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Social animals can identify conspecifics by many forms of sensory input. However, whether the neuronal computations that support this ability to identify individuals rely on modality-independent convergence or involve ongoing synergistic interactions along the multiple sensory streams remains controversial. Direct neuronal measurements at relevant brain sites could address such questions, but this requires better bridging the work in humans and animal models. Here, we overview recent studies in nonhuman primates on voice and face identity-sensitive pathways and evaluate the correspondences to relevant findings in humans. This synthesis provides insights into converging sensory streams in the primate anterior temporal lobe (ATL) for identity processing. Furthermore, we advance a model and suggest how alternative neuronal mechanisms could be tested., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Diffusion magnetic resonance imaging (MRI) allows for the noninvasive in vivo examination of anatomical connections in the human brain, which has an important role in understanding brain function. Validation of this technique is vital, but has proved difficult due to the lack of an adequate gold standard. In this work, the macaque visual system was used as a model as an extensive body of literature of in vivo and postmortem tracer studies has established a detailed understanding of the underlying connections. We performed probabilistic tractography on high angular resolution diffusion imaging data of 2 ex vivo, in vitro macaque brains. Comparisons were made between identified connections at different thresholds of probabilistic connection "strength," and with various tracking optimization strategies previously proposed in the literature, and known connections from the detailed visual system wiring map described by Felleman and Van Essen (1991; FVE91). On average, 74% of connections that were identified by FVE91 were reproduced by performing the most successfully optimized probabilistic diffusion MRI tractography. Further comparison with the results of a more recent tracer study ( Markov et al. 2012) suggests that the fidelity of tractography in estimating the presence or absence of interareal connections may be greater than this., (© The Author 2015. Published by Oxford University Press.)

It has long been assumed that the surface electroencephalography (EEG) signal depends on both the amplitude and spatial synchronization of underlying neural activity, though isolating their respective contribution remains elusive. To address this, we made simultaneous surface EEG measurements along with intracortical recordings of local field potentials (LFPs) in the primary visual cortex of behaving nonhuman primates. We found that trial-by-trial fluctuations in EEG power could be explained by a linear combination of LFP power and interelectrode temporal synchrony. This effect was observed in both stimulus and stimulus-free conditions and was particularly strong in the gamma range (30-100 Hz). Subsequently, we used pharmacological manipulations to show that neural synchrony can produce a positively modulated EEG signal even when the LFP signal is negatively modulated. Taken together, our results demonstrate that neural synchrony can modulate EEG signals independently of amplitude changes in neural activity. This finding has strong implications for the interpretation of EEG in basic and clinical research, and helps reconcile EEG response discrepancies observed in different modalities (e.g., EEG vs. functional magnetic resonance imaging) and different spatial scales (e.g., EEG vs. intracranial EEG).

Effective interactions between conspecific individuals can depend upon the receiver forming a coherent multisensory representation of communication signals, such as merging voice and face content. Neuroimaging studies have identified face- or voice-sensitive areas (Belin et al., 2000; Petkov et al., 2008; Tsao et al., 2008), some of which have been proposed as candidate regions for face and voice integration (von Kriegstein et al., 2005). However, it was unclear how multisensory influences occur at the neuronal level within voice- or face-sensitive regions, especially compared with classically defined multisensory regions in temporal association cortex (Stein and Stanford, 2008). Here, we characterize auditory (voice) and visual (face) influences on neuronal responses in a right-hemisphere voice-sensitive region in the anterior supratemporal plane (STP) of Rhesus macaques. These results were compared with those in the neighboring superior temporal sulcus (STS). Within the STP, our results show auditory sensitivity to several vocal features, which was not evident in STS units. We also newly identify a functionally distinct neuronal subpopulation in the STP that appears to carry the area's sensitivity to voice identity related features. Audiovisual interactions were prominent in both the STP and STS. However, visual influences modulated the responses of STS neurons with greater specificity and were more often associated with congruent voice-face stimulus pairings than STP neurons. Together, the results reveal the neuronal processes subserving voice-sensitive fMRI activity patterns in primates, generate hypotheses for testing in the visual modality, and clarify the position of voice-sensitive areas within the unisensory and multisensory processing hierarchies.

