Publications

Everyday experiences are dynamic, driving fluctuations across simultaneous cognitive processes. A key challenge in the study of naturalistic cognition is to disentangle the complexity of these dynamic processes, without altering the natural experience itself. Retrospective behavioral sampling (RBS) is a novel approach to model the cognitive fluctuations corresponding to the time-course of naturalistic stimulation, across a variety of cognitive dimensions. We tested the effectiveness and reliability of RBS in a web-based experiment, in which 53 participants viewed short movies and listened to a story, followed by retrospective reporting. Participants recalled their experience of 55 discrete events from the stimuli, rating their quality of memory, magnitude of surprise, intensity of negative and positive emotions, perceived importance, reflectivity state, and mental time travel. In addition, a subset of the original cohort re-rated their memory of events in a follow-up questionnaire. Results show highly replicable fluctuation patterns across distinct cognitive dimensions, thereby revealing a stimulus-driven experience that is substantially shared among individuals. Remarkably, memory ratings more than a week after stimulation resulted in an almost identical time-course of memorability as measured immediately following stimulation. In addition, idiosyncratic response patterns were preserved across different stimuli, indicating that RBS characterizes individual differences that are stimulus invariant. The current findings highlight the potential of RBS as a powerful tool for measuring dynamic processes of naturalistic cognition. We discuss the promising approach of matching RBS fluctuations with dynamic processes measured via other testing modalities, such as neuroimaging, to study the neural manifestations of naturalistic cognitive processing.

While most theories of consciousness posit some kind of dependence on global network activities, I consider here an alternative, localist perspectivein 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 awarenesswhich 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 individuals mind, two central conditions must be met. First, a specific configural pattern (\u201cbar-code\u201d) 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 \u201cignitions\u201d.

Research in functional neuroimaging has suggested that category-selective regions of visual cortex, including the ventral temporal cortex (VTC), can be reactivated endogenously through imagery and recall. Face representation in the monkey face-patch system has been well studied and is an attractive domain in which to explore these processes in humans. The VTCs of 8 human subjects (4 female) undergoing invasive monitoring for epilepsy surgery were implanted with microelectrodes. Most (26 of 33) category-selective units showed specificity for face stimuli. Different face exemplars evoked consistent and discriminable responses in the population of units sampled. During free recall, face-selective units preferentially reactivated in the absence of visual stimulation during a 2 s window preceding face recall events. Furthermore, we show that in at least 1 subject, the identity of the recalled face could be predicted by comparing activity preceding recall events to activity evoked by visual stimulation. We show that face-selective units in the human VTC are reactivated endogenously, and present initial evidence that consistent representations of individual face exemplars are specifically reactivated in this manner.

Spontaneous activity of the human brain has been well documented, but little is known about the functional role of this ubiquitous neural phenomenon. It has previously been hypothesized that spontaneous brain activity underlies unprompted (internally generated) behaviour. We tested whether spontaneous brain activity might underlie internally-generated vision by studying the cortical visual system of five blind/visually-impaired individuals who experience vivid visual hallucinations (Charles Bonnet syndrome). Neural populations in the visual system of these individuals are deprived of external input, which may lead to their hyper-sensitization to spontaneous activity fluctuations. To test whether these spontaneous fluctuations can subserve visual hallucinations, the functional MRI brain activity of participants with Charles Bonnet syndrome obtained while they reported their hallucinations (spontaneous internally-generated vision) was compared to the: (i) brain activity evoked by veridical vision (externally-triggered vision) in sighted controls who were presented with a visual simulation of the hallucinatory streams; and (ii) brain activity of non-hallucinating blind controls during visual imagery (cued internally-generated vision). All conditions showed activity spanning large portions of the visual system. However, only the hallucination condition in the Charles Bonnet syndrome participants demonstrated unique temporal dynamics, characterized by a slow build-up of neural activity prior to the reported onset of hallucinations. This build-up was most pronounced in early visual cortex and then decayed along the visual hierarchy. These results suggest that, in the absence of external visual input, a build-up of spontaneous fluctuations in early visual cortex may activate the visual hierarchy, thereby triggering the experience of vision.

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.

