The study of cross-species differences in the organization of the cerebral cortex received significant attention during the past century. However, the evolutionary principles governing changes in brain connectivity and their impact on cognition remain poorly understood. In the current study, we analyzed differences in anatomical input from the cerebral cortex to the hippocampal region across six species spanning more than 100 million years of mammalian evolution-the tenrec, rat, cat, marmoset, macaque and human. Our results demonstrate that, unlike direct transmodal cortical input, direct unimodal cortical input to the hippocampal region was selectively eliminated with the increase in brain size. Additionally, input from primary sensory regions was eliminated prior to input from non-primary sensory regions. Our findings suggest that hippocampus-related processes in different species operate on fundamentally different types of information, potentially underpinning cross-species differences in hippocampus-dependent cognition. Furthermore, our findings outline the evolutionary trajectory of the anatomical circuitry associating the human hippocampal region with the neocortex.

Efficiently interacting with the environment requires weighing and selecting among multiple alternative actions based on their associated outcomes. However, the neural mechanisms underlying these processes are still debated. We show that forming relations between arbitrary action-outcome associations involve building a cognitive map. Using an immersive virtual reality paradigm, participants learned 2D abstract motor action-outcome associations and later compared action combinations while their brain activity was monitored with fMRI. We observe a hexadirectional modulation of the activity in entorhinal cortex while participants compared different action plans. Furthermore, hippocampal activity scales with the 2D similarity between outcomes of these action plans. Conversely, the supplementary motor area represents individual actions, showing a stronger response to overlapping action plans. Crucially, the connectivity between hippocampus and supplementary motor area is modulated by the similarity between the action plans, suggesting their complementary roles in action evaluation. These findings provide evidence for the role of cognitive maps in action selection, challenging classical models of memory taxonomy and its neural bases.

Episodic memory must accomplish two adversarial goals: encoding and storing a multitude of experiences without exceeding the finite neuronal structure of the brain, and recalling memories in vivid detail. Dimensionality reduction and expansion (‘dimensionality transformation’) enable the brain to meet these demands. Reduction compresses sensory input into simplified, storable codes, while expansion reconstructs vivid details. Although these processes are essential to memory, their neural mechanisms for episodic memory remain unclear. Drawing on recent insights from cognitive psychology, systems neuroscience, and neuroanatomy, we propose two accounts of how dimensionality transformation occurs in the brain: structurally (via corticohippocampal pathways) and functionally (through neural oscillations). By examining cross-species evidence, we highlight neural mechanisms that may support episodic memory and identify crucial questions for future research.

In the entorhinal cortex (EC), attempts have been made to identify the human homologue regions of the medial (MEC) and lateral (LEC) subregions using either functional magnetic resonance imaging (fMRI) or diffusion tensor imaging (DTI). However, there are still discrepancies between entorhinal subdivisions depending on the choice of connectivity seed regions and the imaging modality used. While DTI can be used to follow the white matter tracts of the brain, fMRI can identify functionally connected brain regions. In this study, we used both DTI and resting-state fMRI in 103 healthy adults to investigate both structural and functional connectivity between the EC and associated cortical brain regions. Differential connectivity with these regions was then used to predict the locations of the human homologues of MEC and LEC. Our results from combining DTI and fMRI support a subdivision into posteromedial (pmEC) and anterolateral (alEC) EC and reveal a confined border between the pmEC and alEC. Furthermore, the EC subregions obtained by either imaging modality showed similar distinct whole-brain connectivity profiles. Optimizing the delineation of the human homologues of MEC and LEC with a combined, cross-validated DTI-fMRI approach allows to define a likely border between the two subdivisions and has implications for both cognitive and translational neuroscience research.