We introduce a new method for measuring visual population receptive fields (pRF) with functional magnetic resonance imaging (fMRI). The pRF structure is modeled as a set of weights that can be estimated by solving a linear model that predicts the Blood Oxygen Level-Dependent (BOLD) signal using the stimulus protocol and the canonical hemodynamic response function. This method does not make a priori assumptions about the specific pRF shape and is therefore a useful tool for uncovering the underlying pRF structure at different spatial locations in an unbiased way. We show that our method is more accurate than a previously described method (Dumoulin and Wandell, 2008) which directly fits a 2-dimensional isotropic Gaussian pRF model to predict the fMRI time-series. We demonstrate that direct-fit models do not fully capture the actual pRF shape, and can be prone to pRF center mislocalization when the pRF is located near the border of the stimulus space. A quantitative comparison demonstrates that our method outperforms the direct-fit methods in the pRF center modeling by achieving higher explained variance of the BOLD signal. This was true for direct-fit isotropic Gaussian, anisotropic Gaussian, and difference of isotropic Gaussians model. Importantly, our model is also capable of exploring a variety of pRF properties such as surround suppression, receptive field center elongation, orientation, location and size. Additionally, the proposed method is particularly attractive for monitoring pRF properties in the visual areas of subjects with lesions of the visual pathways, where it is difficult to anticipate what shape the reorganized pRF might take. Finally, the method proposed here is more efficient in computation time than direct-fit methods, which need to search for a set of parameters in an extremely large searching space. Instead, this method uses the pRF topography to constrain the space that needs to be searched for the subsequent modeling., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The brain can be envisaged as a complex adaptive system. It is characterized by a very high structural complexity and by massive connectivity, both of which change and evolve in response to experience. Information related to sensors and effectors is processed in both a parallel and a hierarchical fashion; the connectivity between different hierarchical levels is bidirectional, and its effectiveness is continuously controlled by specific associational and neuromodulatory centers. When questions are addressed at the level of a distributed, large-scale whole system such as that underlying perception and cognition, it is not clear what should be considered as an elementary operational unit because the behavior of integral, aggregate systems is always emergent and most often remains unpredicted by the behaviors of single cells. To localize and comprehend the neural mechanisms underlying our perceptual or cognitive capacities, concurrent studies of microcircuits, of local and long-range interconnectivity between small assemblies, and of the synergistic activity of larger neuronal populations are called for. In other words, multimodal methodologies that include invasive neuroscientific methods as well as global neuroimaging techniques are required, such as the various functional aspects of magnetic resonance imaging. These facts were the driving force behind the decision to begin animal-MRI in my lab. The wonderful idea of the editors of NeuroImage to publish a Special Issue commemorating 20years of functional fMRI provides me with the opportunity of sharing not only our first moments of frustration with the readers, but also our successful results., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Motion processing regions apart from V5+/MT+ are still relatively poorly understood. Here, we used functional magnetic resonance imaging to perform a detailed functional analysis of the recently described cingulate sulcus visual area (CSv) in the dorsal posterior cingulate cortex. We used distinct types of visual motion stimuli to compare CSv with V5/MT and MST, including a visual pursuit paradigm. Both V5/MT and MST preferred 3D flow over 2D planar motion, responded less yet substantially to random motion, had a strong preference for contralateral versus ipsilateral stimulation, and responded nearly equally to contralateral and to full-field stimuli. In contrast, CSv had a pronounced preference to 2D planar motion over 3D flow, did not respond to random motion, had a weak and nonsignificant lateralization that was significantly smaller than that of MST, and strongly preferred full-field over contralateral stimuli. In addition, CSv had a better capability to integrate eye movements with retinal motion compared with V5/MT and MST. CSv thus differs from V5+/MT+ by its unique preference to full-field, coherent, and planar motion cues. These results place CSv in a good position to process visual cues related to self-induced motion, in particular those associated to eye or lateral head movements.

