A Liaison Brought to Light: Cerebellum-Hippocampus, Partners for Spatial Cognition.

This review focuses on the functional and anatomical links between the cerebellum and the hippocampus and the role of their interplay in goal-directed navigation and spatial cognition. We will describe the interactions between the cerebellum and the hippocampus at different scales: a macroscopic scale revealing the joint activations of these two structures at the level of neuronal circuits, a mesoscopic scale highlighting the synchronization of neuronal oscillations, and finally a cellular scale where we will describe the activity of hippocampal neuronal assemblies following a targeted manipulation of the cerebellar system. We will take advantage of this framework to summarize the different anatomical pathways that may sustain this multiscale interaction. We will finally consider the possible influence of the cerebellum on pathologies traditionally associated with hippocampal dysfunction.

Interaction Between Hippocampus and Cerebellum Crus I in Sequence-Based but not Place-Based Navigation.

To examine the cerebellar contribution to human spatial navigation we used functional magnetic resonance imaging and virtual reality. Our findings show that the sensory-motor requirements of navigation induce activity in cerebellar lobules and cortical areas known to be involved in the motor loop and vestibular processing. By contrast, cognitive aspects of navigation mainly induce activity in a different cerebellar lobule (VIIA Crus I). Our results demonstrate a functional link between cerebellum and hippocampus in humans and identify specific functional circuits linking lobule VIIA Crus I of the cerebellum to medial parietal, medial prefrontal, and hippocampal cortices in nonmotor aspects of navigation. They further suggest that Crus I belongs to 2 nonmotor loops, involved in different strategies: place-based navigation is supported by coherent activity between left cerebellar lobule VIIA Crus I and medial parietal cortex along with right hippocampus activity, while sequence-based navigation is supported by coherent activity between right lobule VIIA Crus I, medial prefrontal cortex, and left hippocampus. These results highlight the prominent role of the human cerebellum in both motor and cognitive aspects of navigation, and specify the cortico-cerebellar circuits by which it acts depending on the requirements of the task.

The cerebellum promotes sequential foraging strategies and contributes to the directional modulation of hippocampal place cells.

The cerebellum contributes to goal-directed navigation abilities and place coding in the hippocampus. Here we investigated its contribution to foraging strategies. We recorded hippocampal neurons in mice with impaired PKC-dependent cerebellar functions (L7-PKCI) and in their littermate controls while they performed a task where they were rewarded for visiting a subset of hidden locations. We found that L7-PKCI and control mice developed different foraging strategies: while control mice repeated spatial sequences to maximize their rewards, L7-PKCI mice persisted to use a random foraging strategy. Sequential foraging was associated with more place cells exhibiting theta-phase precession and theta rate modulation. Recording in the dark showed that PKC-dependent cerebellar functions controlled how self-motion cues contribute to the selectivity of place cells to both position and direction. Thus, the cerebellum contributes to the development of optimal sequential paths during foraging, possibly by controlling how self-motion and theta signals contribute to place cell coding.

Preserved navigation abilities and spatio-temporal memory in individuals with autism spectrum disorder.

Cerebellar abnormalities have been reported in autism spectrum disorder (ASD). Beyond its role in hallmark features of ASD, the cerebellum and its connectivity with forebrain structures also play a role in navigation. However, the current understanding of navigation abilities in ASD is equivocal, as is the impact of the disorder on the functional anatomy of the cerebellum. In the present study, we investigated the navigation behavior of a population of ASD and typically developing (TD) adults related to their brain anatomy as assessed by structural and functional MRI at rest. We used the Starmaze task, which permits assessing and distinguishing two complex navigation behaviors, one based on allocentric learning and the other on egocentric learning of a route with multiple decision points. Compared to TD controls, individuals with ASD showed similar exploration, learning, and strategy performance and preference. In addition, there was no difference in the structural or functional anatomy of the cerebellar circuits involved in navigation between the two groups. The findings of our work suggest that navigation abilities, spatio-temporal memory, and their underlying circuits are preserved in individuals with ASD.

Perceptual alternations between unbound moving contours and bound shape motion engage a ventral/dorsal interplay.