Film theorists and practitioners suggest that motion can be manipulated in movie scenes to elicit emotional responses in viewers. However, our understanding of the role of motion in emotion perception remains limited. On the one hand, movies continuously depict local motion-movements of objects and humans, which are crucial for generating emotional responses. Movie scenes also frequently portray global motion, mainly induced by large camera movements, global motion being yet another source of information used by the brain during natural vision. Here we used functional MRI to elucidate the contributions of local and global motion to emotion perception during movie viewing. Subjects observed long (1 min) movie segments depicting emotional or neutral content. Brain activity in areas that showed preferential responses to emotional content was strongly linked over time with frame-wide variations in global motion, and to a lesser extent with local motion information. Similarly, stronger responses to emotional content were recorded within regions of interest whose activity was attuned to global and local motion over time. Since global motion fields are experienced during self-motion, we suggest that camera movements may induce illusory self-motion cues in viewers that interact with the movie's narrative and with other emotional cues in generating affective responses.

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 \u201ciconic\u201d 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.

FMRI data described here was recorded during resting-state in Mindfulness Meditators (MM) and control participants (see "Task-induced activity and resting-state fluctuations undergo similar alterations in visual and DMN areas of long-term meditators" Berkovich-Ohana et al. (2016) [1] for details). MM participants were also scanned during meditation. Analyses focused on functional connectivity within and between the default mode network (DMN) and visual network (Vis). Here we show data demonstrating that: 1) Functional connectivity within the DMN and the Visual networks were higher in the control group than in the meditators; 2) Data show an increase for the functional connectivity between the DMN and the Visual networks in the meditators compared to controls; 3) Data demonstrate that functional connectivity both within and between networks reduces during meditation, compared to the resting-state; and 4) A significant negative correlation was found between DMN functional connectivity and meditation expertise. The reader is referred to Berkovich-Ohana et al. (2016) [1] for further interpretation and discussion.

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 naïve 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.

Cortical blood flow can be modulated by local activity across a range of species; from barrel-specific blood flow in the rodent somatosensory cortex to the human cortex, where BOLD- fMRI reveals numerous functional borders. However, it appears that the distribution of blood capillaries largely ignores these functional boundaries. Here we report that, by contrast, astrocytes, a major player in blood-flow control, show a striking morphological sensitivity to functional borders. Specifically, we show that astrocyte processes are structurally confined by barrel boundaries in the mouse, by the border of primary auditory cortex in the rat and by layers IIIa/b and Cytochrome Oxidase (CO)-blobs boundaries in the human primary visual cortex. Thus, astrocytes which are critical elements in neuro-hemodynamic coupling show a significant anatomical segregation along functional boundaries across different mammalian species. These results may open a new anatomical marker for delineating functional borders across species, including post-mortem human brains.

Recent human neurophysiological recordings have uncovered two fundamental modes of cerebral cortex activity with distinct dynamics: an active mode characterized by a rapid and sustained activity ("ignition") and a spontaneous (resting-state) mode, manifesting ultra-slow fluctuations of low amplitude. We propose that both dynamics reflect two faces of the same recurrent loop mechanism: an integration device that accumulates ongoing stochastic activity and, either spontaneously or in a task-driven manner, crosses a dynamic threshold and ignites, leading to content-specific awareness. The hypothesis can explain a rich set of behavioral and neuronal phenomena, such as perceptual threshold, the high non-linearity of visual responses, the subliminal nature of spontaneous activity fluctuations, and the slow activity buildup anticipating spontaneous behavior (e.g., readiness potential). Further elaborations of this unified scheme, such as a cascade of integrators with different ignition thresholds or multi-stable states, can account for additional complexities in the repertoire of human cortical dynamics.