Little is known about mechanisms mediating a stable perception of the world during pursuit eye movements. Here, we used fMRI to determine to what extent human motion-responsive areas integrate planar retinal motion with nonretinal eye movement signals in order to discard self-induced planar retinal motion and to respond to objective ("real") motion. In contrast to other areas, V3A lacked responses to self-induced planar retinal motion but responded strongly to head-centered motion, even when retinally canceled by pursuit. This indicates a near-complete multimodal integration of visual with nonvisual planar motion signals in V3A. V3A could be mapped selectively and robustly in every single subject on this basis. V6 also reported head-centered planar motion, even when 3D flow was added to it, but was suppressed by retinal planar motion. These findings suggest a dominant contribution of human areas V3A and V6 to head-centered motion perception and to perceptual stability during eye movements., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We examined the applicability of manganese-enhanced MRI (MEMRI) to the in vivo tracing of diffuse neuromodulatory projections by means of simultaneous iontophoretic injections of an extremely low, non-toxic concentration of MnCl(2) (10mM) and fluorescent dextran in the locus coeruleus (LC) in the rat. We validated the use of the iontophoretic injection by reproducing previously reported results from pressure injections of MnCl(2) in primary somatosensory cortex. Twenty fourhours after injection in LC, Mn(2+) labeling was detected in major cortical and subcortical targets of LC projections including predominantly ipsilateral primary motor and somatosensory cortices, hippocampus and amygdala. Although the injections were in most cases centered in the core of LC, the pattern of Mn(2+) labeling greatly varied across rats. In addition, despite a certain degree of overlap of the labeling obtained with both MEMRI and classical tracing, MEMRI tracing consistently failed to reliably label not only several minor but also major targets of LC, notably the thalamus. The lack of Mn(2+) labeling in thalamus possibly reflected a weaker functional connectivity within coeruleothalamic projections that could not be predicted by anatomical tracing. Inversely, a number of brain regions, particularly contralateral motor cortex, that were not or only sparsely labeled with fluorescent dextran were strongly labeled by Mn(2+). This discrepancy could be partly due to both the activity-dependent and transsynaptic nature of Mn(2+) transport. The overall labeling produced using MEMRI with iontophoretic injections in LC indicates that the Mn(2+) imaging of highly diffuse projections is in principle feasible. However, the labeling pattern of each individual case needs to be carefully interpreted particularly before submitting data for group analysis or in the case of longitudinal examination of discrete changes in functional connectivity under various physiological or behavioral conditions., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Short-term memory requires communication between multiple brain regions that collectively mediate the encoding and maintenance of sensory information. It has been suggested that oscillatory synchronization underlies intercortical communication. Yet, whether and how distant cortical areas cooperate during visual memory remains elusive. We examined neural interactions between visual area V4 and the lateral prefrontal cortex using simultaneous local field potential (LFP) recordings and single-unit activity (SUA) in monkeys performing a visual short-term memory task. During the memory period, we observed enhanced between-area phase synchronization in theta frequencies (3-9 Hz) of LFPs together with elevated phase locking of SUA to theta oscillations across regions. In addition, we found that the strength of intercortical locking was predictive of the animals' behavioral performance. This suggests that theta-band synchronization coordinates action potential communication between V4 and prefrontal cortex that may contribute to the maintenance of visual short-term memories.

Imaging technologies, such as intrinsic optical imaging (IOI), functional magnetic resonance imaging (fMRI) or multiphoton microscopy provide excellent opportunities to study the relationship between functional signals recorded from a cortical area and the underlying anatomical structure. This, in turn, requires accurate alignment of the recorded functional imaging data with histological datasets from the imaged tissue obtained after the functional experiment. This alignment is complicated by distortions of the tissue which naturally occur during histological treatment, and is particularly difficult to achieve over large cortical areas, such as primate visual areas. We present here a method that uses IOI vessel maps revealed in the time course of the intrinsic signal, in combination with vascular casts and vascular lumen labeling techniques together with a pseudo three dimensional (p3D) reconstruction of the tissue architecture in order to facilitate alignment of IOI data with posthoc histological datasets. We demonstrate that by such a multimodal vessel mapping approach, we are able to constitute a hook in anatomical-functional data alignment that enables the accurate assignment of functional signals over large cortical regions. As an example, we present precise alignments of IOI responses showing orientation selectivity of primate V1 with anatomical sections stained for cytochrome-oxidase-reactivity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The fMRI-BOLD contrast is widely used to study the neural basis of sensory perception and cognition. This signal, however, reflects neural activity only indirectly, and the detailed mechanisms of neurovascular coupling and the neurophysiological correlates of the BOLD signal remain debated. Here we investigate the coupling of BOLD and electrophysiological signals in the motion area MT of the macaque monkey by simultaneously recording both signals. Our results demonstrate that a prominent neuronal response property of area MT, so-called motion opponency, can be used to induce dissociations of BOLD and neuronal firing. During the presentation of a stimulus optimally driving the local neurons, both field potentials [local field potentials (LFPs)] and spiking activity [multi-unit activity (MUA)] correlated with the BOLD signal. When introducing the motion opponency stimulus, however, correlations of MUA with BOLD were much reduced, and LFPs were a much better predictor of the BOLD signal than MUA. In addition, for a subset of recording sites we found positive BOLD and LFP responses in the presence of decreases in MUA, regardless of the stimulus used. Together, these results demonstrate that correlations between BOLD and MUA are dependent on the particular site and stimulus paradigm, and foster the notion that the fMRI-BOLD signal reflects local dendrosomatic processing and synaptic activity rather than principal neuron spiking responses., (Copyright © 2010 Elsevier Inc. All rights reserved.)

