leg motion or imagery. The BCI classification is based on locating the regions of interest (ROIs) related with each of the motor classes, and selecting the ROI with maximum average values online. The subjects performed a cue-based task and a free-choice task, and the analysis includes evaluation of the performance as well as subjective reports. Main results. Six subjects performed the task with high accuracy when allowed to move their fingers and toes, and three subjects achieved high accuracy using imagery alone. In the cue-based task the accuracy was highest 8-12 s after the trigger, whereas in the free-choice task the subjects performed best when the feedback was provided 6 s after the trigger. Significance. We show that subjects are able to perform a navigation task in a virtual environment using an fMRI-based BCI, despite the hemodynamic delay. The same approach can be extended to other mental tasks and other brain areas.

Objective : We have developed an efficient generic machine learning (ML) tool for realtime fMRI whole brain classification, which can be used to explore novel brain-computer interface (BCI) or advanced neurofeedback (NF) strategies.Approach : We use information gain for isolating the most relevant voxels in the brain and a support vector machine classifier.Main results : We have used our tool in three types of experiments: motor movement, motor imagery and visual categories.Significance : We show high accuracy results in real-time, using an optimal number of voxels, with a shorter delay compared to the previous method based on regions of interest (ROI). Finally, our tool is integrated with a virtual environment and can be used to control a virtual avatar or a robot.

Despite the profound reduction in conscious awareness associated with sleep, sensory cortex remains highly active during the different sleep stages, exhibiting complex interactions between different cortical sites. The potential functional significance of such spatial patterns and how they change between different sleep stages is presently unknown. In this electrocorticography study of human patients, we examined this question by studying spatial patterns of activity (broadband gamma power) that emerge during sleep (sleep patterns) and comparing them to the functional organization of sensory cortex that is activated by naturalistic stimuli during the awake state. Our results show a high correlation (p

Complex network analysis (CNA), a subset of graph theory, is an emerging approach to the analysis of functional connectivity in the brain, allowing quantitative assessment of network properties such as functional segregation, integration, resilience, and centrality. Here, we show how a classification framework complements complex network analysis by providing an efficient and objective means of selecting the best network model characterizing given functional connectivity data. We describe a novel kernel-sum learning approach, block diagonal optimization (BDopt), which can be applied to CNA features to single out graph-theoretic characteristics and/or anatomical regions of interest underlying discrimination, while mitigating problems of multiple comparisons. As a proof of concept for the method's applicability to future neurodiagnostics, we apply BDopt classification to two resting state fMRI data sets: a trait (between-subjects) classification of patients with schizophrenia vs. controls, and a state (within-subjects) classification of wake vs. sleep, demonstrating powerful discriminant accuracy for the proposed framework.

Even in the absence of stimulation or task, the cerebral cortex shows an incessant pattern of ultra slow fluctuations which are coherent across brain regions. In the healthy brain these coherent patterns (also termed resting state functional connectivity) often exhibit spatial similarity to the large scale organization of task-induced functional networks. However, it is not clear to what extent the resting state patterns can also reflect task-induced abnormalities in cortical activations which are often detected in various brain pathologies. Here we examined whether an abnormal visual activation pattern is recapitulated in the resting state functional connectivity. We examined LG, a sighted young adult with developmental object agnosia and no apparent cortical structural abnormality. We have previously reported that upon visual stimulation, LG's intermediate visual areas (V2, V3) are paradoxically deactivated. Here, examining LG's resting state functional connectivity revealed the same pattern of functional abnormality including a strong atypical decorrelation between areas V2-V3 and the rest of the visual system. Thus, our results suggest that resting-state functional connectivity could provide a powerful tool which could complement task-specific paradigms in detecting task-related abnormalities in cortical activity without resorting to task performance. (C) 2013 Elsevier Inc. All rights reserved.

