A model for the differentiation between grid and conjunctive units in medial entorhinal cortex

The multiple layers of medial entorhinal cortex (mEC) contain cells that differ in selectivity, connectivity, and cellular properties. Grid cells in layer II and in the deeper layers express triangular grid patterns in the environment. The firing rate of the conjunctive cells found in layer III and below, on the other hand, show grid‐by‐head direction tuning. In this study, we model the differentiation between grid and conjunctive cells in a network with self‐organized connections. Arranged into distinct “layers”, the model grid units and conjunctive units develop, with a similar time course, grid fields resulting from firing rate adaptation and competitive learning. Grid alignment in both layers is delayed with respect to the formation of triangular grids. A common grid orientation among conjunctive units is produced, in the model, by head‐direction modulated collateral interactions, while the grids of grid units inherit the same orientation through connections from conjunctive units. Grid units as well as conjunctive units share a similar spacing but show a random distribution of spatial phases. Grid units however carry more spatial information than conjunctive units, thus providing better inputs for the hippocampus to form spatial memories. © 2013 Wiley Periodicals, Inc.     

High-density EEG coherence analysis using functional units applied to mental fatigue

Electroencephalography (EEG) coherence provides a quantitative measure of functional brain connectivity which is calculated between pairs of signals as a function of frequency. Without hypotheses, traditional coherence analysis would be cumbersome for high-density EEG which employs a large number of electrodes. One problem is to find the most relevant regions and coherences between those regions in individuals and groups. Therefore, we previously developed a data-driven approach for individual as well as group analyses of high-density EEG coherence. Its data-driven regions of interest (ROIs) are referred to as functional units (FUs) and are defined as spatially connected sets of electrodes that record pairwise significantly coherent signals. Here, we apply our data-driven approach to a case study of mental fatigue. We show that our approach overcomes the severe limitations of conventional hypothesis-driven methods which depend on previous investigations and leads to a selection of coherences of interest taking full advantage of the recordings under investigation. The presented visualization of (group) FU maps provides a very economical data summary of extensive experimental results, which otherwise would be very difficult and time-consuming to assess. Our approach leads to an FU selection which may serve as a basis for subsequent conventional quantitative analysis; thus it complements rather than replaces the hypothesis-driven approach.     

Observation of EEG coherence after repetitive transcranial magnetic stimulation.

OBJECTIVE: The effects before and after repetitive transcranial magnetic stimulation (rTMS) on EEG activity were investigated. METHODS: Nineteen healthy subjects received two trains (10 Hz, 100% of motor threshold, 3 s/train) of rTMS to the left frontal area. Directed coherence and ordinary coherence were calculated from EEG epochs recorded before and after (1 approximately 3 and 3 approximately 5 min) rTMS. The results were compared and demonstrated on maps. RESULTS: Directed coherence between cortical areas increased after rTMS (F=5.62, P<0.005), with the intra-hemispheric change being more pronounced than the inter-hemispheric change. Connections from the stimulated site to other sites were selectively reinforced. In contrast, ordinary coherence did not change after the stimulation. rTMS did not influence the dominant frequency at which maximal coherence was calculated. Differences in the directed coherence with opposite directions after rTMS were significantly correlated with the differences before rTMS (r=0.88, 0.89, P<0.001). CONCLUSIONS: (1) rTMS can enhance the connections between cortical areas, especially connections between the stimulated cortex and other sites in the brain. (2) Comparing with connections from the parietal area to frontal area, connections from the frontal area to parietal area are obviously improved by rTMS in both hemispheres. (3) The effects of rTMS can last for several minutes. Therefore, the necessity of EEG monitoring in rTMS studies is suggested.     

