Ripples in macaque V1 and V4 are modulated by top-down visual attention.

Sharp-wave ripples (SWRs) are highly synchronous neuronal activity events. They have been predominantly observed in the hippocampus during offline states such as pause in exploration, slow-wave sleep, and quiescent wakefulness. SWRs have been linked to memory consolidation, spatial navigation, and spatial decision-making. Recently, SWRs have been reported during visual search, a form of remote spatial exploration, in macaque hippocampus. However, the association between SWRs and multiple forms of awake conscious and goal-directed behavior is unknown. We report that ripple activity occurs in macaque visual areas V1 and V4 during focused spatial attention. The occurrence of ripples is modulated by stimulus characteristics, increased by attention toward the receptive field, and by the size of the attentional focus. During attention cued to the receptive field, the monkey's reaction time in detecting behaviorally relevant events was reduced by ripples. These results show that ripple activity is not limited to hippocampal activity during offline states, rather they occur in the neocortex during active attentive states and vigilance behaviors.

Directed information exchange between cortical layers in macaque V1 and V4 and its modulation by selective attention.

Achieving behavioral goals requires integration of sensory and cognitive information across cortical laminae and cortical regions. How this computation is performed remains unknown. Using local field potential recordings and spectrally resolved conditional Granger causality (cGC) analysis, we mapped visual information flow, and its attentional modulation, between cortical layers within and between macaque brain areas V1 and V4. Stimulus-induced interlaminar information flow within V1 dominated upwardly, channeling information toward supragranular corticocortical output layers. Within V4, information flow dominated from granular to supragranular layers, but interactions between supragranular and infragranular layers dominated downwardly. Low-frequency across-area communication was stronger from V4 to V1, with little layer specificity. Gamma-band communication was stronger in the feedforward V1-to-V4 direction. Attention to the receptive field of V1 decreased communication between all V1 layers, except for granular-to-supragranular layer interactions. Communication within V4, and from V1 to V4, increased with attention across all frequencies. While communication from V4 to V1 was stronger in lower-frequency bands (4 to 25 Hz), attention modulated cGCs from V4 to V1 across all investigated frequencies. Our data show that top-down cognitive processes result in reduced communication within cortical areas, increased feedforward communication across all frequency bands, and increased gamma-band feedback communication.

The Representation of Time Windows in Primate Auditory Cortex.

Whether human and nonhuman primates process the temporal dimension of sound similarly remains an open question. We examined the brain basis for the processing of acoustic time windows in rhesus macaques using stimuli simulating the spectrotemporal complexity of vocalizations. We conducted functional magnetic resonance imaging in awake macaques to identify the functional anatomy of response patterns to different time windows. We then contrasted it against the responses to identical stimuli used previously in humans. Despite a similar overall pattern, ranging from the processing of shorter time windows in core areas to longer time windows in lateral belt and parabelt areas, monkeys exhibited lower sensitivity to longer time windows than humans. This difference in neuronal sensitivity might be explained by a specialization of the human brain for processing longer time windows in speech.

Contribution of Ionotropic Glutamatergic Receptors to Excitability and Attentional Signals in Macaque Frontal Eye Field.

Top-down attention, controlled by frontal cortical areas, is a key component of cognitive operations. How different neurotransmitters and neuromodulators flexibly change the cellular and network interactions with attention demands remains poorly understood. While acetylcholine and dopamine are critically involved, glutamatergic receptors have been proposed to play important roles. To understand their contribution to attentional signals, we investigated how ionotropic glutamatergic receptors in the frontal eye field (FEF) of male macaques contribute to neuronal excitability and attentional control signals in different cell types. Broad-spiking and narrow-spiking cells both required N-methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation for normal excitability, thereby affecting ongoing or stimulus-driven activity. However, attentional control signals were not dependent on either glutamatergic receptor type in broad- or narrow-spiking cells. A further subdivision of cell types into different functional types using cluster-analysis based on spike waveforms and spiking characteristics did not change the conclusions. This can be explained by a model where local blockade of specific ionotropic receptors is compensated by cell embedding in large-scale networks. It sets the glutamatergic system apart from the cholinergic system in FEF and demonstrates that a reduction in excitability is not sufficient to induce a reduction in attentional control signals.

