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A fundamental problem in systems neuroscience is how to force a transition from one brain state to another by external driven stimulation in, for example, wakefulness, sleep, coma, or neuropsychiatric diseases. This requires a quantitative and robust definition of a brain state, which has so far proven elusive. Here, we provide such a definition, which, together with whole-brain modeling, permits the systematic study in silico of how simulated brain stimulation can force transitions between different brain states in humans. Specifically, we use a unique neuroimaging dataset of human sleep to systematically investigate where to stimulate the brain to force an awakening of the human sleeping brain and vice versa. We show where this is possible using a definition of a brain state as an ensemble of “metastable substates,” each with a probabilistic stability and occurrence frequency fitted by a generative whole-brain model, fine-tuned on the basis of the effective connectivity. Given the biophysical limitations of direct electrical stimulation (DES) of microcircuits, this opens exciting possibilities for discovering stimulation targets and selecting connectivity patterns that can ensure propagation of DES-induced neural excitation, potentially making it possible to create awakenings from complex cases of brain injury.

Using direct recordings in monkeys, the authors find that theta-band synchronization between V4 and prefrontal cortex is likely to be important for the maintenance of short-term visual memory. These synchronizations provide a means for distant cortical areas to communicate with each other during the performance of a cognitive task. 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.

Extensive in vivo imaging studies investigate the hippocampal neural network function, mainly focusing on the dorsal CA1 region given its optical accessibility. Multi-modality fMRI with simultaneous hippocampal electrophysiological recording reveal broad cortical correlation patterns, but the detailed spatial hippocampal functional map remains lacking given the limited fMRI resolution. In particular, hemodynamic responses linked to specific neural activity are unclear at the single-vessel level across hippocampal vasculature, which hinders the deciphering of the hippocampal malfunction in animal models and the translation to critical neurovascular coupling (NVC) patterns for human fMRI. We simultaneously acquired optogenetically-driven neuronal Ca 2+ signals with single-vessel blood-oxygen-level-dependent (BOLD) and cerebral-blood-volume (CBV)-fMRI from individual venules and arterioles. Distinct spatiotemporal patterns of hippocampal hemodynamic responses were correlated to optogenetically evoked and spreading depression-like calcium events. The calcium event-related single-vessel hemodynamic modeling revealed significantly reduced NVC efficiency upon spreading depression-like (SDL) events, providing a direct measure of the NVC function at various hippocampal states. Detailed characterization of large-scale hemodynamic responses linked to specific neural activity remains to be elucidated at the single-vessel level across the subcentimeter scale hippocampal vasculature in vivo. Here, authors use a novel multi-modal fMRI platform to characterize distinct spatiotemporal patterns of hippocampal hemodynamic responses that were correlated to the optogenetically evoked Ca2+ events and to further demonstrate the significantly reduced neurovascular coupling efficiency upon spreading depression-like Ca 2+ events.

A major debate about the neural correlates of conscious perception concerns its cortical organization, namely, whether it includes the prefrontal cortex (PFC), which mediates executive functions, or it is constrained within posterior cortices. It has been suggested that PFC activity during paradigms investigating conscious perception is conflated with post-perceptual processes associated with reporting the contents of consciousness or feedforward signals originating from exogenous stimulus manipulations and relayed via posterior cortical areas. We addressed this debate by simultaneously probing neuronal populations in the rhesus macaque (Macaca mulatta) PFC during a no-report paradigm, capable of instigating internally generated transitions in conscious perception, without changes in visual stimulation. We find that feature-selective prefrontal neurons are modulated concomitantly with subjective perception and perceptual suppression of their preferred stimulus during both externally induced and internally generated changes in conscious perception. Importantly, this enables reliable single-trial, population decoding of conscious contents. Control experiments confirm significant decoding of stimulus contents, even when oculomotor responses, used for inferring perception, are suppressed. These findings suggest that internally generated changes in the contents of conscious visual perception are reliably reflected within the activity of prefrontal populations in the absence of volitional reports or changes in sensory input. The role of the prefrontal cortex in conscious perception is debated because of its involvement in task relevant behaviour, such as subjective perceptual reports. Here, the authors show that prefrontal activity in rhesus macaques correlates with subjective perception and the contents of consciousness can be decoded from prefrontal population activity even without reports.