Selforganization of modular activity of grid cells

A unique topographical representation of space is found in the concerted activity of grid cells in the rodent medial entorhinal cortex. Many among the principal cells in this region exhibit a hexagonal firing pattern, in which each cell expresses its own set of place fields (spatial phases) at the vertices of a triangular grid, the spacing and orientation of which are typically shared with neighboring cells. Grid spacing, in particular, has been found to increase along the dorso‐ventral axis of the entorhinal cortex but in discrete steps, that is, with a modular structure. In this study, we show that such a modular activity may result from the self‐organization of interacting units, which individually would not show discrete but rather continuously varying grid spacing. Within our “adaptation” network model, the effect of a continuously varying time constant, which determines grid spacing in the isolated cell model, is modulated by recurrent collateral connections, which tend to produce a few subnetworks, akin to magnetic domains, each with its own grid spacing. In agreement with experimental evidence, the modular structure is tightly defined by grid spacing, but also involves grid orientation and distortion, due to interactions across modules. Thus, our study sheds light onto a possible mechanism, other than simply assuming separate networks a priori, underlying the formation of modular grid representations.     

Stability of medial entorhinal cortex representations over time

Distinct functional cell types in the medial entorhinal cortex (mEC) have been shown to represent different aspects of experiences. To further characterize mEC cell populations, we examined whether spatial representations of neurons in mEC superficial layers depended on the scale of the environment and changed over extended time periods. Accordingly, mEC cells were recorded while rats repeatedly foraged in a small or a large environment in sessions that were separated by time intervals from minutes to hours. Comparing between large and small environments, we found that the overall precision of grid and non‐grid cell spatial maps was higher in smaller environments. When examining the stability of spatial firing patterns over time, differences and similarities were observed across cell types. Within‐session stability was higher for grid cells than for non‐grid cell populations. Despite differences in baseline stability between cell types, stability levels remained consistent over time between sessions, up to 1 hr. Even for sessions separated by 6 hrs, activity patterns of grid cells and of most non‐grid cells lacked any systematic decrease in spatial similarity over time. However, a subset of ~15% of mEC non‐grid cells recorded preferentially from layer III exhibited dramatic, time dependent changes in firing patterns across 6 hrs, reminiscent of previous characterizations of the hippocampal CA2 subregion. Collectively, our data suggest that mEC grid cell input to hippocampus in conjunction with many time invariant non‐grid cells may aid in stabilizing hippocampal spatial maps, while a subset of time varying non‐grid cells could provide complementary temporal information.     

Isthmotectal axons make ectopic synapses in monocular regions of the tectum in developing Xenopus laevis frogs.

During the development of binocular maps in the tectum of Xenopus laevis, axons that relay input from the ipsilateral eye via the nucleus isthmi undergo a prolonged period of shifting connections. This shifting accompanies the dramatic change in eye position that takes place as the laterally placed eyes of the tadpole move dorsofrontally. There is a concomitant expansion of the proportion of tectum that receives contralateral retinotectal input corresponding to the binocular portion of the visual field. Electrophysiological recording demonstrates that ipsilateral units are present in those rostral tectal zones, and anatomical methods show that the isthmotectal axons arborize densely in the rostral region but also extend sparser branches into the caudal zone, which is occupied by contralateral inputs with receptive fields in the monocular zone of the visual field. A mechanism that aligns the ipsilateral and contralateral maps is activity-dependent stabilization of isthmotectal axons that exhibit firing patterns correlated with those of nearby retinotectal axons. In order for activity patterns to function in stabilizing correct connections and promoting the withdrawal of incorrect connections, synaptic communication of some sort is hypothesized to be essential. We have investigated whether isthmotectal axons make morphologically identifiable synapses during development and where such synapses are located. We find evidence for morphologically identifiable synapses in all regions of the tectum, along with many growth cones and structures that are probably immature synapses. As in the adult, the synapses contain round, clear vesicles, have asymmetric specializations, and terminate on structures that appear to be dendrites. In both adult and tadpole, the rarity of serial synapses involving isthmotectal terminals suggests that the interactions between retinotectal and isthmotectal inputs are mediated by postsynaptic dendrites.     