High signal-to-noise ratios (SNR) are essential for high-resolution anatomical and functional MRI. Phased arrays are advantageous for this but have the drawback that they often have inflexible and bulky configurations. Particularly in experiments where functional MRI is combined with simultaneous electrophysiology, space constraints can be prohibitive. To this end we developed a highly flexible multiple receive element phased array for use on anesthetized monkeys. The elements are interchangeable and different sizes and combinations of coil elements can be used, for instance, combinations of single and overlapped elements. The preamplifiers including control electronics are detachable and can serve a variety of prefabricated and phase matched arrays of different configurations, allowing the elements to always be placed in close proximity to the area of interest. Optimizing performance of the individual elements ensured high SNR at the cortical surface as well as in deeper laying structures. Performance of a variety of arrangements of gapped linear arrays was evaluated at 4.7 and 7T in high-resolution anatomical and functional MRI., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Electrical stimulation has been used in animals and humans to study potential causal links between neural activity and specific cognitive functions. Recently, it has found increasing use in electrotherapy and neural prostheses. However, the manner in which electrical stimulation-elicited signals propagate in brain tissues remains unclear. We used combined electrostimulation, neurophysiology, microinjection and functional magnetic resonance imaging (fMRI) to study the cortical activity patterns elicited during stimulation of cortical afferents in monkeys. We found that stimulation of a site in the lateral geniculate nucleus (LGN) increased the fMRI signal in the regions of primary visual cortex (V1) that received input from that site, but suppressed it in the retinotopically matched regions of extrastriate cortex. Consistent with previous observations, intracranial recordings indicated that a short excitatory response occurring immediately after a stimulation pulse was followed by a long-lasting inhibition. Following microinjections of GABA antagonists in V1, LGN stimulation induced positive fMRI signals in all of the cortical areas. Taken together, our findings suggest that electrical stimulation disrupts cortico-cortical signal propagation by silencing the output of any neocortical area whose afferents are electrically stimulated.

There is currently a great interest to combine electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to study brain function. Earlier studies have shown different EEG components to correlate well with the fMRI signal arguing for a complex relationship between both measurements. In this study, using separate EEG and fMRI measurements, we show that (1) 0.1 ms visual stimulation evokes detectable hemodynamic and visual-evoked potential (VEP) responses, (2) the negative VEP deflection at approximately 80 ms (N2) co-varies with stimulus duration/intensity such as with blood oxygenation level-dependent (BOLD) response; the positive deflection at approximately 120 ms (P2) does not, and (3) although the N2 VEP-BOLD relationship is approximately linear, deviation is evident at the limit of zero N2 VEP. The latter finding argues that, although EEG and fMRI measurements can co-vary, they reflect partially independent processes in the brain tissue. Finally, it is shown that the stimulus-induced impulse response function (IRF) at 0.1 ms and the intrinsic IRF during rest have different temporal dynamics, possibly due to predominance of neuromodulation during rest as compared with neurotransmission during stimulation. These results extend earlier findings regarding VEP-BOLD coupling and highlight the component- and context-dependency of the relationship between evoked potentials and hemodynamic responses.

The noninvasive imaging of the monkey auditory system with functional magnetic resonance imaging (fMRI) can bridge the gap between electrophysiological studies in monkeys and imaging studies in humans. Some of the recent imaging of monkey auditory cortical and subcortical structures relies on a technique of "sparse imaging," which was developed in human studies to sidestep the negative influence of scanner noise by adding periods of silence in between volume acquisition. Among the various aspects that have gone into the ongoing optimization of fMRI of the monkey auditory cortex, replacing the more common continuous-imaging paradigm with sparse imaging seemed to us to make the most obvious difference in the amount of activity that we could reliably obtain from awake or anesthetized animals. Here, we directly compare the sparse- and continuous-imaging paradigms in anesthetized animals. We document a strikingly greater auditory response with sparse imaging, both quantitatively and qualitatively, which includes a more expansive and robust tonotopic organization. There were instances where continuous imaging could better reveal organizational properties that sparse imaging missed, such as aspects of the hierarchical organization of auditory cortex. We consider the choice of imaging paradigm as a key component in optimizing the fMRI of the monkey auditory cortex.