Cell class-specific modulation of attentional signals by acetylcholine in macaque frontal eye field.

Attention is critical to high-level cognition, and attentional deficits are a hallmark of cognitive dysfunction. A key transmitter for attentional control is acetylcholine, but its cellular actions in attention-controlling areas remain poorly understood. Here we delineate how muscarinic and nicotinic receptors affect basic neuronal excitability and attentional control signals in different cell types in macaque frontal eye field. We found that broad spiking and narrow spiking cells both require muscarinic and nicotinic receptors for normal excitability, thereby affecting ongoing or stimulus-driven activity. Attentional control signals depended on muscarinic, not nicotinic receptors in broad spiking cells, while they depended on both muscarinic and nicotinic receptors in narrow spiking cells. Cluster analysis revealed that muscarinic and nicotinic effects on attentional control signals were highly selective even for different subclasses of narrow spiking cells and of broad spiking cells. These results demonstrate that cholinergic receptors are critical to establish attentional control signals in the frontal eye field in a cell type-specific manner.

MRI monitoring of macaque monkeys in neuroscience: Case studies, resource and normative data comparisons.

Information from Magnetic Resonance Imaging (MRI) is useful for diagnosis and treatment management of human neurological patients. MRI monitoring might also prove useful for non-human animals involved in neuroscience research provided that MRI is available and feasible and that there are no MRI contra-indications precluding scanning. However, MRI monitoring is not established in macaques and a resource is urgently needed that could grow with scientific community contributions. Here we show the utility and potential benefits of MRI-based monitoring in a few diverse cases with macaque monkeys. We also establish a PRIMatE MRI Monitoring (PRIME-MRM) resource within the PRIMatE Data Exchange (PRIME-DE) and quantitatively compare the cases to normative information drawn from MRI data from typical macaques in PRIME-DE. In the cases, the monkeys presented with no or mild/moderate clinical signs, were well otherwise and MRI scanning did not present a significant increase in welfare impact. Therefore, they were identified as suitable candidates for clinical investigation, MRI-based monitoring and treatment. For each case, we show MRI quantification of internal controls in relation to treatment steps and comparisons with normative data in typical monkeys drawn from PRIME-DE. We found that MRI assists in precise and early diagnosis of cerebral events and can be useful for visualising, treating and quantifying treatment response. The scientific community could now grow the PRIME-MRM resource with other cases and larger samples to further assess and increase the evidence base on the benefits of MRI monitoring of primates, complementing the animals' clinical monitoring and treatment regime.

Muscarinic signaling in the brain.

Muscarinic signaling affects attention, action selection, learning, and memory through multiple signaling cascades, which act at different timescales and which alter ion channels in cell type-specific manners. The effects of muscarinic signaling differ between cortical layers and between brain areas. Muscarinic signaling adds flexibility to the processing mode of neuronal networks, thereby supporting processing according to task demands. This review outlines possible scenarios to describe how it contributes to cellular mechanisms of attention and how it affects channeling of information in different neuronal circuits.

Auditory motion-specific mechanisms in the primate brain.

This work examined the mechanisms underlying auditory motion processing in the auditory cortex of awake monkeys using functional magnetic resonance imaging (fMRI). We tested to what extent auditory motion analysis can be explained by the linear combination of static spatial mechanisms, spectrotemporal processes, and their interaction. We found that the posterior auditory cortex, including A1 and the surrounding caudal belt and parabelt, is involved in auditory motion analysis. Static spatial and spectrotemporal processes were able to fully explain motion-induced activation in most parts of the auditory cortex, including A1, but not in circumscribed regions of the posterior belt and parabelt cortex. We show that in these regions motion-specific processes contribute to the activation, providing the first demonstration that auditory motion is not simply deduced from changes in static spatial location. These results demonstrate that parallel mechanisms for motion and static spatial analysis coexist within the auditory dorsal stream.

