John Arsenault

Bottom-Up Dependent Gating of Frontal Signals in Early Visual Cortex

The frontal eye field (FEF) is one of several cortical regions thought to modulate sensory inputs. Moreover, several hypotheses suggest that the FEF can only modulate early visual areas in the presence of a visual stimulus. To test for bottom-up gating of frontal signals, we microstimulated subregions in the FEF of two monkeys and measured the effects throughout the brain with functional magnetic resonance imaging. The activity of higher-order visual areas was strongly modulated by FEF stimulation, independent of visual stimulation. In contrast, FEF stimulation induced a topographically specific pattern of enhancement and suppression in early visual areas, but only in the presence of a visual stimulus. Modulation strength depended on stimulus contrast and on the presence of distractors. We conclude that bottom-up activation is needed to enable top-down modulation of early visual cortex and that stimulus saliency determines the strength of this modulation.

Visual Field Map Clusters in Macaque Extrastriate Visual Cortex

The macaque visual cortex contains >30 different functional visual areas, yet surprisingly little is known about the underlying organizational principles that structure its components into a complete “visual” unit. A recent model of visual cortical organization in humans suggests that visual field maps are organized as clusters. Clusters minimize axonal connections between individual field maps that represent common visual percepts, with different clusters thought to carry out different functions. Experimental support for this hypothesis, however, is lacking in macaques, leaving open the question of whether it is unique to humans or a more general model for primate vision. Here we show, using high-resolution blood oxygen level-dependent functional magnetic resonance imaging data in the awake monkey at 7 T, that the middle temporal area (area MT/V5) and its neighbors are organized as a cluster with a common foveal representation and a circular eccentricity map. This novel view on the functional topography of area MT/V5 and satellites indicates that field map clusters are evolutionarily preserved and may be a fundamental organizational principle of the Old World primate visual cortex.

Modulation of the contrast response function by electrical microstimulation of the macaque frontal eye field

Spatial attention influences representations in visual cortical areas as well as perception. Some models predict a contrast gain, whereas others a response or activity gain when attention is directed to a contrast-varying stimulus. Recent evidence has indicated that microstimulating the frontal eye field (FEF) can produce modulations of cortical area V4 neuronal firing rates that resemble spatial attention-like effects, and we have shown similar modulations of functional magnetic resonance imaging (fMRI) activity throughout the visual system. Here, we used fMRI in awake, fixating monkeys to first measure the response in 12 visual cortical areas to stimuli of varying luminance contrast. Next, we simultaneously microstimulated subregions of the FEF with movement fields that overlapped the stimulus locations and measured how microstimulation modulated these contrast response functions (CRFs) throughout visual cortex. In general, we found evidence for a nonproportional scaling of the CRF under these conditions, resembling a contrast gain effect. Representations of low-contrast stimuli were enhanced by stimulation of the FEF below the threshold needed to evoke saccades, whereas high-contrast stimuli were unaffected or in some areas even suppressed. Furthermore, we measured a characteristic spatial pattern of enhancement and suppression across the cortical surface, from which we propose a simple schematic of this contrast-dependent fMRI response.

Role of the Primate Ventral Tegmental Area in Reinforcement and Motivation

Monkey electrophysiology suggests that the activity of the ventral tegmental area (VTA) helps regulate reinforcement learning and motivated behavior, in part by broadcasting prediction error signals throughout the reward system. However, electrophysiological studies do not allow causal inferences regarding the activity of VTA neurons with respect to these processes because they require artificial manipulation of neuronal firing. Rodent studies fulfilled this requirement by demonstrating that electrical and optogenetic VTA stimulation can induce learning and modulate downstream structures. Still, the primate dopamine system has diverged significantly from that of rodents, exhibiting greatly expanded and uniquely distributed cortical and subcortical innervation patterns. Here, we bridge the gap between rodent perturbation studies and monkey electrophysiology using chronic electrical microstimulation of macaque VTA (VTA-EM). VTA-EM was found to reinforce cue selection in an operant task and to motivate future cue selection using a Pavlovian paradigm. Moreover, by combining VTA-EM with concurrent fMRI, we demonstrated that VTA-EM increased fMRI activity throughout most of the dopaminergic reward system. These results establish a causative role for primate VTA in regulating stimulus-specific reinforcement and motivation as well as in modulating activity throughout the reward system.

