A high-density 1,024-channel probe for brain-wide recordings in non-human primates.

Large-scale neural population recordings with single-cell resolution across the primate brain remain challenging. Here we introduce the Neuroscroll probe that isolates single neuronal activities simultaneously from 1,024 densely spaced channels that are flexibly distributed across the shank of the probe. The Neuroscroll probe length is easily tunable for individual probes from 10 mm to 90 mm, covering the brain size of non-human primates and humans, and the probes remain intact and functional after repeated bending deformations. The Neuroscroll probes provided reliable recordings from large neural populations with high chronic stability up to 105 weeks in rats. Recording with each Neuroscroll probe yielded hundreds of well-isolated single units simultaneously from multiple brain regions distributed across the entire depth of the rhesus macaque brain. With the thousand simultaneously recorded channels, unprecedented probe length, excellent mechanical stability and flexible recording site distribution, the Neuroscroll probes enable a wide range of new experimental paradigms in system neuroscience studies with great versatility.

Stable Neural Population Dynamics in the Regression Subspace for Continuous and Categorical Task Parameters in Monkeys.

Neural population dynamics provide a key computational framework for understanding information processing in the sensory, cognitive, and motor functions of the brain. They systematically depict complex neural population activity, dominated by strong temporal dynamics as trajectory geometry in a low-dimensional neural space. However, neural population dynamics are poorly related to the conventional analytical framework of single-neuron activity, the rate-coding regime that analyzes firing rate modulations using task parameters. To link the rate-coding and dynamic models, we developed a variant of state-space analysis in the regression subspace, which describes the temporal structures of neural modulations using continuous and categorical task parameters. In macaque monkeys, using two neural population datasets containing either of two standard task parameters, continuous and categorical, we revealed that neural modulation structures are reliably captured by these task parameters in the regression subspace as trajectory geometry in a lower dimension. Furthermore, we combined the classical optimal-stimulus response analysis (usually used in rate-coding analysis) with the dynamic model and found that the most prominent modulation dynamics in the lower dimension were derived from these optimal responses. Using those analyses, we successfully extracted geometries for both task parameters that formed a straight geometry, suggesting that their functional relevance is characterized as a unidimensional feature in their neural modulation dynamics. Collectively, our approach bridges neural modulation in the rate-coding model and the dynamic system, and provides researchers with a significant advantage in exploring the temporal structure of neural modulations for pre-existing datasets.

Sequential involvements of the perirhinal cortex and hippocampus in the recall of item-location associative memory in macaques.

The standard consolidation theory suggests that the hippocampus (HPC) is critically involved in acquiring new memory, while storage and recall gradually become independent of it. Converging studies have shown separate involvements of the perirhinal cortex (PRC) and parahippocampal cortex (PHC) in item and spatial processes, whereas HPC relates the item to a spatial context. These 2 strands of literature raise the following question; which brain region is involved in the recall process of item-location associative memory? To solve this question, this study applied an item-location associative (ILA) paradigm in a single-unit study of nonhuman primates. We trained 2 macaques to associate 4 visual item pairs with 4 locations on a background map in an allocentric manner before the recording sessions. In each trial, 1 visual item and the map image at a tilt (-90° to 90°) were sequentially presented as the item-cue and the context-cue, respectively. The macaques chose the item-cue location relative to the context-cue by positioning their gaze. Neurons in the PRC, PHC, and HPC, but not area TE, exhibited item-cue responses which signaled retrieval of item-location associative memory. This retrieval signal first appeared in the PRC, followed by the HPC and PHC. We examined whether neural representations of the retrieved locations were related to the external space that the macaques viewed. A positive representation similarity was found in the HPC and PHC, but not in the PRC, thus suggesting a contribution of the HPC to relate the retrieved location from the PRC with a first-person perspective of the subjects and provide the self-referenced retrieved location to the PHC. These results imply distinct but complementary contributions of the PRC and HPC to recall of item-location associative memory that can be used across multiple spatial contexts.

Allocentric information represented by self-referenced spatial coding in the primate medial temporal lobe.