Attention Induced Gain Stabilization in Broad and Narrow-Spiking Cells in the Frontal Eye-Field of Macaque Monkeys.

UNLABELLED: Top-down attention increases coding abilities by altering firing rates and rate variability. In the frontal eye field (FEF), a key area enabling top-down attention, attention induced firing rate changes are profound, but its effect on different cell types is unknown. Moreover, FEF is the only cortical area investigated in which attention does not affect rate variability, as assessed by the Fano factor, suggesting that task engagement affects cortical state nonuniformly. We show that putative interneurons in FEF of Macaca mulatta show stronger attentional rate modulation than putative pyramidal cells. Partitioning rate variability reveals that both cell types reduce rate variability with attention, but more strongly so in narrow-spiking cells. The effects are captured by a model in which attention stabilizes neuronal excitability, thereby reducing the expansive nonlinearity that links firing rate and variance. These results show that the effect of attention on different cell classes and different coding properties are consistent across the cortical hierarchy, acting through increased and stabilized neuronal excitability. SIGNIFICANCE STATEMENT: Cortical processing is critically modulated by attention. A key feature of this influence is a modulation of "cortical state," resulting in increased neuronal excitability and resilience of the network against perturbations, lower rate variability, and an increased signal-to-noise ratio. In the frontal eye field (FEF), an area assumed to control spatial attention in human and nonhuman primates, firing rate changes with attention occur, but rate variability, quantified by the Fano factor, appears to be unaffected by attention. Using recently developed analysis tools and models to quantify attention effects on narrow- and broad-spiking cell activity, we show that attention alters cortical state strongly in the FEF, demonstrating that its effect on the neuronal network is consistent across the cortical hierarchy.

Cortical state and attention.

The brain continuously adapts its processing machinery to behavioural demands. To achieve this, it rapidly modulates the operating mode of cortical circuits, controlling the way that information is transformed and routed. This article will focus on two experimental approaches by which the control of cortical information processing has been investigated: the study of state-dependent cortical processing in rodents and attention in the primate visual system. Both processes involve a modulation of low-frequency activity fluctuations and spiking correlation, and are mediated by common receptor systems. We suggest that selective attention involves processes that are similar to state change, and that operate at a local columnar level to enhance the representation of otherwise non-salient features while suppressing internally generated activity patterns.

Gaze-dependent topography in human posterior parietal cortex.

The brain must convert retinal coordinates into those required for directing an effector. One prominent theory holds that, through a combination of visual and motor/proprioceptive information, head-/body-centered representations are computed within the posterior parietal cortex (PPC). An alternative theory, supported by recent visual and saccade functional magnetic resonance imaging (fMRI) topographic mapping studies, suggests that PPC neurons provide a retinal/eye-centered coordinate system, in which the coding of a visual stimulus location and/or intended saccade endpoints should remain unaffected by changes in gaze position. To distinguish between a retinal/eye-centered and a head-/body-centered coordinate system, we measured how gaze direction affected the representation of visual space in the parietal cortex using fMRI. Subjects performed memory-guided saccades from a central starting point to locations "around the clock." Starting points varied between left, central, and right gaze relative to the head-/body midline. We found that memory-guided saccadotopic maps throughout the PPC showed spatial reorganization with very subtle changes in starting gaze position, despite constant retinal input and eye movement metrics. Such a systematic shift is inconsistent with models arguing for a retinal/eye-centered coordinate system in the PPC, but it is consistent with head-/body-centered coordinate representations.

Stimulus-dependent variability and noise correlations in cortical MT neurons.