Familiarity expands space and contracts time

When humans draw maps, or make judgments about travel‐time, their responses are rarely accurate and are often systematically distorted. Distortion effects on estimating time to arrival and the scale of sketch‐maps reveal the nature of mental representation of time and space. Inspired by data from rodent entorhinal grid cells, we predicted that familiarity to an environment would distort representations of the space by expanding the size of it. We also hypothesized that travel‐time estimation would be distorted in the same direction as space‐size, if time and space rely on the same cognitive map. We asked international students, who had lived at a college in London for 9 months, to sketch a south‐up map of their college district, estimate travel‐time to destinations within the area, and mark their everyday walking routes. We found that while estimates for sketched space were expanded with familiarity, estimates of the time to travel through the space were contracted with familiarity. Thus, we found dissociable responses to familiarity in representations of time and space. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Cohesiveness of spatial and directional representations recorded from neural ensembles in the anterior thalamus, parasubiculum, medial entorhinal cortex, and hippocampus

Anatomical and physiological evidence suggests that hippocampal place cells derive their spatial firing properties from the medial entorhinal cortex (MEC) and other parahippocampal areas that send spatial and directional input to the MEC. MEC neurons fire in a precise, geometric pattern, forming a hexagonal grid that tessellates the surface of environments. Similar to place cells and head direction cells, the orientation of grid cell firing patterns can be controlled by visual landmarks, but the cells maintain their firing patterns even in the dark. Place cells and head direction cells can also completely decouple from external landmarks in the light, but it is not known whether the MEC and parahippocampal regions exhibit similar properties or are more explicitly tied to external landmarks. We recorded neurons in the MEC, parasubiculum, and CA1 and head direction cells of the anterior thalamus as the rat's internal direction sense was pitted against a salient visual landmark by slowly rotating the rat in a covered bucket while counter-rotating the visual cue. In different sessions, spatial firing rate maps and head direction tuning curves either rotated their preferred firing locations/directions by the same amount as the bucket rotation or maintained their preferences in the external laboratory framework. In few cases, the firing preferences rotated with the cue card. When cells from different regions were recorded simultaneously, the dominant response in one area almost always matched the response of the other areas. Although dominant responses were consistent throughout the recording regions, CA1 ensembles exhibited a greater degree of response heterogeneity than other regions, which nearly all exhibited internally consistent responses. Thus, the parahippocampal and MEC input to the hippocampus can be controlled by the animal's internal direction sense (presumably reflected in the firing of head direction cells) and become completely decoupled from external sensory input, yet maintain internal coherence with each other and in general with the place cell system of the hippocampus.     

Scaling self-organizing maps to model large cortical networks

Self-organizing computational models with specific intracortical connections can explain many functional features of visual cortex, such as topographic orientation and ocular dominance maps. However, due to their computational requirements, it is difficult to use such detailed models to study large-scale phenomenal like object segmentation and binding, object recognition, tilt illusions, optic flow, and fovea-periphery differences. This article introduces two techniques that make large simulations practical. First, we show how parameter scaling equations can be derived for laterally connected self-organizing models. These equations result in quantitatively equivalent maps over a wide range of simulation sizes, making it possible to debug small simulations and then scale them up only when needed. Parameter scaling also allows detailed comparison of biological maps and parameters between individuals and species with different brain region sizes. Second, we use parameter scaling to implement a new growing map method called GLISSOM, which dramatically reduces the memory and computational requirements of large self-organizing networks. With GLISSOM, it should be possible to simulate all of human V1 at the single-column level using current desktop workstations. We are using these techniques to develop a new simulator Topographica, which will help make it practical to perform detailed studies of large-scale phenomena in topographic maps.     