For living organisms, the ability to acquire information regarding the external space around them is critical for future actions. While the information must be stored in an allocentric frame to facilitate its use in various spatial contexts, each case of use requires the information to be represented in a particular self-referenced frame. Previous studies have explored neural substrates responsible for the linkage between self-referenced and allocentric spatial representations based on findings in rodents. However, the behaviors of rodents are different from those of primates in several aspects; for example, rodents mainly explore their environments through locomotion, while primates use eye movements. In this review, we discuss the brain mechanisms responsible for the linkage in nonhuman primates. Based on recent physiological studies, we propose that two types of neural substrates link the first-person perspective with allocentric coding. The first is the view-center background signal, which represents an image of the background surrounding the current position of fixation on the retina. This perceptual signal is transmitted from the ventral visual pathway to the hippocampus (HPC) via the perirhinal cortex and parahippocampal cortex. Because images that share the same objective-position in the environment tend to appear similar when seen from different self-positions, the view-center background signals are easily associated with one another in the formation of allocentric position coding and storage. The second type of neural substrate is the HPC neurons' dynamic activity that translates the stored location memory to the first-person perspective depending on the current spatial context.

A dataset of human fMRI/MEG experiments with eye tracking for spatial memory research using virtual reality.

A dataset consisting of whole-brain fMRI (functional magnetic resonance imaging)/MEG (magnetoencephalography) images, eye tracking files, and behavioral records from healthy adult human participants when they performed a spatial-memory paradigm in a virtual environment was collected to investigate the neural representation of the cognitive map defined by unique spatial relationship of three objects, as well as the neural dynamics of the cognitive map following the task demand from localizing self-location to remembering the target location relative to the self-body. The dataset, including both fMRI and MEG, was also used to investigate the neural networks involved in representing a target within and outside the visual field. The dataset included 19 and 12 university students at Peking University for fMRI and MEG experiments, respectively (fMRI: 12 women, 7 men; MEG: 4 women, 8 men). The average ages of those participants were 24.9 years (MRI: 18-30 years) and 22.5 years (MEG: 19-25 years), respectively. fMRI BOLD and T1-weighted images were acquired using a 3T Siemens Prisma scanner (Siemens, Erlangen, Germany) equipped with a 20-channel receiver head coil. MEG neuromagnetic data were acquired using a 275-channel MEG system (CTF MEG, Canada). The dataset could be further used to investigate a range of neural mechanisms involved in human spatial cognition or to develop a bioinspired deep neural network to enhance machines' abilities in spatial processing.

Distinct networks coupled with parietal cortex for spatial representations inside and outside the visual field.

Our mental representation of egocentric space is influenced by the disproportionate sensory perception of the body. Previous studies have focused on the neural architecture for egocentric representations within the visual field. However, the space representation underlying the body is still unclear. To address this problem, we applied both functional Magnitude Resonance Imaging (fMRI) and Magnetoencephalography (MEG) to a spatial-memory paradigm by using a virtual environment in which human participants remembered a target location left, right, or back relative to their own body. Both experiments showed larger involvement of the frontoparietal network in representing a retrieved target on the left/right side than on the back. Conversely, the medial temporal lobe (MTL)-parietal network was more involved in retrieving a target behind the participants. The MEG data showed an earlier activation of the MTL-parietal network than that of the frontoparietal network during retrieval of a target location. These findings suggest that the parietal cortex may represent the entire space around the self-body by coordinating two distinct brain networks.

Retrospective memory trace sustained by the human hippocampus during working memory task.

Working memory is a subcategory of short-term memory that voluntarily maintains behaviourally relevant information to prepare for a subsequent action. An established theory is that working memory is supported by the prefrontal cortex (PFC) for executive control, while the hippocampus (HPC) is largely involved in long-term episodic memory. Recent studies suggest that the HPC is also involved in perception and short-term storage. However, it remains unclear whether the HPC supports active maintenance of short-term memory as working memory. To address this question, we devised a new delayed matching-to-sample task in which two visual items were presented at different locations one by one as samples. The sequential presentations of sample stimuli allowed us to dissociate the contents of working memory (i.e., identities and locations of two samples) from the constituent perceived information of single samples. By applying representational similarity analysis (RSA) to the blood-oxygen-level-dependent (BOLD) signals of human participants, we investigated the delay activity after the two sample presentations. The results of the RSA showed that the right HPC signalled only the second sample as a conjunctional representation of its item identity and location. In contrast, the right PFC, including both lateral and medial parts, represented the conjunctional information of both samples. These results suggested that the HPC may support short-term memory for retrospective coding to retain information of the last event rather than for prospective coding coupled with working memory.