Visual shape and motion information, processed in distinct brain regions, should be combined to elicit a unitary coherent percept of an object in motion. In an fMRI study, we identified brain regions underlying the perceptual binding of motion and shape independently of the features-contrast, motion, and shape-used to design the moving displays. These displays alternately elicited a bound (moving diamond) or an unbound (disconnected moving segments) percept, and were either physically unchanging yet perceptually bistable or physically changing over time. The joint analysis of the blood-oxygen-level-dependent (BOLD) signals recorded during bound or unbound perception with these different stimuli revealed a network comprising the occipital lobe and ventral and dorsal visual regions. Bound percepts correlated with in-phase BOLD increases within the occipital lobe and a ventral area and decreased activity in a dorsal area, while unbound percepts elicited moderate BOLD modulations in these regions. This network was similarly activated by bistable unchanging displays and by displays periodically changing over time. The uncovered interplay between the two regions is proposed to reflect a generic binding process that dynamically weights the perceptual evidence supporting the different shape and motion interpretations according to the reliability of the neural activity in these regions.

Coupled dynamics of bistable distant motion displays.

This study explores the extent to which a display changing periodically in perceptual interpretation through smooth periodic physical changes-an inducer-is able to elicit perceptual switches in an intrinsically bistable distant probe display. Four experiments are designed to examine the coupling strength and bistable dynamics with displays of varying degree of ambiguity, similarity, and symmetry-in motion characteristics-as a function of their locations in visual space. The results show that periodic fluctuations of a remote inducer influence a bistable probe and regulate its dynamics through coupling. Coupling strength mainly depends on the relative locations of the probe display and the contextual inducer in the visual field, with stronger coupling when both displays are symmetrical around the vertical meridian and weaker coupling otherwise. Smaller effects of common fate and symmetry are also found. Altogether, the results suggest that long-range interhemispheric connections, presumably involving the corpus callosum, are able to synchronize perceptual transitions across the vertical meridian. If true, bistable dynamics may provide a behavioral method to probe interhemispheric connectivity in behaving human. Consequences of these findings for studies using stimuli symmetrical around the vertical meridian are evaluated.

Flexibility as a marker of early cognitive decline in humanized apolipoprotein E ε4 (ApoE4) mice.

To test the hypothesis that ApoE4 may be involved in cognitive deficits associated with aging, we investigated the impact of APOE4 status and aging on the flexibility and memory components of spatial learning in mice. Young adult (6 months) and middle-aged (14 months) ApoE4, ApoE3 and C57BL/6 male mice were tested for flexibility in an aquatic Y-maze, and for spatio-temporal memory acquisition in the Starmaze. Our results revealed a flexibility deficit of the 6-month-old ApoE4 mice compared to controls. However, this deficit was not associated with spatio-temporal memory deficit at the same age. Importantly, the ApoE4 flexibility deficit did not increase with age, nor turn into memory deficit, or was able to predict individual variations of memory performance at 14 months. By contrast, control ApoE3 mice showed a decline of flexibility at 14 months resulting in performance similar to that of ApoE4. Overall, our results suggest that ApoE4 could be associated with an acceleration of the flexibility decrease otherwise observed in normal aging.

Validation of memory assessment in the Starmaze task: Data from 14 month-old APPPS1 mice and controls.

This article describes navigation data of 14 month-old APPPS1 and C57Bl6 in the Starmaze task. These data were acquired as positive controls of memory deficit in a model of the familial form of Alzheimers's disease (see Schmitt et al., Flexibility as a marker of early cognitive decline in humanized Apolipoprotein E ε4 (ApoE4) mice, Neurobiol Aging, 2021). They were acquired in a reduced version of the Starmaze environment and accompanied by a number of acquisitions in different control groups at 6 and 14 months to assess the robustness of the procedure and its associated memory scores. These data illustrate the extraction of a variety of navigation scores (including search strategy, spatial learning and memory) and provide a reference of navigation data in the Starmaze task for healthy 6-month-old controls, normal aging and a model of pathological memory deficit.

Author Correction: A hippocampo-cerebellar centred network for the learning and execution of sequence-based navigation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cerebellar Volume in Autism: Literature Meta-analysis and Analysis of the Autism Brain Imaging Data Exchange Cohort.

