Hippocampal-cortical interaction during periods of subcortical silence.

Hippocampal ripples, episodic high-frequency field-potential oscillations primarily occurring during sleep and calmness, have been described in mice, rats, rabbits, monkeys and humans, and so far they have been associated with retention of previously acquired awake experience. Although hippocampal ripples have been studied in detail using neurophysiological methods, the global effects of ripples on the entire brain remain elusive, primarily owing to a lack of methodologies permitting concurrent hippocampal recordings and whole-brain activity mapping. By combining electrophysiological recordings in hippocampus with ripple-triggered functional magnetic resonance imaging, here we show that most of the cerebral cortex is selectively activated during the ripples, whereas most diencephalic, midbrain and brainstem regions are strongly and consistently inhibited. Analysis of regional temporal response patterns indicates that thalamic activity suppression precedes the hippocampal population burst, which itself is temporally bounded by massive activations of association and primary cortical areas. These findings suggest that during off-line memory consolidation, synergistic thalamocortical activity may be orchestrating a privileged interaction state between hippocampus and cortex by silencing the output of subcortical centres involved in sensory processing or potentially mediating procedural learning. Such a mechanism would cause minimal interference, enabling consolidation of hippocampus-dependent memory.

Can sliding-window correlations reveal dynamic functional connectivity in resting-state fMRI?

During the last several years, the focus of research on resting-state functional magnetic resonance imaging (fMRI) has shifted from the analysis of functional connectivity averaged over the duration of scanning sessions to the analysis of changes of functional connectivity within sessions. Although several studies have reported the presence of dynamic functional connectivity (dFC), statistical assessment of the results is not always carried out in a sound way and, in some studies, is even omitted. In this study, we explain why appropriate statistical tests are needed to detect dFC, we describe how they can be carried out and how to assess the performance of dFC measures, and we illustrate the methodology using spontaneous blood-oxygen level-dependent (BOLD) fMRI recordings of macaque monkeys under general anesthesia and in human subjects under resting-state conditions. We mainly focus on sliding-window correlations since these are most widely used in assessing dFC, but also consider a recently proposed non-linear measure. The simulations and methodology, however, are general and can be applied to any measure. The results are twofold. First, through simulations, we show that in typical resting-state sessions of 10 min, it is almost impossible to detect dFC using sliding-window correlations. This prediction is validated by both the macaque and the human data: in none of the individual recording sessions was evidence for dFC found. Second, detection power can be considerably increased by session- or subject-averaging of the measures. In doing so, we found that most of the functional connections are in fact dynamic. With this study, we hope to raise awareness of the statistical pitfalls in the assessment of dFC and how they can be avoided by using appropriate statistical methods.

Own-species bias in the representations of monkey and human face categories in the primate temporal lobe.

Face categorization is fundamental for social interactions of primates and is crucial for determining conspecific groups and mate choice. Current evidence suggests that faces are processed by a set of well-defined brain areas. What is the fine structure of this representation, and how is it affected by visual experience? Here, we investigated the neural representations of human and monkey face categories using realistic three-dimensional morphed faces that spanned the continuum between the two species. We found an "own-species" bias in the categorical representation of human and monkey faces in the monkey inferior temporal cortex at the level of single neurons as well as in the population response analyzed using a pattern classifier. For monkey and human subjects, we also found consistent psychophysical evidence indicative of an own-species bias in face perception. For both behavioural and neural data, the species boundary was shifted away from the center of the morph continuum, for each species toward their own face category. This shift may reflect visual expertise for members of one's own species and be a signature of greater brain resources assigned to the processing of privileged categories. Such boundary shifts may thus serve as sensitive and robust indicators of encoding strength for categories of interest.

Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: implication for longitudinal studies.

Magnetic resonance imaging (MRI) is widely used in basic and clinical research to map the structural and functional organization of the brain. An important need of MR research is for contrast agents that improve soft-tissue contrast, enable visualization of neuronal tracks, and enhance the capacity of MRI to provide functional information at different temporal scales. Unchelated manganese can be such an agent, and manganese-enhanced MRI (MEMRI) can potentially be an excellent technique for localization of brain activity (for review see Silva et al., 2004). Yet, the toxicity of manganese presents a major limitation for employing MEMRI in behavioral paradigms. We have tested systematically the voluntary wheel running behavior of rats after systemic application of MnCl(2) in a dose range of 16-80 mg/kg, which is commonly used in MEMRI studies. The results show a robust dose-dependent decrease in motor performance, which was accompanied by weight loss and decrease in food intake. The adverse effects lasted for up to 7 post-injection days. The lowest dose of MnCl(2) (16 mg/kg) produced minimal adverse effects, but was not sufficient for functional mapping. We have therefore evaluated an alternative method of manganese delivery via osmotic pumps, which provide a continuous and slow release of manganese. In contrast to a single systemic injection, the pump method did not produce any adverse locomotor effects, while achieving a cumulative concentration of manganese (80 mg/kg) sufficient for functional mapping. Thus, MEMRI with such an optimized manganese delivery that avoids toxic effects can be safely applied for longitudinal studies in behaving animals.