The introduction of functional brain imaging based on BOLD-fMRI, twenty years ago, has revolutionized the field of human brain research. However, right from its inception it became clear that the BOLD signal suffers from a serious limitation- it reflects the averaged activity of large neuronal populations and hence can not, on its own, index the functional properties of individual neurons. The method of fMR-adaptation (also termed repetition suppression) was developed to circumvent this problem and use the BOLD signal to assess functional specializations at the individual neuron level. The approach is based on the tendency of cortical neurons to reduce their activity upon stimulus repetition. By examining the sensitivity of the adaptation effect to stimulus manipulation, insight can be gained about the invariant and selective properties of neuronal networks. It has been argued that the adaptation effect occurs at the level of synaptic inputs- and hence may be mislocalized. However, it is critical to consider the adaptation effect in the context of the cortical network architecture. This cortical anatomical organization, dominated by short range intrinsic connections, ensures that the fMR-adaptation largely reflects the response profile of the neurons located within the imaged voxel proper. (C) 2012 Elsevier Inc. All rights reserved.

Clinical diagnosis of disorders of consciousness (DOC) caused by brain injury poses great challenges since patients are often behaviorally unresponsive. A promising new approach towards objective DOC diagnosis may be offered by the analysis of ultra-slow (

Keywords: ACTIVATION; AWARENESS; CORTEX; SELF

Schizophrenia is a devastating psychiatric illness characterized by deterioration of cognitive and emotional processing. It has been hypothesized that aberrant cortical connectivity is implicated in the disease (Friston, 1998), yet previous studies of functional connectivity (FC) in schizophrenia have shown mixed results (Garrity et al., 2007; Jafri et al., 2008; Lynall et al., 2010). We measured FC using fMRI in human schizophrenia patients and healthy controls during two different tasks and a rest condition, and constructed a voxel-based global FC index. We found a striking FC decrease in patients compared with controls. In the task conditions, relatively weaker FC was specific to regions of cortex not active during the task. In the rest condition, the FC difference between patients and controls was larger and allowed a case-by-case separation between individuals of the two groups. The results suggest that the relative reduction of FC in schizophrenia is dependent on the state of cortical activity, with voxels not activated by the task showing higher levels of FC deficiency. This novel finding may shed light on previous reports of FC in schizophrenia. Whether this neural characteristic is related to the development of the disorder remains to be established.

The effect of stimulus modulation rate on the underlying neural activity in human auditory cortex is not clear. Human studies (using both invasive and noninvasive techniques) have demonstrated that at the population level, auditory cortex follows stimulus envelope. Here we examined the effect of stimulus modulation rate by using a rare opportunity to record both spiking activity and local field potentials (LFP) in auditory cortex of patients during repeated presentations of an audio-visual movie clip presented at normal, double, and quadruple speeds. Mean firing rate during evoked activity remained the same across speeds and the temporal response profile of firing rate modulations at increased stimulus speeds was a linearly scaled version of the response during slower speeds. Additionally, stimulus induced power modulation of local field potentials in the high gamma band (64-128 Hz) exhibited similar temporal scaling as the neuronal firing rate modulations. Our data confirm and extend previous studies in humans and anesthetized animals, supporting a model in which both firing rate, and high-gamma LFP power modulations in auditory cortex follow the temporal envelope of the stimulus across different modulation rates. Hum Brain Mapp 32:1181-1193, 2011. (C) 2010 Wiley-Liss, Inc.

Scalp electroencephalography and magnetoencephalography studies have revealed a rapid evoked potential "adaptation" where one visual stimulus suppresses the event-related potential (ERP) of the second stimulus. Here, we investigated a similar effect revealed in subdural intracranial recordings in humans. Our results show that the suppression of the subdural ERP is not associated with a reduction in the gamma frequency power, considered to reflect the underlying neural activity. Furthermore, the evoked potential suppression (EPS) phenomenon was not reflected in recognition behavior of the patients. Rather, the EPS was tightly linked to the level of gamma activity preceding the event, and this effect was independent of the interstimulus time interval. Analyzing other frequency bands failed to reveal a similar link. Our results thus show a consistent antagonism between subdural ERP and gamma power although both are considered markers for neural activity. We hypothesize that the ERP suppression is due to a desynchronization of neuronal firing resulting from recurrent neural activity in the vicinity of the freshly stimulated neurons and not an attenuation of the overall neural activity.