Brains are restless. We have long known of the existence of a great deal of uninterrupted brain activity that maintains the body in a stable state--from an evolutionary standpoint one of the brain's most ancient tasks. But intrinsic, ongoing activity is not limited to subcortical, life-maintaining structures; cortex, too, is remarkably active even in the absence of a sensory stimulus or a specific behavioral task. This is evident both in its enormous energy consumption at rest and in the large, spontaneous but coherent fluctuations of neural activity that spread across different areas. Not surprisingly, a growing number of electrophysiological and functional magnetic resonance imaging (fMRI) studies are appearing that report on various aspects of the brain's spontaneous activity or "default mode" of operation. One recent study reports results from simultaneously combined electrophysiological and fMRI measurements in the monkey visual cortex (Shmuel, A., Leopold, D.A., 2008. Neuronal correlates of spontaneous fluctuations in fMRI signals in monkey visual cortex: implications for functional connectivity at rest. Hum. Brain Mapp. 29, 751-761). The authors claim to be able to demonstrate correlations between slow fluctuations in blood-oxygen-level-dependent (BOLD) signals and concurrent fluctuations in the underlying, locally measured neuronal activity. They even go on to speculate that the fluctuations display wave-like spatiotemporal patterns across cortex. In the present report, however, we re-analyze the data presented in that study and demonstrate that the measurements were not actually taken during rest. Visual cortex was subject to almost imperceptible but physiologically clearly detectable flicker induced by the visual stimulator. An examination of the power spectral density of the neural responses and the neurovascular impulse response function shows that such imperceptible flicker strongly suppresses the slow oscillations and changes the degree of covariance between neural and vascular signals. In addition, a careful analysis of the spatiotemporal patterns demonstrates that no slow waves of activity exist in visual cortex; instead, the presented wave data reflect differences in signal-to-noise ratio at various cortical sites due to local differences in vascularization. In this report, assuming that the term "spontaneous activity" refers to intrinsic physiological processes at the absence of sensory inputs or motor outputs, we discuss the need for careful selection of experimental protocols and of examining the degree to which the activation of sensory areas might influence the cortical or subcortical processes in other brain regions.

The blood-oxygenation-level-dependent (BOLD) signal is an indirect hemodynamic signal that is sensitive to cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen. Therefore, the BOLD signal amplitude and dynamics cannot be interpreted unambiguously without additional physiological measurements, and thus, there remains a need for a functional magnetic resonance imaging (fMRI) signal, which is more closely related to the underlying neuronal activity. In this study, we measured CBF with continuous arterial spin labeling, CBV with an exogenous contrast agent and BOLD combined with intracortical electrophysiological recording in the primary visual cortex of the anesthetized monkey. During inhalation of 6% CO2, it was observed that CBF and CBV are not further increased by a visual stimulus, although baseline CBF for 6% CO2 is below the maximal value of CBF. In contrast, the electrophysiological response to the stimulation was found to be preserved during hypercapnia. As a consequence, the simultaneously measured BOLD signal responds negatively to a visual stimulation for 6% CO2 inhalation in the same voxels responding positively during normocapnia. These observations suggest that the fMRI response to a sensory stimulus for 6% CO2 inhalation occurs in the absence of a hemodynamic response, and it therefore directly reflects oxygen extraction into the tissue.

The hippocampal formation is a brain system that is implicated in learning and memory. The major input to the hippocampus arrives from the entorhinal cortex (EC) to the dentate gyrus (DG) through the perforant path. In the present work, we have investigated the functional properties of this connection by concomitantly applying electrophysiological techniques, deep-brain electric microstimulation and functional magnetic resonance imaging in anesthetized rats. We systematically delivered different current intensities at diverse stimulation frequencies to the perforant path while recording electrophysiological and blood-oxygenation-level-dependent (BOLD) signals. We observed a linear relationship between the current intensity used to stimulate the hippocampal formation and the amplitude and extension of the induced BOLD response. In addition, we found a frequency-dependent spatial pattern of activation. With stimulation protocols and train frequencies used for kindling, the activity strongly spreads ipsilaterally through the hippocampus, DG, subiculum and EC.

fMRI is a tool to study brain function noninvasively that can reliably identify sites of neural involvement for a given task. However, to what extent can fMRI signals be related to measures obtained in electrophysiology? Can the blood-oxygen-level-dependent signal be interpreted as spatially pooled spiking activity? Here we combine knowledge from neurovascular coupling, functional imaging and neurophysiology to discuss whether fMRI has succeeded in demonstrating one of the most established functional properties in the visual brain, namely directional selectivity in the motion-processing region V5/MT+. We also discuss differences of fMRI and electrophysiology in their sensitivity to distinct physiological processes. We conclude that fMRI constitutes a complement, not a poor-resolution substitute, to invasive techniques, and that it deserves interpretations that acknowledge its stand as a separate signal.