An implanted 8-channel array coil for high-resolution macaque MRI at 3T

An 8-channel receive coil array was constructed and implanted adjacent to the skull in a male rhesus monkey in order to improve the sensitivity of (functional) brain imaging. The permanent implant was part of an acrylic headpost assembly and only the coil element loop wires were implanted. The tuning, matching, and preamplifier circuitry was connected via a removable external assembly. Signal-to-noise ratio (SNR) and noise amplification for parallel imaging were compared to single-, 4-, and 8-channel external receive-only coils routinely used for macaque fMRI. In vivo measurements showed significantly improved SNR within the brain for the implanted versus the external coils. Within a region-of-interest covering the cerebral cortex, we observed a 5.4-, 3.6-fold, and 3.4-fold increase in SNR compared to the external single-, 4-, and 8-channel coils, respectively. In the center of the brain, the implanted array maintained a 2.4×, 2.5×, and 2.1× higher SNR, respectively compared to the external coils. The array performance was evaluated for anatomical, diffusion tensor and functional brain imaging. This study suggests that a stable implanted phased-array coil can be used in macaque MRI to substantially increase the spatial resolution for anatomical, diffusion tensor, and functional imaging.

Focal reversible deactivation of cerebral metabolism affects water diffusion

The underlying biophysical mechanisms which affect cerebral diffusion contrast remain poorly understood. We hypothesized that cerebral metabolism may affect cerebral diffusion contrast. The purpose of this study was to develop the methodology to reversibly deactivate cerebral metabolism and measure the effect on the diffusion MRI signal. We developed an MRI‐compatible cortical cooling system to reversibly deactivate cortical metabolism in rhesus monkey area V1 and used MR thermometry to calculate three‐dimensional temperature maps of the brain to define the extent of deactivated brain in vivo. Significant changes in the apparent diffusion coefficient (ADC) were only observed during those experiments in which the cortex was cooled below the metabolic cutoff temperature of 20°C. ADC decreases (12–20%) were observed during cortical cooling in regions where the temperature did not change. The normalized in vivo ADC as function of temperature was measured and found to be equivalent to the normalized ADC of free water at temperatures above 20°C, but was significantly decreased below 20°C (20–25% decrease). No changes in fractional anisotropy were observed. In future experiments, we will apply this methodology to quantify the effect of reversible deactivation on neural activity as measured by the hemodynamic response and compare water diffusion changes with hemodynamic changes. Magn Reson Med 60:1178–1189, 2008.

Neural Correlates of the Formation and Retention of Cocaine-Induced Stimulus–Reward Associations

BACKGROUND Cocaine can elicit drug-seeking behavior for drug-predicting stimuli, even after a single stimulus-cocaine pairing. Although orbitofrontal cortex is thought to be important during encoding and maintenance of stimulus-reward value, we still lack a comprehensive model of the neural circuitry underlying this cognitive process. METHODS We studied the conditioned effects of cocaine with monkey functional magnetic resonance imaging and classical conditioning by pairing a visual shape (conditioning stimulus [CS+]) with a noncontingent cocaine infusion; a control stimulus was never paired. We correlated the behavioral preference of the monkey for the CS+, as measured offline, with the activity induced by the CS+ relative to the control stimulus as function of time. RESULTS We observed that during formation of stimulus-cocaine associations strong CS+-induced functional magnetic resonance imaging activations emerged in frontal cortex that correlated significantly with behavioral CS+ preference. Afterward, CS+ preference correlated only with activity in early visual cortex. Control experiments suggest that these findings cannot be explained by increased familiarity for the CS+. CONCLUSIONS Our findings suggest a complex interaction between frontal and occipital cortex during cocaine conditioning. Frontal cortex is important for establishing novel representations of stimulus valence when cocaine is used as reinforcer, whereas early visual cortex is involved in retaining these cocaine-stimulus associations.