Using an fMR-adaptation paradigm for different face morphing levels we have recently demonstrated a narrow neuronal tuning to faces even at the sub-exemplar level which was tightly related to perceptual discrimination (Gilaie-Dotan and Malach, 2007). However, it is unclear whether this relationship is unique to faces or is a general property of object representations including unfamiliar objects, and whether the adaptation tuning is due to physical changes in the stimulus or to changes in perceptual discrimination. Here we compared the same face-morph paradigm for upright and inverted faces, thus modulating familiarity and perceptual discrimination effects while equating all low-level features. We found, as expected, a perceptual "inversion effect", i.e. a significant reduction in inverted face discrimination. Importantly. the fMR-adaptation tuning in the fusiform face area (FFA) changed in accordance with the different perceptual sensitivity both for upright and inverted faces. Additional object selective regions displayed differential tuning widths to the two categories. Our results are compatible with a model by which the ability of human observers to discriminate objects depends on the shape tuning properties of individual neurons. (C) 2009 Elsevier Inc. All rights reserved.

Purpose: Recent studies show evidence of multisensory representation in the functionally normal visual cortex, but this idea remains controversial. Occipital cortex activation is often claimed to be a reflection of mental visual imagery processes triggered by other modalities. However, if the occipital cortex is genuinely active during touch, this might be the basis for the massive cross-modal plasticity observed in the congenitally blind. Methods: To address these issues, we used fMRI to compare patterns of activation evoked by a tactile object recognition (TOR) task (right or left hand) in 8 sighted and 8 congenitally blind subjects, with several other control tasks. Results: TOR robustly activated object selective regions in the lateral occipital complex (LOC/LOtv) in the blind (similar to the patterns of activation found in the sighted), indicating that object identification per se (i.e. in the absence of visual imagery) is sufficient to evoke responses in the LOC/LOtv. Importantly, there was negligible occipital activation for hand movements (imitating object palpations) in the occipital cortex, in both groups. Moreover, in both groups, TOR activation in the LOC/LOtv was bilateral, regardless of the palpating hand (similar to the lack of strong visual field preference in the LOC/LOtv for viewed objects). Finally, the most prominent enhancement in TOR activation in the congenitally blind (compared to their sighted peers) was found in the posterior occipital cortex. Conclusions: These findings suggest that visual imagery is not an obligatory condition for object activation in visual cortex. It also demonstrates the massive plasticity in visual cortex of the blind for tactile object recognition that involves both the ventral and dorsal occipital areas, probably to support the high demand for this function in the blind.

A fundamental concept in visual processing is that activity in high-order object-category distinctive regions (e.g., lateral occipital complex, fusiform face area, middle temporal+) is dependent on bottom-up flow of activity in earlier retinotopic areas (V2, V3, V4) whose main input originates from primary visual cortex (V1). Thus, activity in down stream areas should reflect lower-level inputs. Here we qualify this notion reporting case LG, a rare case of developmental object agnosia and prosopagnosia. In this person, V1 was robustly activated by visual stimuli, yet intermediate areas (V2-V4) were strongly deactivated. Despite this intermediate deactivation, activity in down stream visual areas remained robust, showing selectivity for houses and places, while selectivity for faces and objects was impaired. The extent of impairment evident in functional magnetic resonance imaging and electroencephalography activations was somewhat larger in the left hemisphere. This pattern of brain activity, coupled with fairly adequate everyday visual performance is compatible with models emphasizing the role of nonlinear local "amplification" of neuronal inputs in eliciting activity in ventral and dorsal visual pathways as well as perceptual experience in the human brain. Thus, while the proper functioning of intermediate areas appears essential for specialization in the cortex, daily visual behavior and reading are maintained even with deactivated intermediate visual areas.

Purpose: To assess the applicability of T1-weighted images in the presence of a contrast agent for functional mapping free of susceptibility artifacts, in comparison to the blood oxygenation level-dependent (BOLD) imaging. Materials and Methods: Six patients and five control subjects were scanned using BOLD and T1-weighted functional imaging, in the presence of a Gd-DTPA contrast-agent (TOFICA). In the control group, low- and high-resolution BOLD images were performed. Functional stimuli included motor and language activations. Results: Both BOLD and TOFICA methods resulted in activations in the expected anatomical regions. The TOFICA mapping gave less distributed and with higher percent signal changes In comparison with the BOLD images. GdDTPA remained almost constant in the blood for at least 15 min post injection. In one patient with surgical clips, no signal was detected in the left cerebral hemisphere using BOLD imaging, but activation could be mapped using the TOFICA method. Conclusion: T1-weighted imaging in the presence of a contrast agent can be used for functional mapping. This method is insensitive to susceptibility artifacts, and is therefore advantageous in the evaluation of presurgical cases and in areas of the brain close to cavities in which the BOLD method cannot reliably be applied.