The blood oxygenation level-dependent (BOLD) signal is the most commonly used modality of functional magnetic resonance imaging (fMRI) today. Although easy to implement, it is an ambiguous signal since it results from a combination of several hemodynamic factors. Functional cerebral blood flow changes, as measured by using arterial spin labeling (ASL), typically occur in the parenchyma and have been demonstrated to be more closely coupled to neural activation compared with BOLD. However, the intrinsically low signals from ASL techniques have hindered its widespread application to fMRI for basic research and even more so for clinical applications. Here, we report the first implementation of continuous ASL in the anaesthetized macaque at high magnetic field of 7 T. The technique was optimized to permit maximum signal-to-noise ratio of functional perfusion-based images at high spatial resolution. The effect of labeling parameters, such as label time and post-label delay (PLD), on functional cerebral blood flow (fCBF) in the visual cortex was evaluated. Functional cerebral blood flow maps did not change with increasing label time after 2,000 ms, indicating that a label time of 2,000 ms is sufficient for reliable mapping of fCBF. The percent changes obtained using fCBF were better localized to gray matter, than those obtained with BOLD. A short PLD of 200 ms revealed significantly higher fCBF changes at the cortical surface, indicating large-vessel contamination, than a long PLD of 800 ms. However, the effect of the PLD on fCBF was smaller than on baseline CBF. These results are of importance for high-resolution applications, and when accurate quantification is required for studies in monkeys as well as in humans.

To form a coherent percept of the environment, our brain combines information from different senses. Such multisensory integration occurs in higher association cortices; but supposedly, it also occurs in early sensory areas. Confirming the latter hypothesis, we unequivocally demonstrate supra-additive integration of touch and sound stimulation at the second stage of the auditory cortex. Using high-resolution fMRI of the macaque monkey, we quantified the integration of auditory broad-band noise and tactile stimulation of hand and foot in anaesthetized animals. Integration was found posterior to and along the lateral side of the primary auditory cortex in the caudal auditory belt. Integration was stronger for temporally coincident stimuli and obeyed the principle of inverse effectiveness: greater enhancement for less effective stimuli. These findings demonstrates that multisensory integration occurs early and close to primary sensory areas and--because it occurs in anaesthetized animals--suggests that this integration is mediated by preattentive bottom-up mechanisms.

We examined fluctuations in band-limited power (BLP) of local field potential (LFP) signals recorded from multiple electrodes in visual cortex of the monkey during different behavioral states. We asked whether such signals demonstrated coherent fluctuations over time-scales of seconds and minutes, and would thus serve as good candidates for direct comparison with data obtained from functional magnetic resonance imaging (fMRI). We obtained the following results. (i) The BLP of the local field displayed fluctuations at many time-scales, with particularly large amplitude at very low frequencies (<0.1 Hz). (ii) These fluctuations exhibited high coherence between electrode pairs, particularly for BLP signals derived from the gamma frequency range. (iii) Coherence in the BLP, unlike that in the raw LFP, did not fall off sharply as a function of cortical distance. (iv) The structure and coherence of BLP changes were highly similar under distinctly different behavioral states. These results demonstrate the existence of widespread coherent activity fluctuations in the brain of the awake monkey over very long time-scales. We propose that such signals may make a significant contribution to the high variability observed in the time course of physiological signals, including those measured with functional imaging techniques. The results are discussed in the context of combined fMRI/electrophysiological recordings.

We describe the first systematic functional magnetic resonance imaging (fMRI) measurements of visual field maps in macaque visual cortex. The boundaries of visual areas V1, V2, V3, V3A, V4, MT/V5, and TEO/V4A were identified using stimuli that create traveling waves of activity in retinotopically organized areas of the visual cortex. Furthermore, these stimuli were used to measure the dimensions of the representations of the central 11 degrees in V1-V3, quantitative visual field eccentricity functions for V1-V3 and MT, and the distribution of foveal and peripheral signals within the occipital lobe. Within areas V1, V2, MT, and portions of V4, the fMRI signals were 5-10 times the noise level (3 mm3 volumes of interest). Signals were weaker but still significant in other cortical regions, including V3, V3A, and TEO. There is good agreement between the fMRI maps and the visual area maps discovered using local anatomical and physiological measurements. The fMRI measurements allow one to obtain a broad view of the distribution of cortical signals, spanning multiple visual areas at a single point in time. The combination of scale and sensitivity demonstrated here create a good foundation for measuring how localized signals and lesions influence the responses and reorganization in widely separated cortical regions. The ability to measure human and macaque maps using the same technology will make it possible to define computational homologies between the two species.