BACKGROUND: The neuroanatomical bases of autism spectrum disorder remain largely unknown. Among the most widely discussed candidate endophenotypes, differences in cerebellar volume have been often reported as statistically significant. METHODS: We aimed at objectifying this possible alteration by performing a systematic meta-analysis of the literature and an analysis of the ABIDE (Autism Brain Imaging Data Exchange) cohort. Our meta-analysis sought to determine a combined effect size of autism spectrum disorder diagnosis on different measures of the cerebellar anatomy as well as the effect of possible factors of variability across studies. We then analyzed the cerebellar volume of 328 patients and 353 control subjects from the ABIDE project. RESULTS: The meta-analysis of the literature suggested a weak but significant association between autism spectrum disorder diagnosis and increased cerebellar volume (p = .049, uncorrected), but the analysis of ABIDE did not show any relationship. The studies meta-analyzed were generally underpowered; however, the number of statistically significant findings was larger than expected. CONCLUSIONS: Although we could not provide a conclusive explanation for this excess of significant findings, our analyses would suggest publication bias as a possible reason. Finally, age, sex, and IQ were important sources of cerebellar volume variability, although independent of autism diagnosis.

A hospital outbreak of diarrhea due to an emerging epidemic strain of Clostridium difficile.

BACKGROUND: Increased Clostridium difficile-associated disease (CDAD) in a hospital and an affiliated long-term care facility continued despite infection control measures. We investigated this outbreak to determine risk factors and transmission settings. METHODS: The CDAD cases were compared according to where the disease was likely acquired based on health care exposure and characterization of isolates from case patients, asymptomatic carriers, and the environment. Antimicrobial susceptibility testing, strain typing using pulsed-field gel electrophoresis, and toxinotyping were performed, and toxins A and B, binary toxin, and deletions in the tcdC gene were detected using polymerase chain reaction. Risk factors were examined in a case-control study, and overall antimicrobial use was compared at the hospital before and during the outbreak. RESULTS: Significant increases were observed in hospital-acquired (0.19 vs 0.86; P < .001) and long-term care facility-acquired (0.04 vs 0.31; P = .004) CDAD cases per 100 admissions as a result of transmission of a toxinotype III strain at the hospital and a toxinotype 0 strain at the long-term care facility. The toxinotype III strain was positive for binary toxin, an 18-base pair deletion in tcdC, and increased resistance to fluoroquinolones. Independent risk factors for CDAD included use of fluoroquinolones (odds ratio [OR], 3.22; P = .04), cephalosporins (OR, 5.19; P = .006), and proton pump inhibitors (OR, 5.02; P = .02). A significant increase in fluoroquinolone use at the hospital took place during the outbreak (185.5 defined daily doses per 1000 patient-days vs 200.9 defined daily doses per 1000 patient-days; P < .001). CONCLUSIONS: The hospital outbreak of CDAD was caused by transmission of a more virulent, fluoroquinolone-resistant strain of C difficile. More selective fluoroquinolone and proton pump inhibitor use may be important in controlling and preventing such outbreaks.

A hippocampo-cerebellar centred network for the learning and execution of sequence-based navigation.

How do we translate self-motion into goal-directed actions? Here we investigate the cognitive architecture underlying self-motion processing during exploration and goal-directed behaviour. The task, performed in an environment with limited and ambiguous external landmarks, constrained mice to use self-motion based information for sequence-based navigation. The post-behavioural analysis combined brain network characterization based on c-Fos imaging and graph theory analysis as well as computational modelling of the learning process. The study revealed a widespread network centred around the cerebral cortex and basal ganglia during the exploration phase, while a network dominated by hippocampal and cerebellar activity appeared to sustain sequence-based navigation. The learning process could be modelled by an algorithm combining memory of past actions and model-free reinforcement learning, which parameters pointed toward a central role of hippocampal and cerebellar structures for learning to translate self-motion into a sequence of goal-directed actions.

How the cerebellum may monitor sensory information for spatial representation.