Animal studies have shown robust electrophysiological activity in the sensory cortex in the absence of stimuli or tasks. Similarly, recent human functional magnetic resonance imaging (fMRI) revealed widespread, spontaneously emerging cortical fluctuations. However, it is unknown what neuronal dynamics underlie this spontaneous activity in the human brain. Here we studied this issue by combining bilateral single-unit, local field potentials (LFPs) and intracranial electrocorticography (ECoG) recordings in individuals undergoing clinical monitoring. We found slow (

Object-related areas in the ventral visual system in humans are known from imaging studies to be preferentially activated by object images compared with noise or texture patterns. It is unknown, however, which features of the object images are extracted and represented in these areas. Here we tested the extent to which the representation of visual classes used object fragments selected by maximizing the information delivered about the class. We tested functional magnetic resonance imaging blood oxygenation level-dependent activation of highly informative object features in low- and high-level visual areas, compared with noninformative object features matched for low- level image properties. Activation in V1 was similar, but in the lateral occipital area and in the posterior fusiform gyrus, activation by "informative'' fragments was significantly higher for three object classes. Behavioral studies also revealed high correlation between performance and fragments information. The results show that an objective class-information measure can predict classification performance and activation in human object-related areas.

We studied the responses of single neurons in the human medial temporal lobe while subjects viewed familiar faces, animals, and landmarks. By progressively shortening the duration of stimulus presentation, coupled with backward masking, we show two striking properties of these neurons. (i) Their responses are not statistically different for the 33-ms, 66-ms, and 132-ms stimulus durations, and only for the 264-ms presentations there is a significantly higher firing. (it) These responses follow conscious perception, as indicated by the subjects' recognition report. Remarkably, when recognized, a single snapshot as brief as 33 ms was sufficient to trigger strong single-unit responses far outlasting stimulus presentation. These results suggest that neurons in the medial temporal lobe can reflect conscious recognition by "all-or-none" responses.

Just- noticeable differences of physical parameters are often limited by the resolution of the peripheral sensory apparatus. Thus, two- point discrimination in vision is limited by the size of individual photoreceptors. Frequency selectivity is a basic property of neurons in the mammalian auditory pathway(1,2). However, just- noticeable differences of frequency are substantially smaller than the bandwidth of the peripheral sensors(3). Here we report that frequency tuning in single neurons recorded from human auditory cortex in response to random- chord stimuli is far narrower than that typically described in any other mammalian species ( besides bats), and substantially exceeds that attributed to the human auditory periphery. Interestingly, simple spectral filter models failed to predict the neuronal responses to natural stimuli, including speech and music. Thus, natural sounds engage additional processing mechanisms beyond the exquisite frequency tuning probed by the random- chord stimuli.

States of sensory absorption may offer a means to disentangle perception From report. Interestingly, such states lead to an antagonistic relationship between perceptual and cognitive-access networks, suggesting that perceptual awareness does not depend on a read-out by high order cognitive-access mechanisms. Rather, it may emerge internally, through a cooperative coding dynamics, whereby each neuron simultaneously represents and reads-out the perceptual awareness state.

Background: To what extent is activity of individual neurons coupled to the local field potential (LFP) and to blood-oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI)? This issue is of high significance for understanding brain function and for relating animal studies to fMRI, yet it is still under debate. Results: Here we report data from simultaneous recordings of isolated unit activity and LFP by using multiple electrodes in the human auditory cortex. We found a wide range of coupling levels between the activity of individual neurons and gamma LFP. However, this large variability could be predominantly explained (r = 0.66) by the degree of firing-rate correlations between neighboring neurons. Importantly, this phenomenon occurred during both sensory stimulation and spontaneous activity. Concerning the coupling of neuronal activity to BOLD fMRI, we found that gamma LFP was well coupled to BOLD measured across different individuals (r = 0.62). By contrast, the coupling of single units to BOLD was highly variable and, again, tightly related to interneuronal-firing-rate correlations (r = 0.70). Conclusions: Our results offer a resolution to a central controversy regarding the coupling between neurons, LFP, and BOLD signals by demonstrating, for the first time, that the coupling of single units to the other measures is variable yet it is tightly related to the degree of interneuronal correlations in the human auditory cortex.