Goal-directed actions are performed in order to attain certain sensory consequences in the world. However, expected attributes of these consequences can affect the kinetics of the action. In a set of three studies (n = 120), we examined how expected attributes of stimulus outcome (intensity) shape the kinetics of the triggering action (applied force), even when the action kinetic and attribute are independent. We show that during action execution (button presses), the expected intensity of sensory outcome affects the applied force of the stimulus-producing action in an inverse fashion. Thus, participants applied more force when the expected intensity of the outcome was low (vs. high intensity outcome). In the absence of expectations or when actions were performed in response to the sensory event, no intensity-dependent force modulations were found. Thus, expectations of stimulus intensity and causality play an important role in shaping action kinetics. Finally, we examined the relationship between kinetics and perception and found no influence of applied force level on perceptual detection of low intensity (near-threshold) outcome stimuli, suggesting no causal link between the two. Taken together, our results demonstrate that action kinetics are embedded with high-level context such as the expectation of consequence intensity and the causal relationship with environmental cues.

Efficiently interacting with the environment requires weighing and selecting among multiple alternative actions based on their associated outcomes. However, the neural mechanisms underlying these processes are still debated. We showed that forming relations between arbitrary action-outcome associations involved building a cognitive map. Using a novel immersive virtual reality paradigm, participants learned 2D abstract motor action-outcome associations and later compared action combinations while their brain activity was monitored with fMRI. We observed a hexadirectional modulation of the activity in entorhinal cortex while participants compared different action plans. Furthermore, hippocampal activity scaled with the 2D similarity between outcomes of these action plans. Conversely, the supplementary motor area (SMA) represented individual actions, showing a stronger response to overlapping action plans. Crucially, the connectivity between hippocampus and SMA was modulated by the similarity between the action plans, suggesting their complementary roles in action evaluation. These findings provide evidence for the role of cognitive maps in action selection, challenging classical models of memory taxonomy and its neural bases. ### Competing Interest Statement The authors have declared no competing interest.

The wide array of cognitive functions associated with the hippocampus is supported through interactions with the cerebral cortex. However, most of the direct cortical input to the hippocampus originates in the entorhinal cortex, forming the hippocampal-entorhinal system. In humans, the role of the entorhinal cortex in mediating hippocampal-cortical interactions remains unknown. In this study, we used precision neuroimaging to examine the distributed cortical anatomy associated with the human hippocampal-entorhinal system. Consistent with animal anatomy, our results associate different subregions of the entorhinal cortex with different parts of the hippocampus long axis. Furthermore, we find that the entorhinal cortex comprises three band-like zones that are associated with functionally distinct cortical networks. Importantly, the entorhinal cortex bands traverse the proposed human homologs of rodent lateral and medial entorhinal cortices. Finally, we show that the entorhinal cortex is a major convergence area of distributed cortical processing and that the topography of cortical networks associated with the anterior medial temporal lobe mirrors the macroscale structure of high-order cortical processing.

Computational phenotyping has emerged as a powerful tool for characterizing individual variability across a variety of cognitive domains. An individual’s computational phenotype is defined as a set of mechanistically interpretable parameters obtained from fitting computational models to behavioural data. However, the interpretation of these parameters hinges critically on their psychometric properties, which are rarely studied. To identify the sources governing the temporal variability of the computational phenotype, we carried out a 12-week longitudinal study using a battery of seven tasks that measure aspects of human learning, memory, perception and decision making. To examine the influence of state effects, each week, participants provided reports tracking their mood, habits and daily activities. We developed a dynamic computational phenotyping framework, which allowed us to tease apart the time-varying effects of practice and internal states such as affective valence and arousal. Our results show that many phenotype dimensions covary with practice and affective factors, indicating that what appears to be unreliability may reflect previously unmeasured structure. These results support a fundamentally dynamic understanding of cognitive variability within an individual.

Throughout mammalian evolution, the hippocampal region, unlike the neocortex, largely preserved its cytoarchitectural organization and its role in mnemonic functions. This contrast raises the possibility that the hippocampal region receives different types of cortical input across species, which may be reflected in species-specific memory-related differences. To test this hypothesis, we examined differences in unimodal and transmodal cortical input to the hippocampal region in the rat, marmoset, macaque and human. Our results demonstrate that unlike unimodal cortical input, transmodal cortical input to the hippocampal region was selectively preserved during mammalian evolution. These findings suggest that memory-related processes in different species likely operate on different types of sensory information. Our observations provide a comparative anatomical framework elucidating the process of dimensionality reduction underlying the formation of human memory.