•We present the Subcortical Atlas of the Rhesus Macaque (SARM).•Digital maps at multiple spatial scales allow for flexible analysis and labeling.•The maps are based on 210 primary regions-of-interest (ROIs) and composites thereof.•SARM facilitates subcortical neuroimaging analysis and experimental planning.•SARM is in the NMT v2 template space and complements the CHARM atlas for the cortex. Digitized neuroanatomical atlases that can be overlaid onto functional data are crucial for localizing brain structures and analyzing functional networks identified by neuroimaging techniques. To aid in functional and structural data analysis, we have created a comprehensive parcellation of the rhesus macaque subcortex using a high-resolution ex vivo structural imaging scan. This anatomical scan and its parcellation were warped to the updated NIMH Macaque Template (NMT v2), an in vivo population template, where the parcellation was refined to produce the Subcortical Atlas of the Rhesus Macaque (SARM) with 210 primary regions-of-interest (ROIs). The subcortical parcellation and nomenclature reflect those of the 4th edition of the Rhesus Monkey Brain in Stereotaxic Coordinates (Paxinos et al., in preparation), rather than proposing yet another novel atlas. The primary ROIs are organized across six spatial hierarchical scales from small, fine-grained ROIs to broader composites of multiple ROIs, making the SARM suitable for analysis at different resolutions and allowing broader labeling of functional signals when more accurate localization is not possible. As an example application of this atlas, we have included a functional localizer for the dorsal lateral geniculate (DLG) nucleus in three macaques using a visual flickering checkerboard stimulus, identifying and quantifying significant fMRI activation in this atlas region. The SARM has been made openly available to the neuroimaging community and can easily be used with common MRI data processing software, such as AFNI, where the atlas has been embedded into the software alongside cortical macaque atlases.

As high-resolution functional magnetic resonance imaging (fMRI) and fMRI of cortical layers become more widely used, the question how well high-resolution fMRI signals reflect the underlying neural processing, and how to interpret laminar fMRI data becomes more and more relevant. High-resolution fMRI has shown laminar differences in cerebral blood flow (CBF), volume (CBV), and neurovascular coupling. Features and processes that were previously lumped into a single voxel become spatially distinct at high resolution. These features can be vascular compartments such as veins, arteries, and capillaries, or cortical layers and columns, which can have differences in metabolism. Mesoscopic models of the blood oxygenation level dependent (BOLD) response therefore need to be expanded, for instance, to incorporate laminar differences in the coupling between neural activity, metabolism and the hemodynamic response. Here we discuss biological and methodological factors that affect the modeling and interpretation of high-resolution fMRI data. We also illustrate with examples from neuropharmacology and the negative BOLD response how combining BOLD with CBF- and CBV-based fMRI methods can provide additional information about neurovascular coupling, and can aid modeling and interpretation of high-resolution fMRI.

Recordings of local field potentials (LFPs) reveal that the sensory cortex displays rhythmic activity and fluctuations over a wide range of frequencies and amplitudes. Yet, the role of this kind of activity in encoding sensory information remains largely unknown. To understand the rules of translation between the structure of sensory stimuli and the fluctuations of cortical responses, we simulated a sparsely connected network of excitatory and inhibitory neurons modeling a local cortical population, and we determined how the LFPs generated by the network encode information about input stimuli. We first considered simple static and periodic stimuli and then naturalistic input stimuli based on electrophysiological recordings from the thalamus of anesthetized monkeys watching natural movie scenes. We found that the simulated network produced stimulus-related LFP changes that were in striking agreement with the LFPs obtained from the primary visual cortex. Moreover, our results demonstrate that the network encoded static input spike rates into gamma-range oscillations generated by inhibitory-excitatory neural interactions and encoded slow dynamic features of the input into slow LFP fluctuations mediated by stimulus-neural interactions. The model cortical network processed dynamic stimuli with naturalistic temporal structure by using low and high response frequencies as independent communication channels, again in agreement with recent reports from visual cortex responses to naturalistic movies. One potential function of this frequency decomposition into independent information channels operated by the cortical network may be that of enhancing the capacity of the cortical column to encode our complex sensory environment.

