Clustering of cerebral cortical lesions in patients with corticobasal degeneration

Clustering of ballooned neurons (BN) and tau positive neurons with inclusion bodies (tau+ neurons) was studied in the upper and lower laminae of the frontal, parietal and temporal cortex in 12 patients with corticobasal degeneration (CBD). In a significant proportion of brain areas examined, BN and tau+ neurons exhibited clustering with a regular distribution of clusters parallel to the pia mater. A regular pattern of clustering of BN and tau+ neurons was observed equally frequently in all cortical areas examined and in the upper and lower laminae. No significant correlations were observed between the cluster sizes of BN or tau+ neurons in the upper compared with the lower cortex or between the cluster sizes of BN and tau+ neurons. The results suggest that BN and tau+ neurons in CBD exhibit the same type of spatial pattern as lesions in Alzheimer's disease, Lewy body dementia and Pick's disease. The regular periodicity of the cerebral cortical lesions is consistent with the degeneration of the cortico-cortical projections in CBD.

Clustering of Pick bodies in patients with Pick's disease

Clustering of Pick bodies (PB) was studied in the frontal and temporal lobe in 10 cases of Pick's disease (PD). Pick bodies exhibited clustering in 47/50 (94%) brain areas analysed. In 20/50 (40%) brain areas, PB were present in a single large cluster ≤ 6400 μm in diameter, in 27/50 (54%) PB occurred in smaller clusters (200-3200 μm in diameter) which exhibited a regular periodicity relative to the tissue boundary, in 1/50 (2%) there was a regular distribution of individual PB and in 2/50 (4%), PB were randomly distributed. Mean cluster size of the PB was greater in the dentate gyrus compared with the inferior temporal gyrus and lateral occipitotemporal gyrus. Mean cluster size of PB in a brain region was positively correlated with the mean density of PB. Hence, PB exhibit essentially the same spatial patterns as senile plaques and neurofibrillary tangles in Alzheimer's disease (AD) and Lewy bodies in Dementia with Lewy bodies (DLB).

The spatial patterns of Lewy bodies, senile plaques, and neurofibrillary tangles in dementia with Lewy bodies

The spatial patterns of Lewy bodies (LB), senile plaques (SP), and neurofibrillary tangles (NFT) were studied in ubiquitin-stained sections of the temporal lobe in cases of dementia with Lewy bodies (DLB), which varied in the degree of associated Alzheimer's disease (AD) pathology. In all patients, LB, SP, and NFT developed in clusters and in a significant proportion of brain areas, the clusters exhibited a regular periodicity parallel to the tissue boundary. In the lateral occipitotemporal gyrus (LOT) and parahippocampal gyrus (PHG), the clusters of LB were larger than those of the SP and NFT but in the hippocampus, clusters of the three lesions were of similar size. Mean cluster size of the LB, SP, and NFT was similar in cases of DLB with and without significant associated AD pathology. LB density was positively correlated with SP and NFT density in 42 and 17% of brain areas analyzed, respectively, while SP and NFT densities were positively correlated in 7% of brain areas. The data suggest that LB in DLB exhibit similar spatial patterns to SP and NFT in AD and that SP and NFT exhibit similar spatial patterns in DLB and AD. In addition, in some instances, clusters of LB appeared to be more closely related spatially to the clusters of SP than to NFT.

Dementia with Lewy bodies:Clustering of Lewy bodies in human patients

Clustering of Lewy bodies (LB) was studied in four regions of the medial temporal lobe in 12 cases of dementia with LB (DLB). LB exhibited clustering in 67/70 (96%) brain areas analysed. In 34/70 (49%) analyses, LB were present in a single large cluster ≤6400 μm in diameter, in 33/70 (47%) LB occurred in smaller clusters 200-3200 μm in diameter which exhibited a regular periodicity relative to the tissue boundary and in 3/70 (4%), LB were randomly distributed. A regular pattern of LB clusters was observed equally frequently in the cortex and hippocampus, in upper and lower cortical laminae and in 'pure' cases of DLB with negligible Alzheimer's disease (AD) pathology compared with cases of AD with DLB. In cortical regions, there was no significant correlation between LB cluster size in the upper and lower cortical laminae. The regular periodicity of LB clusters suggests that LB develop in relation to the cells of origin of specific cortico-cortical and cortico-hippocampal projections.