Neuronal correlates of subjective visual perception.

Neuronal activity in the superior temporal sulcus of monkeys, a cortical region that plays an important role in analyzing visual motion, was related to the subjective perception of movement during a visual task. Single neurons were recorded while monkeys (Macaca mulatta) discriminated the direction of motion of stimuli that could be seen moving in either of two directions during binocular rivalry. The activity of many neurons was dictated by the retinal stimulus. Other neurons, however, reflected the monkeys' reported perception of motion direction, indicating that these neurons in the superior temporal sulcus may mediate the perceptual experience of a moving object.

Perceptual deficits and the activity of the color-opponent and broad-band pathways at isoluminance.

The deficits in texture, motion, and depth perception incurred in monkeys at isoluminance were compared with the responses of neurons of the color-opponent and broad-band systems in the lateral geniculate nucleus. Texture perception, assumed to be carried by the color-opponent system, and motion and depth perception, ascribed to the broad-band pathway, were all found to be compromised but not abolished at isoluminance. Correspondingly, both the color-opponent and the broad-band systems were affected at isoluminance, but the activity of the neurons in neither system was abolished. These results suggest that impairment of visual capacities at isoluminance cannot be uniquely attributed to either of these systems and that isoluminant stimuli are inappropriate for the psychophysical isolation of these pathways.

Natural vision reveals regional specialization to local motion and to contrast-invariant, global flow in the human brain.

Visual changes in feature movies, like in real-live, can be partitioned into global flow due to self/camera motion, local/differential flow due to object motion, and residuals, for example, due to illumination changes. We correlated these measures with brain responses of human volunteers viewing movies in an fMRI scanner. Early visual areas responded only to residual changes, thus lacking responses to equally large motion-induced changes, consistent with predictive coding. Motion activated V5+ (MT+), V3A, medial posterior parietal cortex (mPPC) and, weakly, lateral occipital cortex (LOC). V5+ responded to local/differential motion and depended on visual contrast, whereas mPPC responded to global flow spanning the whole visual field and was contrast independent. mPPC thus codes for flow compatible with unbiased heading estimation in natural scenes and for the comparison of visual flow with nonretinal, multimodal motion cues in it or downstream. mPPC was functionally connected to anterior portions of V5+, whereas laterally neighboring putative homologue of lateral intraparietal area (LIP) connected with frontal eye fields. Our results demonstrate a progression of selectivity from local and contrast-dependent motion processing in V5+ toward global and contrast-independent motion processing in mPPC. The function, connectivity, and anatomical neighborhood of mPPC imply several parallels to monkey ventral intraparietal area (VIP).

The influence of moderate hypercapnia on neural activity in the anesthetized nonhuman primate.

Hypercapnia is often used as vasodilatory challenge in clinical applications and basic research. In functional magnetic resonance imaging (fMRI), elevated CO(2) is applied to derive stimulus-induced changes in the cerebral rate of oxygen consumption (CMRO(2)) by measuring cerebral blood flow and blood-oxygenation-level-dependent (BOLD) signal. Such methods, however, assume that hypercapnia has no direct effect on CMRO(2). In this study, we used combined intracortical recordings and fMRI in the visual cortex of anesthetized macaque monkeys to show that spontaneous neuronal activity is in fact significantly reduced by moderate hypercapnia. As expected, measurement of cerebral blood volume using an exogenous contrast agent and of BOLD signal showed that both are increased during hypercapnia. In contrast to this, spontaneous fluctuations of local field potentials in the beta and gamma frequency range as well as multiunit activity are reduced by approximately 15% during inhalation of 6% CO(2) (pCO(2) = 56 mmHg). A strong tendency toward a reduction of neuronal activity was also found at CO(2) inhalation of 3% (pCO(2) = 45 mmHg). This suggests that CMRO(2) might be reduced during hypercapnia and caution must be exercised when hypercapnia is applied to calibrate the BOLD signal.

Functional imaging of the monkey brain.