Reunification of Object and View-Center Background Information in the Primate Medial Temporal Lobe.

Recent work has shown that the medial temporal lobe (MTL), including the hippocampus (HPC) and its surrounding limbic cortices, plays a role in scene perception in addition to episodic memory. The two basic factors of scene perception are the object ("what") and location ("where"). In this review, we first summarize the anatomical knowledge related to visual inputs to the MTL and physiological studies examining object-related information processed along the ventral pathway briefly. Thereafter, we discuss the space-related information, the processing of which was unclear, presumably because of its multiple aspects and a lack of appropriate task paradigm in contrast to object-related information. Based on recent electrophysiological studies using non-human primates and the existing literature, we proposed the "reunification theory," which explains brain mechanisms which construct object-location signals at each gaze. In this reunification theory, the ventral pathway signals a large-scale background image of the retina at each gaze position. This view-center background signal reflects the first person's perspective and specifies the allocentric location in the environment by similarity matching between images. The spatially invariant object signal and view-center background signal, both of which are derived from the same retinal image, are integrated again (i.e., reunification) along the ventral pathway-MTL stream, particularly in the perirhinal cortex. The conjunctive signal, which represents a particular object at a particular location, may play a role in scene perception in the HPC as a key constituent element of an entire scene.

Voxel-Wise Linearity Analysis of Increments and Decrements in BOLD Responses in Human Visual Cortex Using a Contrast Adaptation Paradigm.

The linearity of BOLD responses is a fundamental presumption in most analysis procedures for BOLD fMRI studies. Previous studies have examined the linearity of BOLD signal increments, but less is known about the linearity of BOLD signal decrements. The present study assessed the linearity of both BOLD signal increments and decrements in the human primary visual cortex using a contrast adaptation paradigm. Results showed that both BOLD signal increments and decrements kept linearity to long stimuli (e.g., 3 s, 6 s), yet, deviated from linearity to transient stimuli (e.g., 1 s). Furthermore, a voxel-wise analysis showed that the deviation patterns were different for BOLD signal increments and decrements: while the BOLD signal increments demonstrated a consistent overestimation pattern, the patterns for BOLD signal decrements varied from overestimation to underestimation. Our results suggested that corrections to deviations from linearity of transient responses should consider the different effects of BOLD signal increments and decrements.

Hippocampal cells integrate past memory and present perception for the future.

The ability to use stored information in a highly flexible manner is a defining feature of the declarative memory system. However, the neuronal mechanisms underlying this flexibility are poorly understood. To address this question, we recorded single-unit activity from the hippocampus of 2 nonhuman primates performing a newly devised task requiring the monkeys to retrieve long-term item-location association memory and then use it flexibly in different circumstances. We found that hippocampal neurons signaled both mnemonic information representing the retrieved location and perceptual information representing the external circumstance. The 2 signals were combined at a single-neuron level to construct goal-directed information by 3 sequentially occurring neuronal operations (e.g., convergence, transference, and targeting) in the hippocampus. Thus, flexible use of knowledge may be supported by the hippocampal constructive process linking memory and perception, which may fit the mnemonic information into the current situation to present manageable information for a subsequent action.

Automatic Encoding of a View-Centered Background Image in the Macaque Temporal Lobe.

Perceptual processing along the ventral visual pathway to the hippocampus (HPC) is hypothesized to be substantiated by signal transformation from retinotopic space to relational space, which represents interrelations among constituent visual elements. However, our visual perception necessarily reflects the first person's perspective based on the retinotopic space. To investigate this two-facedness of visual perception, we compared neural activities in the temporal lobe (anterior inferotemporal cortex, perirhinal and parahippocampal cortices, and HPC) between when monkeys gazed on an object and when they fixated on the screen center with an object in their peripheral vision. We found that in addition to the spatially invariant object signal, the temporal lobe areas automatically represent a large-scale background image, which specify the subject's viewing location. These results suggest that a combination of two distinct visual signals on relational space and retinotopic space may provide the first person's perspective serving for perception and presumably subsequent episodic memory.