Despite extensive research, the spatiotemporal span of neuronal activations associated with the emergence of a conscious percept is still debated. The debate can be formulated in the context of local vs. global models, emphasizing local activity in visual cortex vs. a global fronto-parietal "workspace" as the key mechanisms of conscious visual perception. These alternative models lead to differential predictions with regard to the precise magnitude, timing and anatomical spread of neuronal activity during conscious perception. Here we aimed to test a specific aspect of these predictions in which local and global models appear to differ - namely the extent to which fronto-parietal regions modulate their activity during task performance under similar perceptual states. So far the main experimental results relevant to this debate have been obtained from non-invasive methods and led to conflicting interpretations. Here we examined these alternative predictions through large-scale intracranial measurements (Electrocorticogram - ECoG) in 43 patients and 4445 recording sites. Both ERP and broadband high frequency (50-150. Hz - BHF) responses were examined through the entire cortex during a simple 1-back visual recognition memory task. Our results reveal short latency intense visual responses, localized first in early visual cortex followed (at ~200. ms) by higher order visual areas, but failed to show significant delayed (300. ms) visual activations. By contrast, oddball image repeat events, linked to overt motor responses, were associated with a significant increase in a delayed (300. ms) peak of BHF power in fronto-parietal cortex. Comparing BHF responses with ERP revealed an additional peak in the ERP response - having a similar latency to the well-studied P3 scalp EEG response. Posterior and temporal regions demonstrated robust visual category selectivity. An unexpected observation was that high-order visual cortex responses were essentially concurrent (at ~200. ms) with an ultra-fast spread of signals of lower magnitude that invaded selected sites throughout fronto-parietal cortical areas. Our results are compatible with local models in demonstrating a clear task-dependence of the 300. ms fronto-parietal activation. However, they also reveal a more global component of low-magnitude and poor content selectivity that rapidly spreads into fronto-parietal sites. The precise functional role of this global "glow" remains to be elucidated.

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.

Even in absence of overt tasks, the human cortex manifests rich patterns of spontaneous "resting state" BOLD-fMRI fluctuations. However, the link of these spontaneous fluctuations to behavior is presently unclear. Attempts to directly investigate this link invariably lead to disruptions of the resting state. Here we took advantage of the well-established association between pupil diameter and attentional gain to address this issue by examining the correlation between the resting state BOLD and pupil fluctuations. Our results uncover a spontaneously emerging spatiotemporal pupil-BOLD correlation whereby a slow buildup of activity in default mode areas preceded both pupil dilation and wide-spread BOLD suppression in sensorimotor cortex. Control experiments excluded a role for luminance fluctuations or fixation. Comparing the pupil-correlated patterns to activation maps during visual imagery revealed a substantial overlap. Our results indicate a link between behavior, as indexed by pupil diameter, and resting state BOLD fluctuations. These pupil dilations, assumed to be related to attentional gain, were associated with spontaneously emerging antagonism between fundamental cortical networks.

While brain imaging studies emphasized the category selectivity of face-related areas, the underlying mechanisms of our remarkable ability to discriminate between different faces are less understood. Here, we recorded intracranial local field potentials from face-related areas in patients presented with images of faces and objects. A highly significant exemplar tuning within the category of faces was observed in high-Gamma (80-150 Hz) responses. The robustness of this effect was supported by single-trial decoding of face exemplars using a minimal (n = 5) training set. Importantly, exemplar tuning reflected the psychophysical distance between faces but not their low-level features. Our results reveal a neuronal substrate for the establishment of perceptual distance among faces in the human brain. They further imply that face neurons are anatomically grouped according to well-defined functional principles, such as perceptual similarity.

Recent brain imaging research has highlighted a new global system of areas termed the Default Mode network (DM), which appears to specialize in intrinsically oriented functions. However, it is still unresolved to what extent this system contains functional subsystems as in the better known sensory and motor cortices. Here, we report that functional subdivisions can be revealed within individual nodes of the DM, such as the Inferior Parietal Lobule (IPL), through the use of different categories of self-oriented tasks. Subjects underwent BOLD fMRI scans during which they were asked to recall self-related positive and negative information in the categories of people and food. These tasks elicited distinct regions of activation within the DM. Importantly, the observed activations were above the activity level in the baseline, no-task condition for these regions. The main subdivision within the DM was observed in the inferior and posterior parietal cortex. Analysis of coherent resting state fluctuations (functional connectivity analysis) revealed that these regions of activation were part of a distinct network of regions within the DM. These results argue against viewing the DM as a unitary system, and are compatible with the notion that, similar to the rest of the cerebral cortex, the DM consists of distinct, functionally specialized subregions.

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.