When exposing subjects to a continuous segment of an audiovisual movie, a large expanse of human cortex, especially in the posterior half of the cerebral cortex, shows stimulus-driven activity. However, embedded within this widespread activity, there are cortical regions whose activity is dissociated from the external stimulation. These regions are intercorrelated among themselves, forming a functional network, which largely overlaps with cortical areas previously shown to be deactivated by task-oriented paradigms. Moreover, the network of areas whose neuronal dynamics are associated with external inputs and the network of areas that appears to be intrinsically driven complement each other, providing coverage of most of the posterior cortex. Thus, we propose that naturalistic stimuli reveal a fundamental neuroanatomical partition of the human posterior cortex into 2 global networks: an "extrinsic" system, comprising areas associated with the processing of external inputs, and an "intrinsic" system, largely overlapping with the task-negative, default-mode network, comprising areas associated with-as yet not fully understood-intrinsically oriented functions.

Keywords: BRAIN; CONSCIOUSNESS; SELF; EXPERIENCE; VISION

Functional magnetic resonance imaging (fMRI) is an important tool. for investigating human brain function, but the relationship between the hemodynamicatly based fMRI signals in the human brain and the underlying neuronal activity is unclear. We recorded single unit activity and local field potentials in auditory cortex of two neurosurgical patients and compared them with the fMRI signals of 11 healthy subjects during presentation of an identical movie segment. The predicted fMRI signals derived from single units and the measured fMRI signals from auditory cortex showed a highly significant correlation (r = 0.7S, P

To what extent does neural activation in human visual cortex follow the temporal dynamics of the optical retinal stimulus? Specifically, to what extent does stimulus evoked neural activation persist after stimulus termination? In the present study, we used functional magnetic resonance imaging (fMRI) to explore the resulting temporal non-linearities across the entire constellation of human visual areas. Gray-scale images of animals, houses and faces were presented at two different presentation rates - 1 and 4 Hz - and the fMRI signal was analyzed in retinotopic and in high order occipito-temporal visual areas. In early visual areas and the motion sensitive area MT/V5, a fourfold increase in stimulus presentation rate evoked a twofold increase in signal amplitude. However, in high order visual areas, signal amplitude increased only by 25%. A control experiment ruled out the possibility that this difference was due to signal saturation ('ceiling') effects. A likely explanation for the stronger non-linearities in occipito-temporal cortex is a persistent neuronal activation that continues well after stimulus termination in the 1 Hz condition. These persistent activations might serve as a short term (iconic) memory mechanism for preserving a trace of the stimulus even in its absence and for future integration with temporally correlated stimuli. Two alternative models of persistence (inhibitory and excitatory) are proposed to explain the data.

To what extent do all brains work alike during natural conditions? We explored this question by letting Five subjects freely view half an hour of a popular movie while undergoing functional brain imaging. Applying an unbiased analysis in which spatiotemporal activity patterns in one brain were used to "model" activity in another brain, we found a striking level of voxel-by-voxel synchronization between individuals, not only in primary and secondary visual and auditory areas but also in association cortices. The results reveal a surprising tendency of individual brains to "tick collectively" during natural vision. The intersubject synchronization consisted of a widespread cortical activation pattern correlated with emotionally arousing scenes and regionally selective components. The characteristics of these activations were revealed with the use of an open-ended "reverse-correlation" approach, which inverts the conventional analysis by letting the brain signals themselves "pick up" the optimal stimuli for each specialized cortical area.

The visual cortex may be more modifiable than previously considered. Using functional magnetic resonance imaging (fMRI) in ten congenitally blind human participants, we found robust occipital activation during a verbal-memory task (in the absence of any sensory input), as well as during verb generation and Braille reading. We also found evidence for reorganization and specialization of the occipital cortex, along the anterior-posterior axis. Whereas anterior regions showed preference for Braille, posterior regions (including V1) showed preference for verbal-memory and verb generation (which both require memory of verbal material). No such occipital activation was found in sighted subjects. This difference between the groups was mirrored by superior performance of the blind in various verbal-memory tasks. Moreover, the magnitude of V1 activation during the verbal-memory condition was highly correlated with the blind individual's abilities in a variety of verbal-memory tests, suggesting that the additional occipital activation may have a functional role.