Sharp-wave–ripple (SPW-R) complexes are believed to mediate memory reactivation, transfer, and consolidation. However, their underlying neuronal dynamics at multiple scales remains poorly understood. Using concurrent hippocampal local field potential (LFP) recordings and functional MRI (fMRI), we study local changes in neuronal activity during SPW-R episodes and their brain-wide correlates. Analysis of the temporal alignment between SPW and ripple components reveals well-differentiated SPW-R subtypes in the CA1 LFP. SPW-R–triggered fMRI maps show that ripples aligned to the positive peak of their SPWs have enhanced neocortical metabolic up-regulation. In contrast, ripples occurring at the trough of their SPWs relate to weaker neocortical up-regulation and absent subcortical down-regulation, indicating differentiated involvement of neuromodulatory pathways in the ripple phenomenon mediated by long-range interactions. To our knowledge, this study provides the first evidence for the existence of SPW-R subtypes with differentiated CA1 activity and metabolic correlates in related brain areas, possibly serving different memory functions.

Distributed neural processing likely entails the capability of networks to reconfigure dynamically the directionality and strength of their functional connections. Yet, the neural mechanisms that may allow such dynamic routing of the information flow are not yet fully understood. We investigated the role of gamma band (50-80 Hz) oscillations in transient modulations of communication among neural populations by using measures of direction-specific causal information transfer. We found that the local phase of gamma-band rhythmic activity exerted a stimulus-modulated and spatially-asymmetric directed effect on the firing rate of spatially separated populations within the primary visual cortex. The relationships between gamma phases at different sites (phase shifts) could be described as a stimulus-modulated gamma-band wave propagating along the spatial directions with the largest information transfer. We observed transient stimulus-related changes in the spatial configuration of phases (compatible with changes in direction of gamma wave propagation) accompanied by a relative increase of the amount of information flowing along the instantaneous direction of the gamma wave. These effects were specific to the gamma-band and suggest that the time-varying relationships between gamma phases at different locations mark, and possibly causally mediate, the dynamic reconfiguration of functional connections.

An alerting sound elicits the Acoustic Startle Response (ASR) that is dependent on the sound volume and organisms’ state, which is regulated by neuromodulatory centers. The locus coeruleus (LC) neurons respond to salient stimuli and noradrenaline release affects sensory processing, including auditory. The LC hyperactivity is detrimental for sensorimotor gating. We report here that priming microstimulation of the LC (100-ms at 20, 50, and 100 Hz) attenuated the ASR in rats. The ASR reduction scaled with frequency and 100 Hz-stimulation mimicked pre-exposure to a non-startling tone (prepulse). A rapid (~ 40 ms) EEG desynchronization following the LC stimulation suggested that the ASR reduction was due to elevated cortical arousal. The effects of LC stimulation on the ASR and EEG were consistent with systematic relationships between the ASR, awake/sleep state, and the cortical arousal level; for that matter, a lower ASR amplitude corresponded to a higher arousal level. Thus, the LC appears to modulate the ASR circuit via its diffuse ascending projections to the forebrain saliency network. The LC modulation directly in the brainstem and/or spinal cord may also play a role. Our findings suggest the LC as a part of the brain circuitry regulating the ASR, while underlying neurophysiological mechanisms require further investigation.