Functional magnetic resonance imaging (fMRI) has become an essential tool for studying human brain function. Here we describe the application of this technique to anesthetized monkeys. We present spatially resolved functional images of the monkey cortex based on blood oxygenation level dependent (BOLD) contrast. Checkerboard patterns or pictures of primates were used to study stimulus-induced activation of the visual cortex, in a 4.7-Tesla magnetic field, using optimized multi-slice, gradient-recalled, echo-planar imaging (EPI) sequences to image the entire brain. Under our anesthesia protocol, visual stimulation yielded robust, reproducible, focal activation of the lateral geniculate nucleus (LGN), the primary visual area (V1) and a number of extrastriate visual areas, including areas in the superior temporal sulcus. Similar responses were obtained in alert, behaving monkeys performing a discrimination task.

Shape representation in the inferior temporal cortex of monkeys.

BACKGROUND: The inferior temporal cortex (IT) of the monkey has long been known to play an essential role in visual object recognition. Damage to this area results in severe deficits in perceptual learning and object recognition, without significantly affecting basic visual capacities. Consistent with these ablation studies is the discovery of IT neurons that respond to complex two-dimensional visual patterns, or objects such as faces or body parts. What is the role of these neurons in object recognition? Is such a complex configurational selectivity specific to biologically meaningful objects, or does it develop as a result of extensive exposure to any objects whose identification relies on subtle shape differences? If so, would IT neurons respond selectively to recently learned views of features of novel objects? The present study addresses this question by using combined psychophysical and electrophysiological experiments, in which monkeys learned to classify and recognize computer-generated three-dimensional objects. RESULTS: A population of IT neurons was found that responded selectively to views of previously unfamiliar objects. The cells discharged maximally to one view of an object, and their response declined gradually as the object was rotated away from this preferred view. No selective responses were ever encountered for views that the animal systematically failed to recognize. Most neurons also exhibited orientation-dependent responses during view-plane rotations. Some neurons were found to be tuned around two views of the same object, and a very small number of cells responded in a view-invariant manner. For the five different objects that were used extensively during the training of the animals, and for which behavioral performance became view-independent, multiple cells were found that were tuned around different views of the same object. A number of view-selective units showed response invariance for changes in the size of the object or the position of its image within the parafovea. CONCLUSION: Our results suggest that IT neurons can develop a complex receptive field organization as a consequence of extensive training in the discrimination and recognition of objects. None of these objects had any prior meaning for the animal, nor did they resemble anything familiar in the monkey's environment. Simple geometric features did not appear to account for the neurons' selective responses. These findings support the idea that a population of neurons--each tuned to a different object aspect, and each showing a certain degree of invariance to image transformations--may, as an ensemble, encode at least some types of complex three-dimensional objects. In such a system, several neurons may be active for any given vantage point, with a single unit acting like a blurred template for a limited neighborhood of a single view.

Nonmonotonic noise tuning of BOLD fMRI signal to natural images in the visual cortex of the anesthetized monkey.

BACKGROUND: The perceptual ability of humans and monkeys to identify objects in the presence of noise varies systematically and monotonically as a function of how much noise is introduced to the visual display. That is, it becomes more and more difficult to identify an object with increasing noise. Here we examine whether the blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) signal in anesthetized monkeys also shows such monotonic tuning. We employed parametric stimulus sets containing natural images and noise patterns matched for spatial frequency and intensity as well as intermediate images generated by interpolation between natural images and noise patterns. Anesthetized monkeys provide us with the unique opportunity to examine visual processing largely in the absence of top-down cognitive modulations and can thus provide an important baseline against which work with awake monkeys and humans can be compared. RESULTS: We measured BOLD activity in occipital visual cortical areas as natural images and noise patterns, as well as intermediate interpolated patterns at three interpolation levels (25%, 50%, and 75%) were presented to anesthetized monkeys in a block paradigm. We observed reliable visual activity in occipital visual areas including V1, V2, V3, V3A, and V4 as well as the fundus and anterior bank of the superior temporal sulcus (STS). Natural images consistently elicited higher BOLD levels than noise patterns. For intermediate images, however, we did not observe monotonic tuning. Instead, we observed a characteristic V-shaped noise-tuning function in primary and extrastriate visual areas. BOLD signals initially decreased as noise was added to the stimulus but then increased again as the pure noise pattern was approached. We present a simple model based on the number of activated neurons and the strength of activation per neuron that can account for these results. CONCLUSIONS: We show that, for our parametric stimulus set, BOLD activity varied nonmonotonically as a function of how much noise was added to the visual stimuli, unlike the perceptual ability of humans and monkeys to identify such stimuli. This raises important caveats for interpreting fMRI data and demonstrates the importance of assessing not only which neural populations are activated by contrasting conditions during an fMRI study, but also the strength of this activation. This becomes particularly important when using the BOLD signal to make inferences about the relationship between neural activity and behavior.