Recently we reported that the topographic organization of visual field eccentricity in human visual cortex extends into high-order, ventral occipitotemporal (VOT) cortex. Within this cortex, regions that respond preferentially to faces and buildings have specific eccentricity biases, suggesting that this category-eccentricity association may reflect differential needs of recognition processes. However, it is still not clear to what extent this center/periphery differentiation within high-order occipitotemporal cortex depends on immediate, moment-to-moment, task demands. Previous attention studies were confined either to exploring the visual field topography (spatial attention) or to object identity (object-based attention). Here, we combined the investigation of these two different attentional mechanisms in the same study. We found that the main source of attentional modulation in occipitotemporal cortex was object-based attention. Shifting attention to different object categories (buildings, faces, and arrows) substantially modulated the object-related activations. The differential activation to each object category in occipitotemporal object areas was maintained, albeit at a reduced level, even when attention was focused on different spatial locations. A slight eccentricity-related attentional differentiation was observed in the more dorsal lateral occipital region, but not in the VOT cortex. These results argue against the possibility that the source of the eccentricity differentiation in VOT cortex is due solely, to moment-to-moment shifts in spatial attention mechanism and supports the notion that the eccentricity-biased maps found in this region are due to built-in shape selectivity established over long-term processes. (C) 2003 Elsevier Science (USA). All rights reserved.

Congenital prosopagnosia is a severe impairment in face identification manifested from early childhood in the absence of any evident brain lesion. in this study, we used fMRI to compare the brain activity elicited by faces in a congenital prosopagnosic subject (YT) relative to a control group of 12 subjects in an attempt to shed more light on the nature of the brain mechanisms subserving face identification. The face-related activation pattern of YT in the ventral occipito-temporal cortex was similar to that observed in the control group on several parameters: anatomical location, activation profiles, and hemispheric laterality. In addition, using a modified vase-face illusion, we found that YT's brain activity in the face-related regions manifested global grouping processes. However, subtle differences in the degree of selectivity between objects and faces were observed in the lateral occipital cortex. These data suggest that face-related activation in the ventral occipito-temporal cortex, although necessary, might not be sufficient by itself for normal face identification.

An important characteristic of visual perception is the fact that object recognition is largely immune to changes in viewing conditions. This invariance is obtained within a sequence of ventral stream visual areas beginning in area V1 and ending in high order occipito-temporal object areas (the lateral occipital complex, LOC). Here we studied whether this transformation could be observed in the contrast response of these areas. Subjects were presented with line drawings of common objects and faces in five different contrast levels (0, 4, 6, 10, and 100%). Our results show that indeed there was a gradual trend of increasing contrast invariance moving from area V1, which manifested high sensitivity to contrast changes, to the LOC, which showed a significantly higher degree of invariance at suprathreshold contrasts (from 10 to 100%). The trend toward increased invariance could be observed for both face and object images; however, it was more complete for the face images, while object images still manifested substantial sensitivity to contrast changes. Control experiments ruled out the involvement of attention effects or hemodynamic "ceiling" in producing the contrast invariance. The transition from V1 to LOC was gradual with areas along the ventral stream becoming increasingly contrast-invariant. These results further stress the hierarchical and gradual nature of the transition from early retinotopic areas to high order ones, in the build-up of abstract object representations.

We have recently proposed a center-periphery organization based on resolution needs, in which objects engaging in recognition processes requiring central-vision (e.g., face-related) are associated with center-biased representations, while objects requiring large-scale feature integration (e.g., buildings) are associated with periphery-biased representations. Here we tested this hypothesis by comparing the center-periphery organization with activations to five object categories: faces, buildings, tools, letter strings, and words. We found that faces, letter strings, and words were mapped preferentially within the center-biased representation. Faces showed a hemispheric lateralization opposite to that of letter strings and words. In contrast, buildings were mapped mainly to the periphery-biased representation, while tools activated both central and peripheral representations. The results are compatible with the notion that center-periphery organization allows the optimal allocation of cortical magnification to the specific requirements of various recognition processes.