A big-world network in ASD: dynamical connectivity analysis reflects a deficit in long-range connections and an excess of short-range connections

Over the last years, increasing evidence has fuelled the hypothesis that Autism Spectrum Disorder (ASD) is a condition of altered brain functional connectivity. The great majority of these empirical studies relies on functional magnetic resonance imaging (fMRI) which has a relatively poor temporal resolution. Only a handful of studies has examined networks emerging from dynamic coherence at the millisecond resolution and there are no investigations of coherence at the lowest frequencies in the power spectrum—which has recently been shown to reflect long-range cortico-cortical connections. Here we used electroencephalography (EEG) to assess dynamic brain connectivity in ASD focusing in the low-frequency (delta) range. We found that connectivity patterns were distinct in ASD and control populations and reflected a double dissociation: ASD subjects lacked long-range connections, with a most prominent deficit in fronto-occipital connections. Conversely, individuals with ASD showed increased short-range connections in lateral-frontal electrodes. This effect between categories showed a consistent parametric dependency: as ASD severity increased, short-range coherence was more pronounced and long-range coherence decreased. Theoretical arguments have been proposed arguing that distinct patterns of connectivity may result in networks with different efficiency in transmission of information. We show that the networks in ASD subjects have less Clustering coefficient, greater Characteristic Path Length than controls - indicating that the topology of the network departs from small-world behaviour - and greater modularity. Together these results show that delta-band coherence reveal qualitative and quantitative aspects associated with ASD pathology.     

Cortico-cortical associations and EEG coherence: a two-compartmental model

EEG coherence was computed from 19 scalp locations from 189 children ranging in age from 5 to 16 years. Tests of spatial homogeneity of EEG coherence were conducted by comparing EEG coherence as a function of different interelectrode distances in the anterior-to-posterior versus posterior-to-anterior directions. Highly significant inhomogeneities were observed since greater coherence was present in the anterior-to-posterior direction than in the posterior-to-anterior directions. Greater coherence was also present in frontal derivations than in posterior derivations and from the right hemisphere in comparison to the left hemisphere. These data indicate that at least two separate sources of EEG coherence were present (1) coherence produced through the action of short length axonal connections, and (2) coherence produced through the action of long distance connections. Measures of phase delays as a function of interelectrode distance supported the development of a 'two-compartmental' model of EEG coherence in which different features of coherence are produced by different length fiber systems. Based on this model a number of hypotheses were developed to explain differences in connectivity between left and right hemispheres and frontal versus occipital cortex.     

EEG coherence in pathological conditions.

Coherence analysis of the electroencephalogram is considered an indicator of functional cortico-cortical connections, which makes it suitable for the neurophysiologic investigation of brain connectivity in normal and pathological conditions. In the clinical environment, coherence analysis has been applied in the study of brain development and in the assessment of diseases potentially involving brain connectivity, such as cortical and subcortical dementia, schizophrenia, and corpus callosum lesions. Whereas coherence decrease, at least for the high-frequency bands, is considered the expression of decreased functional cortico-cortical connections, more work needs to be performed in interpreting coherence increases. A special consideration is also required by technical aspects, such as the recording conditions and the reference used, which may greatly influence the results and need to be accounted for when drawing physiopathological interpretations. At present, whereas coherence analysis resulted successful in differentiating patients groups from the normal population, the specificity of coherence changes in various pathological conditions is questionable at the best. The same limits apply to the diagnostic value of the technique in individual patients.     

Is It Better to Train Power First or Coherence First?

Introduction. This study was done to see to what extent power training would correct coherence abnormalities in head-injured patients and to what extent coherence training would correct power abnormalities in a similar group of head-injured patients.

Method. Ten patients had power training first, and 10 patients had coherence training first (4 protocols with 5 sessions/protocol in each case).

Results. Either power or coherence training first resulted in normalization of most power and coherence abnormalities. Coherence training first resulted in significantly more new power abnormalities (10/client vs. 5/client for new power abnormalities). Power training first resulted in significantly more new coherence abnormalities (6/client vs. 2/client).