View-dependent object recognition by monkeys.

BACKGROUND: How do we recognize visually perceived three-dimensional objects, particularly when they are seen from novel view-points? Recent psychophysical studies have suggested that the human visual system may store a relatively small number of two-dimensional views of a three-dimensional object, recognizing novel views of the object by interpolation between the stored sample views. In order to investigate the neural mechanisms underlying this process, physiological experiments are required and, as a prelude to such experiments, we have been interested to know whether the observations made with human observers extend to monkeys. RESULTS: We trained monkeys to recognize computer-generated images of objects presented from an arbitrarily chosen training view and containing sufficient three-dimensional information to specify the object's structure. We subsequently tested the trained monkeys' ability to generalize recognition of the object to views generated by rotation of the target object around any arbitrary axis. The monkeys recognized as the target only those two-dimensional views that were close to the familiar, training view. Recognition became increasingly difficult for the monkeys as the stimulus was rotated away from the experienced viewpoint, and failed for views farther than about 40 degrees from the training view. This suggests that, in the early stages of learning to recognize a previously unfamiliar object, the monkeys build two-dimensional, viewer-centered object representations, rather than a three-dimensional model of the object. When the animals were trained with as few as three views of the object, 120 degrees apart, they could often recognize all the views of the object resulting from rotations around the same axis. CONCLUSION: Our experiments show that recognition of three-dimensional novel objects is a function of the object's retinal projection. This suggests that non-human primates, like humans, may accomplish view-invariant recognition of familiar objects by a viewer-centered system that interpolates between a small number of stored views. The measures of recognition performance can be simulated by a regularization network that stores a few familiar views, and is endowed with the ability to interpolate between these views. Our results provide the basis for physiological studies of object-recognition by monkeys and suggest that the insights gained from such studies should apply also to humans.

The color-opponent and broad-band channels of the primate visual system.

Physiological, anatomical and psychophysical studies have identified several parallel channels of information processing in the primate visual system. Two of these, the color-opponent and the broad-band channels, originate in the retina and remain in part segregated through several higher cortical stations. To improve understanding of their function, recent studies have examined the visual capacities of monkeys following selective disruption of these channels. Color vision, fine- but not coarse-form vision and stereopsis are severely impaired in the absence of the color-opponent channel, whereas motion and flicker perception are impaired at high but not low temporal frequencies in the absence of the broad-band channel. The results suggest that the color-opponent channel extends the range of vision in the spatial and wavelength domains, and that the broad-band channel extends it in the temporal domain. Lesion studies also indicate that these channels must reach higher cortical centers through extrastriate regions other than just area V4 and the middle temporal area, and that the analysis performed by these two regions cannot be uniquely identified with specific visual capacities.

Sensory systems.

Our understanding of sensory systems has grown impressively in recent years as a result of intense efforts to characterize the mechanisms underlying perception. A large body of evidence has accrued regarding the processes through which sensory information at the biochemical, electrophysiological, and systems levels contributes to the conscious experience of a stimulus. Our efforts to understand the function of sensory systems have been aided by the development of new techniques, including powerful methods of molecular biology, refined short- and long-term approaches to recording from single and multiple neurons, and non-invasive neuroimaging techniques that allow us to study activity within the human brain while subjects perform a variety of cognitive tasks. In future research, the last approach is likely to form a bridge between the large body of electrophysiological knowledge acquired in animal experiments and that currently being obtained in human imaging research.

Noticing familiar objects in real world scenes: the role of temporal cortical neurons in natural vision.

During natural vision, the brain efficiently processes views of the external world as the eyes actively scan the environment. To better understand the neural mechanisms underlying this process, we recorded the activity of individual temporal cortical neurons while monkeys looked for and identified familiar targets embedded in natural scenes. We found a group of visual neurons that exhibited stimulus-selective neuronal bursts just before the monkey's response. Most of these cells showed similar selectivity whether effective targets were viewed in isolation or encountered in the course of exploring complex scenes. In addition, by embedding target stimuli in natural scenes, we could examine the activity of these stimulus-selective cells during visual search and at the time targets were fixated and identified. We found that, during exploration, neuronal activation sometimes began shortly before effective targets were fixated, but only if the target was the goal of the next fixation. Furthermore, we found that the magnitude of this early activation varied inversely with reaction time, indicating that perceptual information was integrated across fixations to facilitate recognition. The behavior of these visually selective cells suggests that they contribute to the process of noticing familiar objects in the real world.