The ability of the human visual system to recognize partially occluded objects is a striking feat, which has received extensive psychophysical documentation. Here we studied the manifestation of completion effects in the functional magnetic resonance imaging (fMRI) activation of high-order object areas (the lateral occipital complex - LOC). Subjects were presented with three types of images: (i) whole line drawings of animal or unfamiliar shapes ('whole'); (ii) the same shapes, occluded by parallel stripes which occupied roughly half of the surface area of the images ('grid'); and (iii) the same stripes, 'scrambled' so that the relative position of the regions between the stripes was changed while the local feature structure remained intact. Behavioral measurements showed a high degree of object completion in the 'grid' condition, but not in the 'scrambled' condition. The fMRI results show a significantly higher activation to the 'grid' images compared to the 'scrambled' images. This enhanced activation indicates the operation of non-local completion effects, since the local features in both sets of images were the same. The cortical regions showing the highest 'completion' effects co-localized with regions in the LOC which showed the highest activation to the 'whole' images compared to the 'scrambled' images. Activation in early retinotopic areas was similar in both the 'grid' and the 'scrambled' conditions. Our results point to the LOC as a central site in which object completion effects are manifested.

Recent neuroimaging studies have described a differential activation pattern associated with specific object images (e.g., face-related and building-related activation) in human occipito-temporal cortex. However, it is as yet unclear to what extent this selectivity is Clue to differences in the statistics of local object features present in the different object categories, and to what extent it reflects holistic grouping processes operating across the entire object image. To resolve this question it is essential to use images in which identical sets of local features elicit the perception of different object categories, The classic Rubin vase-face illusion provides an excellent experimental set to test this question. In the illusion, the same local contours lead to the perception of different objects (vase or face). Here we employed a modified Rubin vase-face illusion to explore to what extent the activation in face-related regions is attributable to the presence of local face features, or is due to a more holistic grouping process that involves the entire face figure. Biasing cues (gratings and color) were used to control the perceptual state of the observer. We found enhanced activation in face-related regions during the "face profile" perceptual state compared to the "vase" perceptual state. Control images ruled out the involvement of the biasing cues in the effect. Thus, object-selective activation in human face-related regions entails global grouping processes that go beyond the local processing of stimulus features.

How are objects represented in the human visual cortex? Two conflicting theories suggest either a holistic representation, in which objects are represented by a collection of object templates, or a part based representation, in which objects are represented as collections of features or object parts. We studied this question using a gradual object-scrambling paradigm in which pictures of objects (faces and cars) were broken in a stepwise manner into an increasing number of blocks. Our results reveal a hierarchical axis oriented anterior-posteriorly in the organization of ventral object-areas. Along this axis, representations are arranged in bands of increasing sensitivity to image scrambling. The axis starts in early visual areas through retinotopic areas V4/V8 and continues into the lateral-occipital sulcus dorsally and the posterior fusiform girus ventrally, corresponding together to the previously described object related lateral occipital complex (LOC). Regions showing the highest sensitivity to scrambling tended to be located at the most anterior-lateral regions of the complex. In these more anterior regions, breaking the images into 16 parts produced a significant reduction in activation. Interestingly, activation was not affected when images were cut in two halves, either horizontally or vertically. Car images generally produced a weaker activation compared to faces in the lateral occipital complex but showed the same tendency of increased scrambling sensitivity along the anterior-posterior axis. These results suggest the existence of a hierarchical axis along ventral occipito-temporal object-areas, in which the neuronal properties shift from sensitivity to local object features to a more global and holistic representation.

The extent to which primary visual cues such as motion or luminance are segregated in different cortical areas is a subject of controversy. To address this issue, we examined cortical activation in the human occipital lobe using functional magnetic resonance imaging (fMRI) while subjects performed a fixed visual task, object recognition, using three different primary visual cues: motion, texture, or luminance contrast. in the first experiment, a region located on the lateral aspect of the occipital lobe (LO complex) was preferentially activated in all 11 subjects both by luminance and motion-defined object silhouettes compared to full-field moving and stationary noise (ratios, 2.00 +/- 0.19 and 1.86 +/- 0.65, respectively). In the second experiment, all subjects showed enhanced activation in the LO complex to objects defined both by luminance and texture contrast compared to full-field texture patterns (ratios, 1.43 +/- 0.08 and 1.32 +/- 0.08, respectively). An additional smaller dorsal focus that exhibited convergence of object-related cues appeared to correspond to area V3a or a region slightly anterior to it. These results show convergence of visual cues in LO and provide strong evidence for its role in object processing.