Medial Prefrontal Cortex Represents the Object-Based Cognitive Map When Remembering an Egocentric Target Location.

A cognitive map, representing an environment around oneself, is necessary for spatial navigation. However, compared with its constituent elements such as individual landmarks, neural substrates of coherent spatial information, which consists in a relationship among the individual elements, remain largely unknown. The present study investigated how the brain codes map-like representations in a virtual environment specified by the relative positions of three objects. Representational similarity analysis revealed an object-based spatial representation in the hippocampus (HPC) when participants located themselves within the environment, while the medial prefrontal cortex (mPFC) represented it when they recollected a target object's location relative to their self-body. During recollection, task-dependent functional connectivity increased between the two areas implying exchange of self-location and target location signals between the HPC and mPFC. Together, the object-based cognitive map, whose coherent spatial information could be formed by objects, may be recruited in the HPC and mPFC for complementary functions during navigation, which may generalize to other aspects of cognition, such as navigating social interactions.

Convergence of distinct functional networks supporting naming and semantic recognition in the left inferior frontal gyrus.

Naming individual objects is accompanied with semantic recognition. Previous studies examined brain-networks responsible for these operations individually. However, it remains unclear how these brain-networks are related. To address this problem, we examined the brain-networks during a novel object-naming task, requiring participants to name animals in photographs at a specific-level (e.g., "pigeon"). When the participants could not remember specific names, they answered basic names (e.g., "bird"). After fMRI scanning during the object-naming task, the participants rated familiarity of the animals based on their sense of knowing. Since participants tend to remember specific names for familiar objects compared with unfamiliar objects, a typical issue in an object-naming task is an internal covariance between the naming and familiarity levels. We removed this confounding factor by adjusting the familiarity/naming level of stimuli, and demonstrated distinct brain regions related to the two operations. Among them, the left inferior frontal gyrus triangularis (IFGtri) contained object-naming and semantic-recognition related areas in its anterior-ventral and posterior-dorsal parts, respectively. Psychophysiological interaction analyses suggested that both parts show connectivity with the brain regions related to object-naming. By examining the connectivity under control tasks requiring nonlexical semantic retrieval (e.g., animal's body color), we found that both IFGtri parts altered their targeting brain areas according to the required memory attributes, while only the posterior-dorsal part connected the brain regions related to semantic recognition. Together, the semantic recognition may be processed by distinct brain network from those for voluntary semantic retrievals including object-naming although all these networks are mediated by the posterior-dorsal IFGtri.

Forward Processing of Object-Location Association from the Ventral Stream to Medial Temporal Lobe in Nonhuman Primates.

While the hippocampus (HPC) is a prime candidate combining object identity and location due to its strong connections to the ventral and dorsal pathways via surrounding medial temporal lobe (MTL) areas, recent physiological studies have reported spatial information in the ventral pathway and its downstream target in MTL. However, it remains unknown whether the object-location association proceeds along the ventral MTL pathway before HPC. To address this question, we recorded neuronal activity from MTL and area anterior inferotemporal cortex (TE) of two macaques gazing at an object to retain its identity and location in each trial. The results showed significant effects of object-location association at a single-unit level in TE, perirhinal cortex (PRC), and HPC, but not in the parahippocampal cortex. Notably, a clear area difference emerged in the association form: 1) representations of object identity were added to those of subjects' viewing location in TE; 2) PRC signaled both the additive form and the conjunction of the two inputs; and 3) HPC signaled only the conjunction signal. These results suggest that the object and location signals are combined stepwise at TE and PRC each time primates view an object, and PRC may provide HPC with the conjunctional signal, which might be used for encoding episodic memory.

Contributions of primate prefrontal cortex and medial temporal lobe to temporal-order memory.