Population codes assume that neural systems represent sensory inputs through the firing rates of populations of differently tuned neurons. However, trial-by-trial variability and noise correlations are known to affect the information capacity of neural codes. Although recent studies have shown that stimulus presentation reduces both variability and rate correlations with respect to their spontaneous level, possibly improving the encoding accuracy, whether these second order statistics are tuned is unknown. If so, second-order statistics could themselves carry information, rather than being invariably detrimental. Here we show that rate variability and noise correlation vary systematically with stimulus direction in directionally selective middle temporal (MT) neurons, leading to characteristic tuning curves. We show that such tuning emerges in a stochastic recurrent network, for a set of connectivity parameters that overlaps with a single-state scenario and multistability. Information theoretic analysis shows that second-order statistics carry information that can improve the accuracy of the population code.

Distinct feedforward and feedback pathways for cell-type specific attention effects.

Selective attention is thought to depend on enhanced firing activity in extrastriate areas. Theories suggest that this enhancement depends on selective inter-areal communication via gamma (30-80 Hz) phase-locking. To test this, we simultaneously recorded from different cell types and cortical layers of macaque V1 and V4. We find that while V1-V4 gamma phase-locking between local field potentials increases with attention, the V1 gamma rhythm does not engage V4 excitatory-neurons, but only fast-spiking interneurons in L4 of V4. By contrast, attention enhances V4 spike-rates in both excitatory and inhibitory cells, most strongly in L2/3. The rate increase in L2/3 of V4 precedes V1 in time. These findings suggest enhanced signal transmission with attention does not depend on inter-areal gamma phase-locking and show that the endogenous gamma rhythm has cell-type- and layer-specific effects on downstream target areas. Similar findings were made in the mouse visual system, based on opto-tagging of identified interneurons.

Contribution of cholinergic and GABAergic mechanisms to direction tuning, discriminability, response reliability, and neuronal rate correlations in macaque middle temporal area.

Previous studies have investigated the effects of acetylcholine (ACh) on neuronal tuning, coding, and attention in primary visual cortex, but its contribution to coding in extrastriate cortex is unexplored. Here we investigate the effects of ACh on tuning properties of macaque middle temporal area MT neurons and contrast them with effects of gabazine, a GABA(A) receptor blocker. ACh increased neuronal activity, it had no effect on tuning width, but it significantly increased the direction discriminability of a neuron. Gabazine equally increased neuronal activity, but it widened tuning curves and decreased the direction discriminability of a neuron. Although gabazine significantly reduced response reliability, ACh application had little effect on response reliability. Finally, gabazine increased noise correlation of simultaneously recorded neurons, whereas ACh reduced it. Thus, both drugs increased firing rates, but only ACh application improved neuronal tuning and coding in line with effects seen in studies in which attention was selectively manipulated.

Perceptual learning of contrast discrimination in macaca mulatta.

Rhesus monkeys underwent training in a contrast discrimination task, in which grating stimuli were presented at parafoveal and peripheral visual field locations. Subjects had to compare a sample stimulus that had a fixed contrast of 30% to a test stimulus that varied in contrast from trial to trial. Extensive practice yielded improvements in contrast discrimination that were observed across the full range of test stimulus contrasts. These improvements occurred across multiple sessions, as well as across trials within individual sessions. The finer the contrast discriminations required, the longer it took for subjects to improve. Improvements in psychophysical performance resulted in the steepening of psychometric functions and/or shifts in the point of subjective equality towards the contrast of the sample stimulus. Enhancement in discrimination was especially pronounced around the contrast level of the sample stimulus, to which the subject was consistently exposed. The changes resulted in increased accuracy overall, lower discrimination thresholds, and faster response times. Partial transfer of learning, from vertically oriented training stimuli to horizontally oriented testing stimuli, was observed, while transfer to stimuli with different spatial frequencies was less pronounced. The results demonstrate the existence of perceptual learning in the contrast domain, whereby learning affects multiple performance-related psychophysical metrics.

Tissue-type plasminogen activator induces conditioned receptive field plasticity in the mouse auditory cortex.