A fundamental debate in the study of cortical sensory systems concerns the scale of functional selectivity in cortical networks. Brain imaging studies have repeatedly demonstrated functional selectivity in entire cortical areas and networks using predetermined stimuli. However, it is not clear to what extent these networks are heterogeneous, i.e., whether the selectivity profiles in subregions within each sensory network show significant dissimilarity. Here, we studied local functional selectivity in the human cortex using naturalistic movie clips shown to 12 patients implanted with intracranial electrocorticography electrodes (590 in total), providing extensive cortical coverage. We examined the similarity of response profiles (40 to 80-Hz gamma-power modulations) across electrodes using a novel data driven approach without assuming any predefined category. Our results show that the functional selectivity of each highly responsive electrode was different from that of all other electrodes across the sensory cortex. Thus most responsive electrodes showed an activation profile that was unique in each patient and was similar to that of only 0.3% (1-2) of all other electrodes across all patients. Functional similarity between electrodes was linked to anatomical proximity. While in most electrodes the source of selectivity was complex, a small subset showed the welldocumented selectivity to faces and actions. Our results indicate that the human sensory cortex is organized as a mosaic of functionally unique subregions in which each site manifests its own special response profile.

Autism has been described as a disorder of general neural processing, but the particular processing characteristics that might be abnormal in autism have mostly remained obscure. Here, we present evidence of one such characteristic: poor evoked response reliability. We compared cortical response amplitude and reliability (consistency across trials) in visual, auditory, and somatosensory cortices of high-functioning individuals with autism and controls. Mean response amplitudes were statistically indistinguishable across groups, yet trial-by-trial response reliability was significantly weaker in autism, yielding smaller signal-to-noise ratios in all sensory systems. Response reliability differences were evident only in evoked cortical responses and not in ongoing resting-state activity. These findings reveal that abnormally unreliable cortical responses, even to elementary nonsocial sensory stimuli, may represent a fundamental physiological alteration of neural processing in autism. The results motivate a critical expansion of autism research to determine whether (and how) basic neural processing properties such as reliability, plasticity, and adaptation/habituation are altered in autism.

While research of human cortical function has typically focused on task-related increases in neuronal activity, there is a growing interest in the complementary phenomenon-namely, task-induced reductions. Recent human BOLD fMRI studies have associated such reductions with a specific network termed the default mode network (DMN). However, detailed understanding of the spatiotemporal patterns of task-negative responses and particularly how they compare across different cortical networks is lacking. Here we examined this issue in a large-scale electrocorticography study in patients performing a demanding backward masking task. Our results uncovered rapid (

Objectives: Recent fMRI studies have shown that it is possible to reliably identify the default-mode network (DMN) in the absence of any task, by resting-state connectivity analyses in healthy volunteers. We here aimed to identify the DMN in the challenging patient population of disorders of consciousness encountered following coma. Experimental design: A spatial independent component analysis-based methodology permitted DMN assessment, decomposing connectivity in all its different sources either neuronal or artifactual. Three different selection criteria were introduced assessing anticorrelation-corrected connectivity with or without an automatic masking procedure and calculating connectivity scores encompassing both spatial and temporal properties. These three methods were validated on 10 healthy controls and applied to an independent group of 8 healthy controls and 11 severely brain-damaged patients [locked-in syndrome (n = 2), minimally conscious (n = 1), and vegetative state (n = 8)]. Principal observations: All vegetative patients showed fewer connections in the default-mode areas, when compared with controls, contrary to locked-in patients who showed near-normal connectivity. In the minimally conscious-state patient, only the two selection criteria considering both spatial and temporal properties were able to identify an intact right lateralized BOLD connectivity pattern, and metabolic PET data suggested its neuronal origin. Conclusions: When assessing resting-state connectivity in patients with disorders of consciousness, it is important to use a methodology excluding non-neuronal contributions caused by head motion, respiration, and heart rate artifacts encountered in all studied patients.

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 voxelbased 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, theFCdifference 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.

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.

Memory formation requires the placement of experienced events in the same order in which they appeared. A large body of evidence from human studies indicates that structures in the medial temporal lobe are critically involved in forming and maintaining such memories, and complementing evidence from lesion and electrophysiological work in animals support these findings. However, it remains unclearhowsingle cells and networks of cells can signal this temporal relationship between events. Here we used recordings from single cells in the human brain obtained while subjects viewed repeated presentations of cinematic episodes. We found that neuronal activity in successive time segments became gradually correlated, and, as a result, activity in a given timewindowbecamea faithful predictor of the activity to follow. This correlation emerged rapidly, within two to three presentations of an episode and exceeded both context-independent and pure stimulus-driven correlations. The correlation was specific for hippocampal neurons, did not occur in theamygdala andanterior cingulate cortex,andwas found for single cells, cell pairs, and triplets of cells, supporting the notion that cell assemblies code for the temporal relationships between sensory events. Importantly, this neuronal measure of temporal binding successfully predicted subjects' ability to recall and verbally report the viewed episodes later. Our findings suggest a neuronal substrate for the formation of memory of the temporal order of events.