Magnetic resonance imaging (MRI) has rapidly become an important tool in clinical medicine and biological research. Its functional variant (functional magnetic resonance imaging; fMRI) is currently the most widely used method for brain mapping and studying the neural basis of human cognition. While the method is widespread, there is insufficient knowledge of the physiological basis of the fMRI signal to interpret the data confidently with respect to neural activity. This paper reviews the basic principles of MRI and fMRI, and subsequently discusses in some detail the relationship between the blood-oxygen-level-dependent (BOLD) fMRI signal and the neural activity elicited during sensory stimulation. To examine this relationship, we conducted the first simultaneous intracortical recordings of neural signals and BOLD responses. Depending on the temporal characteristics of the stimulus, a moderate to strong correlation was found between the neural activity measured with microelectrodes and the BOLD signal averaged over a small area around the microelectrode tips. However, the BOLD signal had significantly higher variability than the neural activity, indicating that human fMRI combined with traditional statistical methods underestimates the reliability of the neuronal activity. To understand the relative contribution of several types of neuronal signals to the haemodynamic response, we compared local field potentials (LFPs), single- and multi-unit activity (MUA) with high spatio-temporal fMRI responses recorded simultaneously in monkey visual cortex. At recording sites characterized by transient responses, only the LFP signal was significantly correlated with the haemodynamic response. Furthermore, the LFPs had the largest magnitude signal and linear systems analysis showed that the LFPs were better than the MUAs at predicting the fMRI responses. These findings, together with an analysis of the neural signals, indicate that the BOLD signal primarily measures the input and processing of neuronal information within a region and not the output signal transmitted to other brain regions.

Recently, an MRI-detectable, neuronal tract-tracing method in living animals was introduced that exploits the anterograde transport of manganese (Mn2+). We present the results of experiments simultaneously tracing manganese chloride and wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) to evaluate the specificity of the former by tracing the neuronal connections of the basal ganglia of the monkey. Mn2+ and WGA-HRP yielded remarkably similar and highly specific projection patterns. By showing the sequential transport of Mn2+ from striatum to pallidum-substantia nigra and then to thalamus, we demonstrated MRI visualization of transport across at least one synapse in the CNS of the primate. Transsynaptic tract tracing in living primates will allow chronic studies of development and plasticity and provide valuable anatomical information for fMRI and electrophysiological experiments in primates.

Using fMRI in anesthetized monkeys, this study investigates how the primate visual system constructs representations of three-dimensional (3D) shape from a variety of cues. Computer-generated 3D objects defined by shading, random dots, texture elements, or silhouettes were presented either statically or dynamically (rotating). Results suggest that 3D shape representations are highly localized, although widely distributed, in occipital, temporal, parietal, and frontal cortices and may involve common brain regions regardless of shape cue. This distributed network of areas cuts across both "what" and "where" processing streams, reflecting multiple uses for 3D shape representation in perception, recognition, and action.

Functional brain development is not well understood. In the visual system, neurophysiological studies in nonhuman primates show quite mature neuronal properties near birth although visual function is itself quite immature and continues to develop over many months or years after birth. Our goal was to assess the relative development of two main visual processing streams, dorsal and ventral, using BOLD fMRI in an attempt to understand the global mechanisms that support the maturation of visual behavior. Seven infant macaque monkeys (Macaca mulatta) were repeatedly scanned, while anesthetized, over an age range of 102 to 1431 days. Large rotating checkerboard stimuli induced BOLD activation in visual cortices at early ages. Additionally we used static and dynamic Glass pattern stimuli to probe BOLD responses in primary visual cortex and two extrastriate areas: V4 and MT-V5. The resulting activations were analyzed with standard GLM and multivoxel pattern analysis (MVPA) approaches. We analyzed three contrasts: Glass pattern present/absent, static/dynamic Glass pattern presentation, and structured/random Glass pattern form. For both GLM and MVPA approaches, robust coherent BOLD activation appeared relatively late in comparison to the maturation of known neuronal properties and the development of behavioral sensitivity to Glass patterns. Robust differential activity to Glass pattern present/absent and dynamic/static stimulus presentation appeared first in V1, followed by V4 and MT-V5 at older ages; there was no reliable distinction between the two extrastriate areas. A similar pattern of results was obtained with the two analysis methods, although MVPA analysis showed reliable differential responses emerging at later ages than GLM. Although BOLD responses to large visual stimuli are detectable, our results with more refined stimuli indicate that global BOLD activity changes as behavioral performance matures. This reflects an hierarchical development of the visual pathways. Since fMRI BOLD reflects neural activity on a population level, our results indicate that, although individual neurons might be adult-like, a longer maturation process takes place on a population level. [ABSTRACT FROM AUTHOR]