Tract-tracing studies in primates indicate that different subregions of the medial temporal lobe (MTL) are connected with multiple brain regions. However, no clear framework defining the distributed anatomy associated with the human MTL exists. This gap in knowledge originates in notoriously low MRI data quality in the anterior human MTL and in group-level blurring of idiosyncratic anatomy between adjacent brain regions, such as entorhinal and perirhinal cortices, and parahippocampal areas TH/TF. Using MRI, we intensively scanned four human individuals and collected whole-brain data with unprecedented MTL signal quality. Following detailed exploration of cortical networks associated with MTL subregions within each individual, we discovered three biologically meaningful networks associated with the entorhinal cortex, perirhinal cortex, and parahippocampal area TH, respectively. Our findings define the anatomical constraints within which human mnemonic functions must operate and are insightful for examining the evolutionary trajectory of the MTL connectivity across species.

Aims Modalities for rehabilitation of the neurologically affected upper-limb (UL) are generally of limited benefit. The majority of patients seriously affected by UL paresis remain with severe motor disability, despite all rehabilitation efforts. Consequently, extensive clinical research is dedicated to develop novel strategies aimed to improve the functional outcome of the affected UL. We have developed a novel virtual-reality training tool that exploits the voluntary control of one hand and provides real-time movement-based manipulated sensory feedback as if the other hand is the one that moves. The aim of this study was to expand our previous results, obtained in healthy subjects, to examine the utility of this training setup in the context of neuro-rehabilitation. Methods We tested the training setup in patient LA, a young man with significant unilateral UL dysfunction stemming from hemi-parkinsonism. LA underwent daily intervention in which he intensively trained the non-affected upper limb, while receiving online sensory feedback that created an illusory perception of control over the affected limb. Neural changes were assessed using functional magnetic resonance imaging (fMRI) scans before and after training. Results Training-induced behavioral gains were accompanied by enhanced activation in the pre-frontal cortex and a widespread increase in resting-state functional connectivity. Discussion Our combination of cutting edge technologies, insights gained from basic motor neuroscience in healthy subjects and well-known clinical treatments, hold promise for the pursuit of finding novel and more efficient rehabilitation schemes for patients suffering from hemiplegia.

Sensory perception is a product of interactions between the internal state of an organism and the physical attributes of a stimulus. It has been shown across the animal kingdom that perception and sensory-evoked physiological responses are modulated depending on whether or not the stimulus is the consequence of voluntary actions. These phenomena are often attributed to motor signals sent to relevant sensory regions that convey information about upcoming sensory consequences. However, the neurophysiological signature of action-locked modulations in sensory cortex, and their relationship with perception, is still unclear. In the current study, we recorded neurophysiological (using Magnetoencephalography) and behavioral responses from 16 healthy subjects performing an auditory detection task of faint tones. Tones were either generated by subjects' voluntary button presses or occurred predictably following a visual cue. By introducing a constant temporal delay between button press/cue and tone delivery, and applying source-level analysis, we decoupled action-locked and auditory-locked activity in auditory cortex. We show action-locked evoked-responses in auditory cortex following sound-triggering actions and preceding sound onset. Such evoked-responses were not found for button-presses that were not coupled with sounds, or sounds delivered following a predictive visual cue. Our results provide evidence for efferent signals in human auditory cortex that are locked to voluntary actions coupled with future auditory consequences.

Sensory perception is a product of interactions between the internal state of an organism and the physical attributes of a stimulus. It has been shown across the animal kingdom that perception and sensory-evoked physiological responses are modulated depending on whether or not the stimulus is the consequence of voluntary actions. These phenomena are often attributed to motor signals sent to relevant sensory regions that convey information about upcoming sensory consequences. However, the neurophysiological signature of action-locked modulations in sensory cortex, and their relationship with perception, is still unclear. In the current study, we recorded neurophysiological (using Magnetoencephalography) and behavioral responses from 16 healthy subjects performing an auditory detection task of faint tones. Tones were either generated by subjects' voluntary button presses or occurred predictably following a visual cue. By introducing a constant temporal delay between button press/cue and tone delivery, and applying source-level analysis, we decoupled action-locked and auditory-locked activity in auditory cortex. We show action-locked evoked-responses in auditory cortex following sound-triggering actions and preceding sound onset. Such evoked-responses were not found for button-presses that were not coupled with sounds, or sounds delivered following a predictive visual cue. Our results provide evidence for efferent signals in human auditory cortex that are locked to voluntary actions coupled with future auditory consequences.