Response reliability is complementary to more conventional measurements of response amplitudes, and can reveal phenomena that response amplitudes do not. Here we review studies that measured reliability of cortical activity within or between human subjects in response to naturalistic stimulation (e.g. free viewing of movies). Despite the seemingly uncontrolled nature of the task, some of these complex stimuli evoke highly reliable, selective and time-locked activity in many brain areas, including some regions that show little response modulation in most conventional experimental protocols. This activity provides an opportunity to address novel questions concerning natural vision, temporal scale of processing, memory and the neural basis of inter-group differences.

The question of how people recognize themselves and separate themselves from the environment and others has long intrigued philosophers and scientists. Recent findings have linked regions of the 'default brain' or 'intrinsic system' to self-related processing. We used a paradigm in which subjects had to rely on subtle sensory-motor synchronization differences to determine whether a viewed movement belonged to them or to another person, while stimuli and task demands associated with the "responded self" and "responded other" conditions were precisely matched. Self recognition was associated with enhanced brain activity in several ROIs of the intrinsic system, whereas no differences emerged within the extrinsic system. This self-related effect was found even in cases where the sensory-motor aspects were precisely matched. Control conditions ruled out task difficulty as the source of the differential self-related effects. The findings shed light on the neural systems underlying bodily self recognition.

A novel computer game environment was designed to assess self-initiated motivated behavior and was used to measure its neural correlates in healthy subjects using functional magnetic resonance imaging. The results show a network of brain regions involved in these processes, including dorsolateral prefrontal, medial prefrontal and posterior parietal cortices. Our paradigm could potentially be used as a basis for assessment and rehabilitation method of self-initiated behavior and apathy.

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. (ii) 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. However, just-noticeable differences of frequency are substantially smaller than the bandwidth of the peripheral sensors. 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.

We address the problem of testing in every brain voxel v whether at least u out of n conditions (or subjects) considered shows a real effect. The only statistic suggested so far, the maximum p-value method, fails under dependency (unless u = n) and in particular under positive dependency that arises if all stimuli are compared to the same control stimulus. Moreover, it tends to have low power under independence. For testing that at least u out of n conditions shows a real effect, we suggest powerful test statistics that are valid under dependence between the individual condition p-values as well as under independence and other test statistics that are valid under independence. We use the above approach, replacing conditions by subjects, to produce informative group maps and thereby offer an alternative to mixed/random effect analysis.

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

A common theme in theories of subjective awareness poses a self-related "observer" function, or a homunculus, as a critical element without which awareness can not emerge. Here, we examined this question using fMRI. In our study, we compared brain activity patterns produced by a demanding sensory categorization paradigm to those engaged during self-reflective introspection, using similar sensory stimuli. Our results show a complete segregation between the two patterns of activity. Furthermore, regions that showed enhanced activity during introspection underwent a robust inhibition during the demanding perceptual task. The results support the notion that self-related processes are not necessarily engaged during sensory perception and can be actually suppressed.

Functional magnetic resonance imaging (fMRI) is an important tool for investigating human brain function, but the relationship between the hemodynamically 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 = 0.75, P -47). Thus, fMRI signals can provide a reliable measure of the firing rate of human cortical neurons.

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 white 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.

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.

Background: A prevailing assumption in neuroimaging studies is that relatively low fMRI signals are due to weak neuronal activation and therefore they are commonly ignored. However lower fMRI signals may also result from intense activation by highly selective albeit small subsets of neurons in the imaged voxel. We report on an approach that could form a basis for resolving this ambiguity imposed by the low (mm range) spatial resolution of fMRI. Our approach employs fMR-adaptation as an indicator for highly active neuronal populations even when the measured fMRI signal is low. Results: In this study we first showed that fMRI-adaptation is diminished when overall neuronal activity is lowered substantially by reducing image contrast. We then applied the same adaptation paradigm but this time we lowered the fMRI signal by changing object shape. While the overall fMRI signal in category-related regions such as the face-related pFs was drastically reduced for non-face stimuli the adaptation level obtained for these stimuli remained high. We hypothesize that the relatively greater adaptation level following exposure to "nonoptimal" object shapes is indicative of small subsets of neurons responding vigorously to these "nonoptimal" objects even when the overall fMRI activity is low. Conclusions: Our results show that fMR-adaptation can be used to differentiate between neuronal activation patterns that appear similar in the overall fMRI signal. The results suggest that it may be possible to employ fMR-adaptation to reveal functionally heterogeneous islands of activity which are too small to image using conventional imaging methods.