Intravascular contrast agents are used in functional magnetic resonance imaging to obtain cerebral blood volume (CBV) maps of cortical activity. Cerebral blood volume imaging with MION (monocrystalline-iron-oxide-nanoparticles) increases the sensitivity of functional imaging compared with the blood oxygenation level-dependent (BOLD) signal (Leite et al, 2002; Mandeville et al, 1998; Vanduffel et al, 2001). It therefore represents an attractive method for obtaining detailed maps of cortical organization (Vanduffel et al, 2001; Zhao et al, 2005). However, it remains to be determined how the spatial profile of CBV maps of cortical activity derived with MION compares with the profile of BOLD activation maps under a variety of different stimulation conditions. We used several stimulation paradigms to compare the spatial specificity of CBV versus BOLD activation maps in macaque area V1 at 4.7 T. We observed that: (1) CBV modulation is relatively stronger in deep cortical layers compared with BOLD, in agreement with studies in cats (Harel et al, 2006) and rodents (Lu et al, 2004; Mandeville and Marota, 1999) and (2) surprisingly, under large surround stimulation conditions, CBV maps extend along the cortical surface to cover large (>10 mm) regions of the cortex that are devoid of significant BOLD modulation. We conclude that the spatial profiles of BOLD and CBV activity maps do not coregister across all stimulus conditions, and therefore do not necessarily represent equivalent transforms of the neural response. Cerebral blood volume maps should be interpreted with care, in the context of the particular experimental paradigm applied.Journal of Cerebral Blood Flow & Metabolism (2007) 27, 1248–1261; doi:10.1038/sj.jcbfm.9600434; published online 10 January 2007 [ABSTRACT FROM AUTHOR]

Since its early development in the late 1940s, nuclear magnetic resonance has become a powerful tool for applications ranging from chemical analysis or the study of the structure of solids to biomedical investigations. In the early 1990s the potential of this technique for functional brain mapping was demonstrated, causing unprecedented excitement in both basic and clinical neuroscience. It was shown that by using the appropriate pulse sequences the so-called functional magnetic resonance imaging (fMRI) technique can be made sensitive to local magnetic susceptibility alterations produced by changes in the concentration of deoxyhemoglobin in venous blood vessels. This blood-oxygenation-level-dependent (BOLD) contrast mechanism was successfully implemented in awake human subjects, in small animals, and recently in the non-human primate — the experimental animal of choice for the study of cognitive behavior. Simultaneous imaging and electrode recordings promise new insights into the mechanisms by which large-scale networks in the brain contribute to the local neural activity recorded at a given cortical site. Moreover, the use of MRI-visible tracers and of electrical microstimulation applied during imaging proves to be ideal for the study of connectivity in the living animal. [Copyright &y& Elsevier]

Neurons in the inferior temporal (IT) cortex respond selectively to complex objects, and maintain their selectivity despite partial occlusion. However, relatively little is known about how the occlusion of different shape parts influences responses in the IT cortex. Here, we determine experimentally which parts of complex objects monkeys are relying on in a discrimination task. We then study the effect of occlusion of parts with different behavioral relevance on neural responses in the IT cortex at the level of spiking activity and local field potentials (LFPs). For both spiking activity and LFPs, we found that the diagnostic object parts, which were important for behavioral judgments, were preferentially represented in the IT cortex. Our data show that the effects of diagnosticity grew systematically stronger along a posterior-anterior axis for LFPs, but were evenly distributed for single units, suggesting that diagnosticity is first encoded in the posterior IT cortex. Our findings highlight the power of combined analysis of field potentials and spiking activity for mapping structure to computational function in the brain. [ABSTRACT FROM AUTHOR]