The cerebellum has already been shown to participate in the navigation function. We propose here that this structure is involved in maintaining a sense of direction and location during self-motion by monitoring sensory information and interacting with navigation circuits to update the mental representation of space. To better understand the processing performed by the cerebellum in the navigation function, we have reviewed: the anatomical pathways that convey self-motion information to the cerebellum; the computational algorithm(s) thought to be performed by the cerebellum from these multi-source inputs; the cerebellar outputs directed toward navigation circuits and the influence of self-motion information on space-modulated cells receiving cerebellar outputs. This review highlights that the cerebellum is adequately wired to combine the diversity of sensory signals to be monitored during self-motion and fuel the navigation circuits. The direct anatomical projections of the cerebellum toward the head-direction cell system and the parietal cortex make those structures possible relays of the cerebellum influence on the hippocampal spatial map. We describe computational models of the cerebellar function showing that the cerebellum can filter out the components of the sensory signals that are predictable, and provides a novelty output. We finally speculate that this novelty output is taken into account by the navigation structures, which implement an update over time of position and stabilize perception during navigation.

Beta, but not gamma, band oscillations index visual form-motion integration.

Electrophysiological oscillations in different frequency bands co-occur with perceptual, motor and cognitive processes but their function and respective contributions to these processes need further investigations. Here, we recorded MEG signals and seek for percept related modulations of alpha, beta and gamma band activity during a perceptual form/motion integration task. Participants reported their bound or unbound perception of ambiguously moving displays that could either be seen as a whole square-like shape moving along a Lissajou's figure (bound percept) or as pairs of bars oscillating independently along cardinal axes (unbound percept). We found that beta (15-25 Hz), but not gamma (55-85 Hz) oscillations, index perceptual states at the individual and group level. The gamma band activity found in the occipital lobe, although significantly higher during visual stimulation than during base line, is similar in all perceptual states. Similarly, decreased alpha activity during visual stimulation is not different for the different percepts. Trial-by-trial classification of perceptual reports based on beta band oscillations was significant in most observers, further supporting the view that modulation of beta power reliably index perceptual integration of form/motion stimuli, even at the individual level.

Speeding up the brain: when spatial facilitation translates into latency shortening.

Waves of activity following a focal stimulation are reliably observed to spread across the cortical tissue. The origin of these waves remains unclear and the underlying mechanisms and function are still debated. In this study, we ask whether waves of activity modulate the magnetoencephalography (MEG) signals recorded in humans during visual stimulation with Gabor patches sequentially flashed along a vertical path, eliciting a perception of vertical apparent motion. Building upon the functional properties of long-rang horizontal connections, proposed to contribute to spreading activity, we specifically probe the amplitude and latency of MEG responses as a function of Gabor contrast and orientation. The results indicate that in the left hemisphere the response amplitude is enhanced and the half height response latency is shortened for co-aligned Gabor as compared to misaligned Gabor patches at a low but not at a high contrast. Building upon these findings, we develop a biologically plausible computational model that performs a "spike time alignment" of the responses to elongated contours with varying contrast, endowing them with a phase advance relative to misaligned contours.

Activity in the lateral occipital cortex between 200 and 300 ms distinguishes between physically identical seen and unseen stimuli.

There is converging evidence that electrophysiological responses over posterior cortical regions in the 200-300 ms range distinguish between physically identical stimuli that reach consciousness or remain unseen. Here, we attempt at determining the sources of this awareness-related activity using magneto-encephalographic (MEG). Fourteen subjects were presented with faint colored gratings at threshold for contrast and reported on each trial whether the grating was seen or unseen. Subjects were primed with a color cue that could be congruent or incongruent with the color of the grating, to probe to what extent two co-localized features (color and orientation) would be bound in consciousness. The contrast between neural responses to seen and unseen physically identical gratings revealed a sustained posterior difference between 190 and 350 ms, thereby replicating prior studies. We further show that the main sources of the awareness-related activity were localized bilaterally on the lateral convexity of the occipito-temporal region, in the Lateral Occipital (LO) complex, as well as in the right posterior infero-temporal region. No activity differentiating seen and unseen trials could be observed in frontal or parietal regions in this latency range, even at lower threshold. Color congruency did not improve grating's detection, and the awareness-related activity was independent from color congruency. However, at the neural level, color congruency was processed differently in grating-present and grating-absent trials. The pattern of results suggests the existence of a neural process of color congruency engaging left parietal regions that is affected by the mere presence of another feature, whether this feature reaches consciousness or not. Altogether, our results reveal an occipital source of visual awareness insensitive to color congruency, and a simultaneous parietal source not engaged in visual awareness, but sensitive to the manipulation of co-localized features.