Cortical topography is one of the most fundamental organizing principles of cortical areas. One such topography - eccentricity mapping - is present even in high-order, ventral stream visual areas. Within these areas, different object categories have specific eccentricity biases. In particular, faces, letters and words appear to be associated with central visual-field bias, whereas buildings are associated with a peripheral one. We propose that resolution needs are an important factor in organizing object representations: objects whose recognition depends on analysis of fine detail will be associated with central-biased representations, whereas objects whose recognition entails large-scale integration will be more peripherally biased.

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 due 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 tho 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 V1. Orientation and CO 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 μm; mean length, 342 μm) 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 range of orientation domains, but appeared to avoid domains having orthogonal orientation preference to that found at the injection site. To conclude, our results show, on the one hand, a measure of functional specificity for the CO stripes and the intrinsic connections. On the other hand, they indicate additional substructures within area V2, whose precise relationship to the known compartmental organization remains to be clarified.

Neuronal response properties vary markedly at increasing levels of the cortical hierarchy. At present it is unclear how these variations are reflected in the organization of the intrinsic cortical circuitry. Here we analyze patterns of intrinsic horizontal connections at different hierarchical levels in the visual cortex of the macaque monkey. The connections were studied in tangential sections of flattened cortices, which were injected with the anterograde tracer biocytin. We directly compared the organization of connections in four cortical areas representing four different levels in the cortical hierarchy. The areas were visual areas 1, 2, 4 and Brodman's area 7a (V1, V2, V4 and 7a, respectively). In all areas studied, injections labeled numerous horizontally coursing axons that formed dense halos around the injection sites. Further away, the fibers tended to form separate clusters. Many fibers could be traced along the way from the injection sites to the target clusters. At progressively higher order areas, there was a striking increase in the spread of intrinsic connections: from a measured distance of 2.1 mm in area V1 to 9.0 mm in area 7a. Average interpatch distance also increased from 0.61 mm in area V1 to 1.56 mm in area 7a. In contrast, patch size changed far less at higher order areas, from an average width of 230 m̈M in area V1 to 310 m̈m in area 7a. Analysis of synaptic bouton distribution along axons revealed that average interbouton distance remained constant at 6.4 m̈m (median) in and out of the clusters and in the different cortical areas. Larger injections resulted in a marked increase in the number of labeled patches but only a minor increase in the spread of connections or in patch size. Thus, in line with the more global computational roles proposed for the higher order visual areas, the spread of intrinsic connections is increased with the hierarchy level. On the other hand, the clustered organization of the connections is preserved at higher order areas. These clusters may reflect the existence of cortical modules having bloblike dimensions throughout macaque monkey visual cortex. © 1993 WileyLiss, Inc.

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 actions 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.

Vasoactive intestinal polypeptide (VIP) is a regulatory peptide widely distributed in the central and peripheral nervous systems. To understand the activities of VIP it is necessary to study the mechanisms governing its production. The highest concentration of VIP-producing cells occurs in the suprachiasmatic nucleus (SCN) of the hypothalamus. Because the SCN is directly innervated by the optic nerve, we decided to investigate the effect of visual input on VIP gene expression. By means of Northern blot hybridization, we measured VIP mRNA levels in the hypothalami of 36-day-old normal rats and rats that had been enucleated at birth. The concentration of VIP mRNA in the hypothalami of enucleated rats was approximately double that in the hypothalami of normal rats. In contrast, the concentration of VIP mRNA in the cerebral cortex significantly decreased after enucleation. The concentrations of VIP mRNA were also measured by in situ hybridization to brain sections. The hypothalamic VIP mRNA was located mainly in the SCN. Enucleation resulted in an increase of VIP transcripts in the SCN. These results indicate that visual input may participate in the regulation of VIP production.