Attention Shifts Recruit the Monkey Default Mode Network

A unifying function associated with the default mode network (DMN), which is more active during rest than under active task conditions, has been difficult to define. The DMN is activated during monitoring the external world for unexpected events, as a sentinel, and when humans are engaged in high-level internally focused tasks. The existence of DMN correlates in other species, such as mice, challenge the idea that internally focused, high-level cognitive operations, such as introspection, autobiographical memory retrieval, planning the future, and predicting someone elses thoughts, are evolutionarily preserved defining properties of the DMN. A recent human study demonstrated that demanding cognitive shifts could recruit the DMN, yet it is unknown whether this holds for nonhuman species. Therefore, we tested whether large changes in cognitive context would recruit DMN regions in female and male nonhuman primates. Such changes were measured as displacements of spatial attentional weights based on internal rules of relevance (spatial shifts) compared with maintaining attentional weights at the same location (stay events). Using fMRI in macaques, we detected that a cortical network, activated during shifts, largely overlapped with the DMN. Moreover, fMRI time courses sampled from independently defined DMN foci showed significant shift selectivity during the demanding attention task. Finally, functional clustering based on independent resting state data revealed that DMN and shift regions clustered conjointly, whereas regions activated during the stay events clustered apart. We therefore propose that cognitive shifting in primates generally recruits DMN regions. This might explain a breakdown of the DMN in many neurological diseases characterized by declined cognitive flexibility. SIGNIFICANCE STATEMENT Activation of the human default mode network (DMN) can be measured with fMRI when subjects shift thoughts between high-level internally directed cognitive states, when thinking about the self, the perspective of others, when imagining future and past events, and during mind wandering. Furthermore, the DMN is activated as a sentinel, monitoring the environment for unexpected events. Arguably, these cognitive processes have in common fast and substantial changes in cognitive context. As DMN activity has also been reported in nonhuman species, we tested whether shifts in spatial attention activated the monkey DMN. Core monkey DMN and shift-selective regions shared several functional properties, indicating that cognitive shifting, in general, might constitute one of the evolutionarily preserved functions of the DMN.

In Vivo Identification of Thick, Thin, and Pale Stripes of Macaque Area V2 Using Submillimeter Resolution (f)MRI at 3 T

Primate area V2 contains a repetitive pattern of thick, thin and pale cytochrome oxidase stripes that are characterized by largely discrete in- and output channels, as well as differences in function, and myelo- and cytoarchitecture. Stripes have been identified mainly using microscope-based imaging of tiny portions of superficially located V2, or by postmortem methods, hence, the quest for (quasi) noninvasive tools to study these mesoscale functional units. Only recently, stripe-like V2 patterns have been demonstrated in humans with high-field (functional) magnetic resonance imaging (f)MRI, but in both such studies only 2 stripe compartments could be identified. Although interstripe distances in monkeys are ~half of those in humans, we show that all 3 V2 stripe classes can be reliably separated using submillimeter (f)MRI (0.6 mm isotropic voxels) on regular 3 T scanners by combining contrast agents and implanted phased-array coils. Specifically, we show highly reproducible fMRI patterns, both within and across subjects, of color-selective thin and disparity-selective thick stripes. Furthermore, reliable MRI-based higher myelin-density was observed in pale stripes. Hence, this is the first study showing segregation of columns using (f)MRI-based methods in macaque cortex, which opens the possibility of studying these elementary building blocks of the visual system noninvasively on a large scale.

Noisy Neurons, Neat Networks

In this issue of Neuron, Kiani et al. (2015) show that the correlated activity of multiple simultaneously recorded neurons can be used to identify, in a completely un-biased manner, distinct functional domains within prefrontal and (pre)motor cortex of macaque monkeys.