Sensory perception is a product of complex interactions between the internal state of an organism and the physical attributes of a stimulus. One factor that modulates the internal state of the perceiving agent is voluntary movement. It has been shown across the animal kingdom that perception and sensory-evoked physiological responses are modulated depending on whether or not the stimulus is the consequence of voluntary actions. These phenomena are often attributed to motor signals sent to relevant sensory regions (efference copies), that convey information about expected upcoming sensory consequences. However, to date, there is no direct evidence in humans for efferent signals underlying these motor-sensory interactions. In the current study we recorded neurophysiological (using Magnetoencephalography) and behavioral responses from 16 healthy subjects performing an auditory detection task of faint tones. Tones were either generated by subjects’ voluntary button presses or occurred predictably following a visual cue. By introducing a constant temporal delay between button press/cue and tone delivery and applying source-level analysis we decoupled motor-evoked and auditory-evoked activity in auditory cortex. We show motor-related evoked-responses in auditory cortex following sound-triggering actions and preceding sound onset. Such evoked-responses were not found for button-presses that were not coupled with expected sounds. Furthermore, the amplitude of these evoked-responses corresponded with subsequent sound detection, suggesting their functional relevance to auditory processing. Our results provide first direct evidence for efferent signals in sensory cortex that are evoked by voluntary actions coupled with sensory consequences.

Evoked neural activity in sensory regions, and perception of sensory stimuli, are modulated when the stimuli are the consequence of voluntary movement as opposed to an external source. It has been suggested that such modulations are due to efference copies of the motor command that are sent to relevant sensory regions during voluntary movement. Given the anatomical-functional laterality bias of the motor system, it is plausible that the pattern of such behavioral and neural sensory modulations will exhibit a similar bias, depending on the effector that was used to trigger the stimulus (e.g. right / left hand). Here we examined this issue in the visual domain using behavioral and neural measures (fMRI). Healthy participants judged the relative brightness of identical visual stimuli that were either self-triggered (using right or left hand button presses), or triggered by the computer. By presenting stimuli to either the right or left visual field, we biased visual-evoked responses to left / right visual cortex. We found stronger perceptual modulations when the triggering hand was ipsi (rather than contra) lateral to the stimulated visual field. At the neural level, we found that despite identical physical properties of the visual consequence, evoked fMRI responses in right and left visual cortices differentiate the identity of the triggering hand (left / right). Our findings support a model in which voluntary actions induce sensory modulations that follow the anatomical-functional bias of the motor system.

Cross education is a phenomenon in which motor training of one hand induces motor learning in the other hand. We have recently shown in healthy subjects that the effect of cross-education is significantly augmented by provision of real-time manipulated bi-modal (visual and kinesthetic) sensory feedback, creating an illusory sensation of voluntary training with the other hand. Here we tested whether this training method may be applicable also in pathological conditions affecting one side of the body. We present here data showing behavioral gain accompanied by changes in functional magnetic resonance imaging dynamics following training with this setup in the case of patient LA, a young man with significant unilateral upper-limb dysfunction stemming from hemi-Parkinson’s disease. Following two weeks of daily sessions in which he intensively trained the non-affected upper limb, he showed improvement in motor capacity of the affected limb, accompanied by enhanced activation in the pre-frontal cortex and a widespread increase in functional coupling in the brain. Results from the current feasibility study suggest that combining cross-education with manipulated sensory input may have beneficial effects in clinical conditions.