Conclusion. We did not find a clear-cut advantage for doing either power or coherence training first. However, we would recommend a repeat QEEG after doing either power or coherence first, since most original abnormalities will have resolved and there are likely to be several new abnormalities to be remediated.     

Grid cells correlation structure suggests organized feedforward projections into superficial layers of the medial entorhinal cortex

Navigation requires integration of external and internal inputs to form a representation of location. Part of this integration is considered to be carried out by the grid cells network in the medial entorhinal cortex (MEC). However, the structure of this neural network is unknown. To shed light on this structure, we measured noise correlations between 508 pairs of simultaneous previously recorded grid cells. We differentiated between pure grid and conjunctive cells (pure grid in Layers II, III, and VI vs. conjunctive in Layers III and V—only Layer III was bi‐modal), and devised a new method to classify cell pairs as belonging/not‐belonging to the same module. We found that pairs from the same module show significantly more correlations than pairs from different modules. The correlations between pure grid cells decreased in strength as their relative spatial phase increased. However, correlations were mostly at 0 time‐lag, suggesting that the source of correlations was not only synaptic, but rather resulted mostly from common input. Given our measured correlations, the two functional groups of grid cells (pure vs. conjunctive), and the known disorganized recurrent connections within Layer II, we propose the following model: conjunctive cells in deep layers form an attractor network whose activity is governed by velocity‐controlled signals. A second manifold in Layer II receives organized feedforward projections from the deep layers, giving rise to pure grid cells. Numerical simulations indicate that organized projections induce such correlations as we measure in superficial layers. Our results provide new evidence for the functional anatomy of the entorhinal circuit—suggesting that strong phase‐organized feedforward projections support grid fields in the superficial layers. © 2015 Wiley Periodicals, Inc.     

Cinema seating in right, mixed and left handers

Two hundred and sixty four right-handed, 246 mixed-handed and 360 left-handed students were requested to indicate on five maps of cinema halls what place they would choose. All three handedness groups showed a preference for the right and a corresponding directional bias towards the left space. However, they differed significantly from each other on the magnitude of this bias which was most pronounced in right and less in left handers. It is assumed that lateralized mechanisms underlying such biases have developed evolutionarily and serve right-handed persons best. Non-dextrality considerably reduces their phenotypic expressions, but even left-handedness does not reverse the directional bias towards the left. It is also hypothesized that right, mixed and left handers differ in a large number of behavioral choices and strategies, modeled by cerebrally lateralized mechanisms and that the cinema seating preference is only one of them.     

Cajal and brain plasticity: insights relevant to emerging concepts of mind

The main legacies of Cajal are his drawings of brain structure and their connections, and his ideas of brain plasticity, not only in the mature brain but also during development and after brain injury. As the 21st century begins, many scientists are asking an old question: "how does the brain express the mind?" Although most models of mind incorporate the brain connections produced by Cajal, his ideas of plasticity are largely ignored. The purpose of this chapter is to review how some of Cajal's ideas can be useful in understanding the expression of the mind. I have also introduced several concepts and facts not available during Cajal's life. I cover the concept of homeostasis, the global projections of the monoamine neurons, and the actions of "mind-expanding" drugs. The global projecting neurons, because their monoamine transmitters have such a long history, are considered 1st order systems. The point-to-point connections are considered 2nd order systems. Their importance in theories of functional localization studies is briefly reviewed. Finally, a new model is presented called "Plastic Homeostasis," which incorporates the plastic interactions between 1st and 2nd order neurons. It is hoped that this review will encourage others to study the ideas presented by Cajal when considering functions of the brain. The emerging models of the mind would be well served by a review of the theoretical writing of Cajal.     