Neuropsychological and neurophysiological studies have emphasized the role of the prefrontal cortex (PFC) in maintaining information about the temporal order of events or items for upcoming actions. However, the medial temporal lobe (MTL) has also been considered critical to bind individual events or items to their temporal context in episodic memory. Here we characterize the contributions of these brain areas by comparing single-unit activity in the dorsal and ventral regions of macaque lateral PFC (d-PFC and v-PFC) with activity in MTL areas including the hippocampus (HPC), entorhinal cortex, and perirhinal cortex (PRC) as well as in area TE during the encoding phase of a temporal-order memory task. The v-PFC cells signaled specific items at particular time periods of the task. By contrast, MTL cortical cells signaled specific items across multiple time periods and discriminated the items between time periods by modulating their firing rates. Analysis of the temporal dynamics of these signals showed that the conjunctive signal of item and temporal-order information in PRC developed earlier than that seen in v-PFC. During the delay interval between the two cue stimuli, while v-PFC provided prominent stimulus-selective delay activity, MTL areas did not. Both regions of PFC and HPC exhibited an incremental timing signal that appeared to represent the continuous passage of time during the encoding phase. However, the incremental timing signal in HPC was more prominent than that observed in PFC. These results suggest that PFC and MTL contribute to the encoding of the integration of item and timing information in distinct ways.

Declarative association in the perirhinal cortex.

Declarative memories are our so-called daily language memories, which we are able to describe or explicitly experience through the act of remembering. This conscious recollection makes it possible for us to think about the future based on our previous experience (episodic memory) and knowledge (semantic memory). This cognitive function is substantiated by the medial temporal lobe (MTL), a hierarchically organized complex in which the perirhinal cortex and parahippocampal cortex provide item and context information to the hippocampus via the entorhinal cortex, and the hippocampus plays the main role in association and recollection. This conventional view provides an easily understood structure to the declarative memory system. However, neurophysiological studies reporting the activities of single neurons bring a more complicated view. In this article, I review single-unit studies, particularly those focused on the perirhinal cortex and hippocampus, and suggest that association processes for declarative memory are more distributed over the MTL areas. The perirhinal cortex represents both between-domain associations (e.g., item-reward, item-place and item-time) and within-domain associations (e.g., item-item) and contributes to both subcategories of declarative memory (i.e., episodic and semantic memory) in a way that is complementary with the hippocampus.

Context-dependent incremental timing cells in the primate hippocampus.

We examined timing-related signals in primate hippocampal cells as animals performed an object-place (OP) associative learning task. We found hippocampal cells with firing rates that incrementally increased or decreased across the memory delay interval of the task, which we refer to as incremental timing cells (ITCs). Three distinct categories of ITCs were identified. Agnostic ITCs did not distinguish between different trial types. The remaining two categories of cells signaled time and trial context together: One category of cells tracked time depending on the behavioral action required for a correct response (i.e., early vs. late release), whereas the other category of cells tracked time only for those trials cued with a specific OP combination. The context-sensitive ITCs were observed more often during sessions where behavioral learning was observed and exhibited reduced incremental firing on incorrect trials. Thus, single primate hippocampal cells signal information about trial timing, which can be linked with trial type/context in a learning-dependent manner.

The perirhinal cortex.

Anatomically, the perirhinal cortex sits at the boundary between the medial temporal lobe and the ventral visual pathway. It has prominent interconnections not only with both these systems, but also with a wide range of unimodal and polymodal association areas. Consistent with these diverse projections, neurophysiological studies reveal a multidimensional set of mnemonic signals that include stimulus familiarity, within- and between-domain associations, associative recall, and delay-based persistence. This wide range of perirhinal memory signals not only includes signals that are largely unique to the perirhinal cortex (i.e., object familiarity), consistent with dual-process theories, but also includes a range of signals (i.e., associative flexibility and recall) that are strongly associated with the hippocampus, consistent with single-process theories. These neurophysiological findings have important implications for bridging the gap between single-process and dual-process models of medial temporal lobe function.

Two routes for remembering the past.

Which brain circuits underlie retrieval of distant memories? Goshen et al. (2011) use a powerful optogenetic-based approach to reveal the critical contribution of the hippocampus to remote memory retrieval. In so doing, they provide new evidence toward resolving a long-standing debate in cognitive neuroscience.