Motion processing in the macaque: revisited with functional magnetic resonance imaging.

A great deal is known about the response properties of single neurons processing sensory information. In contrast, less is understood about the collective characteristics of networks of neurons that may underlie sensory capacities of animals. We used functional magnetic resonance imaging to study the emergent properties of populations of neurons processing motion across different brain areas. Using a visual adaptation paradigm, we localized a distributed network of visual areas that process information about the direction of motion as expected from single-cell recording studies. However, we found an apparent discrepancy between the directional signals in certain visual areas as measured with blood oxygenation level-dependent imaging compared with an estimate based on the spiking of single neurons. We propose a hypothesis that may account for this difference based on the postulate that neuronal selectivity is a function of the state of adaptation. Consequently, neurons classically thought to lack information about certain attributes of the visual scene may nevertheless receive and process this information. We further hypothesize that this adaptation-dependent selectivity may arise from intra- or inter-area cellular connections, such as feedback from higher areas. This network property may be a universal principle the computational goal of which is to enhance the ability of neurons in earlier visual areas to adapt to statistical regularities of the input and therefore increase their sensitivity to detect changes along these stimulus dimensions.

Parallel pathways in the visual system: their role in perception at isoluminance.

It has been proposed that the functions of the two major parallel channels of the primate visual system, the color-opponent and the broad-band, can be determined in psychophysical experiments by eliminating luminance but maintaining chrominance information (isoluminance), since under such conditions the broad-band channel is believed to be silenced. To test this proposition we examined the visual functions of monkeys after blocking either of these channels and we also assessed the responses of neurons to isoluminant stimuli in the lateral geniculate nucleus. We show that color, texture, stereopsis and pattern perception in the absence of the color-opponent channel, and flicker and motion perception in the absence of the broad-band channel are compromised. Yet isoluminance functions for stereopsis and texture in the absence of the broad-band channel and for motion in the absence of the color-opponent channel are indistinguishable from normal. Our recordings show that the neuronal responses of the broad-band cells for isoluminant exchange of red and green lights are reduced but not eliminated and that the color-opponent cells also become similarly less responsive under these conditions. We conclude that perceptual losses at isoluminance are not specific for either channel.

Binocular motion rivalry in macaque monkeys: eye dominance and tracking eye movements.

When the two eyes are exposed to markedly different patterns, perception becomes unstable, falling into oscillations, so that the image of one eye is seen first and then that from the other. With large stimuli the alternation is piecemeal, whilst when small stimuli are used the whole pattern alternates in unison. The purpose of this study was to determine whether a reliable, objective indicator of the perceptual state during binocular rivalry could be developed in the nonhuman primate. Monkeys (Macaca mulatta) were trained to discriminate direction of motion when presented with vertically drifting gratings moving in opposite directions in the two eyes. A high correlation was found between the direction of the slow phase of the optokinetic nystagmus (OKN) elicited by the drifting gratings during rivalry and the direction of motion reported by the monkey even though the gain of the OKN was reduced during rivalry, and the latency was longer. Behavioral eye dominance during rivalry varied significantly over time, between individuals and as a function of interocular contrast differences. Since the direction of tracking eye movements can be used to reliably monitor perceptual state during binocular motion rivalry, the opportunity exists in nonhuman primates to study the neurophysiological mechanisms underlying motion perception during the perceptually ambiguous condition of binocular rivalry.

The minimum motion technique applied to determine isoluminance in psychophysical experiments with monkeys.

Isoluminance ratios for red/green, red/blue and blue/green sinusoidal gratings were determined in macaque monkeys using the minimum motion heterochromatic photometry technique (Anstis & Cavanagh, 1983), in which the motion of specially constructed test grating reverses at the point of isoluminance. The point of luminance equality between the two colors was determined using (1) overt responses of monkeys trained to discriminate motion direction and (2) reversals in the direction of the nystagmic eye movements. Both measures yielded essentially identical isoluminance points. Both the spatial and the temporal frequency of the grating patterns were found to influence the isoluminance settings in all animals tested. The amount of blue equating a preset red or green value was found to increase consistently with increased spatial frequency and with increasing eccentricity. These results show the necessity of spatial and temporal frequency dependent adjustment of visual patterns used in psychophysical and physiological experiments dealing with the processing of color. Furthermore, eye movement measurements appear to be sufficiently in order to determine isoluminance in foveally presented moving patterns with nonhuman primates.