Tissue-type plasminogen activator (tPA) is a serine protease that is expressed in various compartments in the brain. It is involved in neuronal plasticity, learning and memory, and addiction. We evaluated whether tPA, exogenously applied, could influence neuroplasticity within the mouse auditory cortex. We used a frequency-pairing paradigm to determine whether neuronal best frequencies shift following the pairing protocol. tPA administration significantly affected the best frequency after pairing, whereby this depended on the pairing frequency relative to the best frequency. When the pairing frequency was above the best frequency, tPA caused a best frequency shift away from the conditioned frequency. tPA significantly widened auditory tuning curves. Our data indicate that regional changes in proteolytic activity within the auditory cortex modulate the fine-tuning of auditory neurons, supporting the function of tPA as a modulator of neuronal plasticity.

Intrinsic timescales in the visual cortex change with selective attention and reflect spatial connectivity.

Intrinsic timescales characterize dynamics of endogenous fluctuations in neural activity. Variation of intrinsic timescales across the neocortex reflects functional specialization of cortical areas, but less is known about how intrinsic timescales change during cognitive tasks. We measured intrinsic timescales of local spiking activity within columns of area V4 in male monkeys performing spatial attention tasks. The ongoing spiking activity unfolded across at least two distinct timescales, fast and slow. The slow timescale increased when monkeys attended to the receptive fields location and correlated with reaction times. By evaluating predictions of several network models, we found that spatiotemporal correlations in V4 activity were best explained by the model in which multiple timescales arise from recurrent interactions shaped by spatially arranged connectivity, and attentional modulation of timescales results from an increase in the efficacy of recurrent interactions. Our results suggest that multiple timescales may arise from the spatial connectivity in the visual cortex and flexibly change with the cognitive state due to dynamic effective interactions between neurons.

Stimulus dependence of directed information exchange between cortical layers in macaque V1.

Perception and cognition require the integration of feedforward sensory information with feedback signals. Using different sized stimuli, we isolate spectral signatures of feedforward and feedback signals, and their effect on communication between layers in primary visual cortex of male macaque monkeys. Small stimuli elicited gamma frequency oscillations predominantly in the superficial layers. These Granger-causally originated in upper layer 4 and lower supragranular layers. Unexpectedly, large stimuli generated strong narrow band gamma oscillatory activity across cortical layers. They Granger-causally arose in layer 5, were conveyed through layer six to superficial layers, and violated existing models of feedback spectral signatures. Equally surprising, with large stimuli, alpha band oscillatory activity arose predominantly in granular and supragranular layers and communicated in a feedforward direction. Thus, oscillations in specific frequency bands are dynamically modulated to serve feedback and feedforward communication and are not restricted to specific cortical layers in V1.

Dopamine influences attentional rate modulation in Macaque posterior parietal cortex.

Cognitive neuroscience has made great strides in understanding the neural substrates of attention, but our understanding of its neuropharmacology remains incomplete. Although dopamine has historically been studied in relation to frontal functioning, emerging evidence suggests important dopaminergic influences in parietal cortex. We recorded single- and multi-unit activity whilst iontophoretically administering dopaminergic agonists and antagonists while rhesus macaques performed a spatial attention task. Out of 88 units, 50 revealed activity modulation by drug administration. Dopamine inhibited firing rates according to an inverted-U shaped dose-response curve and increased gain variability. D1 receptor antagonists diminished firing rates according to a monotonic function and interacted with attention modulating gain variability. Finally, both drugs decreased the pupil light reflex. These data show that dopamine shapes neuronal responses and modulates aspects of attentional processing in parietal cortex.

Reconstructing the world: switching from segmentation to integration allows neurons in area MT to make "sense" of the visual scene.

Huang et al. in this issue of Neuron show that primate area MT neurons exploit contextual cues to adequately interpret motion information. MT neurons switch from segmentation to integration when motion arises from single rather than multiple objects. This switching may help solve the aperture problem and bind distant object components into a perceptual whole.