Behavior is a complex product of interactions between sensory influx arising from the environment and the neural state of the organism. Therefore, identical sensory input can elicit different behavioral responses. Research in recent years has demonstrated that perception is modulated when an organism is engaged in active behavior - suggesting that neural activity in motor pathways is one factor governing the neural state of networks engaged in sensory processing. In the current manuscript, we focus on the auditory modality and propose a mechanism by which activity in motor cortex changes the neural state in auditory cortex through global inhibition. In turn, such global inhibition reduces auditory net population activity, sharpens auditory frequency tuning curves, shifts the auditory oscillatory state and increases the signal-to-noise ratio of auditory evoked neural activity. These changes can result in either attenuated or enhanced behavioral responses depending on the environmental context. We base our model on animal and human literature and suggest that these motor-induced shifts in sensory states may explain reported phenomena and apparent discrepancies in the literature of motor-sensory interactions, such as sensory attenuation or sensory enhancement.

Sensory stimuli triggered by voluntary action are perceived differently and evoke differential neural activity in sensory regions, relative to identical stimuli triggered by an external source. Such modulations are suggested to occur through corollary discharges sent from the motor system to sensory regions prior to re-afferent stimulus arrival. Given the strong laterality of the motor system, it is plausible that the magnitude of such sensory modulation will also exhibit a laterality effect, depending on the stimulus-triggering hand (right/left). In the auditory domain, we have recently provided evidence in support of such a mechanism. The aim of the current study was to further probe this model in the visual domain. In a behavioral study, 24 subjects judged the relative brightness of self-generated visual stimuli to identical stimuli triggered by the computer. Self-generated stimuli were triggered using either right or left hand and presented either in right or left visual field. Some subjects reported experiencing the self-generated stimuli as brighter and others as darker relative to the externally generated visual stimuli. However, examining the absolute modulation magnitude (proportion of trials) demonstrates that it depended on the relation between stimulus-triggering hand and stimulated visual field. In the left visual field, perception of stimuli triggered with the left hand was more strongly modulated than perception of stimuli triggered with the right hand. In the right visual field, no such effect was found. We further probed this issue using fMRI. Preliminary results from 10 subjects show differential neural response in both visual cortices for identical visual stimuli, depending on the triggering hand. Our findings support the model predicting lateralized modulation of sensory regions, consistent with the known laterality of the motor cortices. Meeting abstract presented at VSS 2018

Movement is intrinsically linked to perception such that observing an action induces in the observer behavioral changes during execution of similar actions. Electroencephalogram (EEG) studies have revealed that at the group level, action observation suppresses oscillatory power in mu (8-12 Hz) and beta (15-25 Hz) bands over the sensorimotor cortex - a phenomenon associated with increased excitability of cortical neurons. However, it is unclear whether differences in suppression level across individuals is linked with individual differences in subsequent behavioral changes. Here 32 subjects performed self-paced finger tapping with their right hand before and after observation of a video displaying finger-tapping at either 2 or 4 Hz. Behaviorally, subjects' rate of self-pace tapping increased following observation, with higher increases following 4 Hz observation. The level of EEG power suppression in the low frequency range (low mu; 8-10 Hz) during observation corresponded to subsequent behavioral changes in tapping rate across individuals. Our results demonstrate that observing actions implicitly shifts subsequent execution rates, and that individual differences in the level of this implicit shift can be explained by activity in the sensorimotor cortex during observation. (C) 2018 Elsevier B.V. All rights reserved.

Self-generated, voluntary actions, are preceded by a slow negativity in the scalp electroencephalography (EEG) signal recorded from frontal regions (termed 'readiness potential'; RP). This signal, and its lateralized subcomponent (LRP), is mainly regarded as preparatory motor activity associated with the forthcoming voluntary motor act. However, it is not clear whether this neural signature is associated with preparatory motor activity, expectation of its associated sensory consequences, or both. Here we recorded EEG data from 14 healthy subjects while they performed self-paced button presses with their right index and middle fingers. Button-presses with one finger triggered a sound (motor+sound condition), while button-presses with the other finger did not (motor-only condition). Additionally, subjects listened to externally-generated sounds delivered in expected timings (sound-only condition). We found that the RP amplitude (locked to time of button press) was significantly more negative in the motor+sound compared with motor-only conditions. Importantly, no signal negativity was observed prior to expected sound delivery in the sound-only condition. Thus, the differences in RP amplitude between motor+sound and motor-only conditions are beyond differences in mere expectation of a forthcoming auditory sound. Our results suggest that information regarding expected auditory consequences is represented in the RP preceding voluntary action execution.