Brain plasticity and stroke rehabilitation. The Willis lecture

Neuronal connections and cortical maps are continuously remodeled by our experience. Knowledge of the potential capabilityof the brain to compensate for lesions is a prerequisite for optimal stroke rehabilitation strategies. Experimental focal cortical lesions induce changes in adjacent cortex and in the contralateral hemisphere. Neuroimaging studies in stroke patients indicate altered poststroke activation patterns, which suggest some functional reorganization. To what extent functional imaging data correspond to outcome data needs to be evaluated. Reorganization may be the principle process responsible for recovery of function after stroke, but what are the limits, and to what extent can postischemic intervention facilitate such changes? Postoperative housing of animals in an enriched environment can significantly enhance functional outcome and can also interact with other interventions, including neocortical grafting. What role will neuronal progenitor cells play in future rehabilitation-stimulated in situ or as neural replacement? And what is the future for blocking neural growth inhibitory factors? Better knowledge of postischemic molecular and neurophysiological events, and close interaction between basic and applied research, will hopefully enable us to design rehabilitation strategies based on neurobiological principles in a not-too-distant future.     

New model of retinocollicular mapping predicts the mechanisms of axonal competition and explains the role of reverse molecular signaling during development

Precise connections in the brain result from elaborate processes during development. In the visual system, axonal projections from retinal ganglion cells (RGCs) onto the superior colliculus form a precise retinotopic map. Studies have revealed that the development of retinocollicular maps involves three main factors: graded expression of molecular guidance cues such as EphAs and ephrin-As, activity-dependent processes driven by spontaneous activity in RGCs, and different forms of axonal competition. In this study, we developed a new, versatile model including these factors. We first modeled the selective arborization of RGC axons, mediated by EphA/ephrin-A signaling, without assuming that this initial process instructed the map's final topology. We also derived an integro-differential equation modeling a second, dynamic phase in which activity-dependent plasticity of axonal arbors combined with their competition for collicular resources can deeply remodel the topology of immature maps. Our model hence challenges the view that retinotopic maps are instructed by matching molecular gradients and then merely refined by activity-dependent processes. We reproduce fine features of retinotopic map development in wild-type and various transgenic mice, allowing a new understanding of the underlying mechanisms. Our model predicts that competition is not based on comparisons of axonal EphA receptor levels but rather relies on the optimization of collicular resources mediated by neurotrophic receptors such as p75(NTR). Our model finally clarifies the elusive role of reverse signaling between retinal ephrin-As and collicular EphAs by reproducing for the first time the phenotypes of two mouse genotypes in which this function is altered.     

Visual interhemispheric transfer to areas 17 and 18 in cats with convergent strabismus

Commissural connections between primary visual cortical maps of the two hemispheres are essential to unify the split representation of the visual field. In normal adult cats, callosal connections are essentially restricted to the border between areas A17 and A18, where the central vertical meridian is projected. In contrast, early convergent strabismus leads to an expanded callosal-receiving zone, as repeatedly indicated by anatomical experiments. We investigated here the functional correlates of this widespread distribution of callosal terminals by analysing transcallosal visual responses in five anaesthetized and paralysed 4-10-month-old cats whose right eye had been surgically deviated on postnatal day 6. After acute section of the optic chiasm, single-unit activity was recorded from A17 and A18 of the right hemisphere while the left eye was visually stimulated. A total of 108/406 units were transcallosally activated. While they were more frequent at the 17/18 border (46% of the units recorded within this region), numerous transcallosally activated units were located throughout A17 (16%), A18 (27%) or within the white matter (17%). In all regions, transcallosally driven units displayed functional deficits usually associated with strabismus, such as decreased binocularity and ability to respond to fast-moving stimuli, and increased receptive field size. Many units also displayed reduced orientation selectivity and increased position disparity. In addition, transcallosal receptive fields were manifestly located within the hemifield ipsilateral to the explored cortex, with almost no contact with the central vertical meridian. Comparison with data from normal adults revealed that strabismus induced a considerable expansion of the callosal receiving zone, both in terms of the cortical region and of the extent of the visual field involved in interhemispheric transfer, with implications in the integration of visual information across the hemispheres.