Magnetoencephalographic signatures of visual form and motion binding.

This study investigates neural magneto-encephalographic (MEG) correlates of visual form and motion binding. Steady-state visual evoked fields (SSVEF) were recorded in MEG while observers reported their bound or unbound perception of moving bars arranged in a square shape. By using pairs of oscillating vertical and horizontal bars, "frequency-tagged" at f1 and f2, we identified a region with enhanced sustained power at 2f1+2f2 intermodulation frequency correlated with perceptual reports. Intermodulation power is more important during perceptual form/motion integration than during the perceptual segmentation of the stimulus into individual component motions, indicating that intermodulation frequency power is a neuromarker of form/motion integration. Source reconstruction of cortical activities at the relevant frequencies further reveals well segregated activity in the occipital lobe at the fundamental of the stimulation, f1 and f2, widely spread activity at 2f1 and 2f2 and a focal activity in the medial part of the right precentral sulcus region at the intermodulation component, 2f1+2f2. The present findings indicate that motion tagging provides a powerful way of investigating the processes underlying visual form/motion binding non-invasively in humans.

Reference frames for spatial cognition: different brain areas are involved in viewer-, object-, and landmark-centered judgments about object location.

Functional magnetic resonance imaging was used to compare the neural correlates of three different types of spatial coding, which are implicated in crucial cognitive functions of our everyday life, such as visuomotor coordination and orientation in topographical space. By manipulating the requested spatial reference during a task of relative distance estimation, we directly compared viewer-centered, object-centered, and landmark-centered spatial coding of the same realistic 3-D information. Common activation was found in bilateral parietal, occipital, and right frontal premotor regions. The retrosplenial and ventromedial occipital-temporal cortex (and parts of the parietal and occipital cortex) were significantly more activated during the landmark-centered condition. The ventrolateral occipital-temporal cortex was particularly involved in object-centered coding. Results strongly demonstrate that viewer-centered (egocentric) coding is restricted to the dorsal stream and connected frontal regions, whereas a coding centered on external references requires both dorsal and ventral regions, depending on the reference being a movable object or a landmark.

Brain processing of visual sexual stimuli in healthy men: a functional magnetic resonance imaging study.

The brain plays a central role in sexual motivation. To identify cerebral areas whose activation was correlated with sexual desire, eight healthy male volunteers were studied with functional magnetic resonance imaging (fMRI). Visual stimuli were sexually stimulating photographs (S condition) and emotionally neutral photographs (N condition). Subjective responses pertaining to sexual desire were recorded after each condition. To image the entire brain, separate runs focused on the upper and the lower parts of the brain. Statistical Parametric Mapping was used for data analysis. Subjective ratings confirmed that sexual pictures effectively induced sexual arousal. In the S condition compared to the N condition, a group analysis conducted on the upper part of the brain demonstrated an increased signal in the parietal lobes (superior parietal lobules, left intraparietal sulcus, left inferior parietal lobule, and right postcentral gyrus), the right parietooccipital sulcus, the left superior occipital gyrus, and the precentral gyri. In addition, a decreased signal was recorded in the right posterior cingulate gyrus and the left precuneus. In individual analyses conducted on the lower part of the brain, an increased signal was found in the right and/or left middle occipital gyrus in seven subjects, and in the right and/or left fusiform gyrus in six subjects. In conclusion, fMRI allows to identify brain responses to visual sexual stimuli. Among activated regions in the S condition, parietal areas are known to be involved in attentional processes directed toward motivationally relevant stimuli, while frontal premotor areas have been implicated in motor preparation and motor imagery. Further work is needed to identify those specific features of the neural responses that distinguish sexual desire from other emotional and motivational states.