Area V2, the main target of primary visual cortex projections, is characterized by a striking functional and connectional compartmentalization. Many aspects of this organization are correlated to three sets of stripes (thick, thin, and pale) revealed by cytochrome oxidase (CO) staining, Several questions related to the physiological properties of these compartments, their intrinsic connections, and points of similarity with area V1 modules are still unresolved. We have addressed some of these questions by combining the techniques of optical imaging of intrinsic signals, tract tracing, and CO histochemistry in the same patches of areas V1 and V2 of the squirrel monkey. The following observations were made. Orientation domains: in area V1 these are organized in narrow bands, while in area V2 they form patches. In area V2, domain width and distance between domains are approximately double that found in area Vt, Orientation and Ca stripe organization: orientation tuning was organized so that highly selective regions were centered on thick CO stripes while regions of broad orientation selectivity were centered on thin CO stripes. However, the orientation domains appeared to ignore borders between thick and pale stripes, Intrinsic connections: injections of the sensitive tracer biocytin into area V2 labeled a dense network of horizontally projecting fibers that were organized in columnar patches. Patches were small (mean width, 211 mu m; mean length, 342 mu m) and the labeling pattern extended over 4-5 mm. Axonal patches and CO stripes: Axonal patches found were in all three stripe compartments. However, injections that straddled the borders of thick/pale stripe compartments produced axonal projections that tended to cluster around border regions. Axonal patches and orientation domains: V2 injections produced labeling in V1 that appeared to be organized in narrow bands, reminiscent of orientation domain distribution in V1. Within area V2, axonal patches targeted a wide

The potential for peripheral modification of intrinsic horizontal connections was studied in the primary visual cortex (area 17) of adult, hooded rats that underwent monocular enucleation (ME) or binocular enucleation (BE) at the day of birth. The intrinsic connections were labelled by localized tracer injections at various sites in area 17. The pattern of interhemispheric callosal connections was revealed in the same animals by extensive injections of a distinguishable tracer in the contralateral hemisphere. The results show marked and consistent changes in area 17 intrinsic connections as a result of the neonatal enucleations. Specifically, in contrast to normally reared rats in which intrinsic connections are short ranged and are organized fairly uniformly around the injection site, in ME cases intrinsic connections extend over half the width of area 17, usually targeting a second field within area 17. In BE cases, the injection sites result in the appearance of elongated tongues and patches of label that protrude in different directions from the injection site. The observed modifications of intrinsic connections are clearly related to the abnormalities induced by enucleations in the pattern of callosal connections, such that intrinsic connections tend to form either between callosally connected sites or between a-callosal sites but avoid intermixing the two. The results reveal a high level of plasticity in the developing intrinsic connections. A Hebbian rule of connectivity is proposed as the underlying process guiding the formation of horizontal intrinsic connections in area 17.

Cells in layers II-III or VI were activated by microdrop application of acetylcholine (ACh), while monitoring the intracellular response of layer V pyramidal cells. This enabled the tracing of functional connections between the cells of layers II-III or VI with those of layer V. ACh activation of layer II-III or VI cells resulted in a small depolarization of these cells, accompanied by a burst of excitatory postsynaptic potentials (EPSPs) from layer V pyramidal cells. These effects of ACh were blocked by tetrodotoxin (TTX), suggesting the involvement of action potentials in their production. The input resistance of layer V pyramidal cells during and after the EPSP burst was not significantly different from control values, further suggesting an indirect effect of ACh on layer V pyramidal cells. Isolation of the supragranular layer, by horizontal cutting, did not prevent the EPSP burst evoked by ACh application to the lower layer VI, suggesting a direct input from layer VI to layer V pyramidal cells. ACh applied near pyramidal cells in layers II-III, V or VI caused transient hyperpolarization associated with a decrease in input resistance followed by a large depolarization, an increase in input resistance, and action potential discharges. The ACh-mediated hyperpolarization and the train of action potentials of layer II-III pyramidal cells were blocked by TTX. Thus the ACh-activated cells in layers II-III and VI make an excitatory synaptic contact with layer V pyramidal cells, producing the EPSP burst observed in layer V.