Laminar distribution of ballooned neurons and tau positive neurons with inclusions in patients with corticobasal degeneration

The laminar distribution of ballooned neurons (BN) and tau positive neurons with inclusions (tau+ neurons) was studied in the frontal and temporal cortex in twelve patients with corticobasal degeneration (CBD). In the majority of brain areas, the density of BN and tau+ neurons was maximal in the lower and upper cortical laminae respectively. The densities of tau+ neurons in the upper and lower cortex were positively correlated. In the majority of brain areas, however, no correlations were observed between the densities of BN and tau+ neurons. The laminar distribution of the BN may reflect the degeneration of the feedback cortico-cortical and/or the efferent cortical pathways. By contrast, the distribution of the tau+ neurons may reflect the degeneration of the feed-forward cortico-cortical pathways. In addition, BN and tau+ neurons may arise as a result of distinct pathological processes.

Clustering patterns of neurofibrillary tangles in Alzheimer’s disease

Clustering of cellular neurofibrillary tangles (NFT) was studied in the cerebral cortex and hippocampus in cases of Alzheimer’s disease (AD) using a regression method. The objective of the study was to test the hypothesis that clustering of NFTs reflects the degeneration of the cortico-cortical pathways. In 25/38 (66%) of analyses of individual brain areas, a significant peak to trough and peak to peak distance was obtained suggesting that the clusters of NFTs were regularly distributed in bands parallel to the tissue boundary. In analyses of cortical tissues with regularly distributed clusters, peak to peak distance was between 1000 and 1600 microns in 13/24 (54%) of analyses, >1600 microns in 10/24 (42%) and <1000 microns in 1/24 (4%) of analyses. A regular distribution of NFT clusters was less evident in the CA sectors of the hippocampus than in the cortex. Hence, in a significant proportion of brain areas, the spacing of NFT clusters along the cerebral cortex was consistent with the predicted distribution of the cells of origin of specific cortico-cortical projections. However, in many brain regions, the sizes of the NFT clusters were larger than predicted which may be attributable to the spread of NFTs to adjacent groups of cells as the disease progresses.

The spatial patterns of Pick bodies, Pick cells and Alzheimer’s disease pathology in Pick’s disease

The spatial patterns of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and neurofibrillary tangles (NFT) were studied in the frontal and temporal lobe in nine cases of Pick’s disease (PD). Pick bodies exhibited clustering in 41/44 (93%) of analyses and clusters of PB were regularly distributed parallel to the tissue boundary in 24/41 (58%) of analyses. Pick cells exhibited clustering with regular periodicity of clusters in 14/16 (88%) analyses, SP in three out of four (75%) analyses and NFT in 21/27 (78%) analyses. The largest clusters of PB were observed in the dentate gyrus and PC in the frontal cortex. In 10/17 (59%) brain areas studied, a positive or negative correlation was observed between the densities of PB and PC. The densities of PB and NFT were not significantly correlated in the majority of brain areas but a negative correlation was observed in 7/29 (24%) brain areas. The data suggest that PB and PC in patients with PD exhibit essentially the same spatial patterns as SP and NFT in Alzheimer’s disease (AD) and Lewy bodies (LB) in dementia with Lewy bodies (DLB). In addition, there was a spatial correlation between the clusters of PB and PC, suggesting a pathogenic relationship between the two lesions. However, in the majority of tissues examined there was no spatial correlation between the clusters of PB and NFT, suggesting that the two lesions develop in association with different populations of neurons.

The anatomical and functional correlates of category-specificity

The dramatic effects of brain damage can provide some of the most interesting insights into the nature of normal cognitive performance. In recent years a number of neuropsychological studies have reported a particular form of cognitive impairment where patients have problems recognising objects from one category but remain able to recognise those from others. The most frequent ‘category-specific’ pattern is an impairment identifying living things, compared to nonliving things. The reverse pattern of dissociation, i.e., an impairment recognising and naming nonliving things relative to living things, has been reported albeit much less frequently. The objective of the work carried out in this thesis was to investigate the organising principles and anatomical correlates of stored knowledge for categories of living and nonliving things. Three complementary cognitive neuropsychological research techniques were employed to assess how, and where, this knowledge is represented in the brain: (i) studies of normal (neurologically intact) subjects, (ii) case-studies of neurologically impaired patients with selective deficits in object recognition, and (iii) studies of the anatomical correlates of stored knowledge for living and nonliving things on the brain using magnetoencephalography (MEG). The main empirical findings showed that semantic knowledge about living and nonliving things is principally encoded in terms of sensory and functional features, respectively. In two case-study chapters evidence was found supporting the view that category-specific impairments can arise from damage to a pre-semantic system, rather than the assumption often made that the system involved must be semantic. In the MEG study, rather than finding evidence for the involvement of specific brain areas for different object categories, it appeared that, when subjects named and categorised living and nonliving things, a non-differentiated neural system was involved.

Glutamatergic input-output properties of thalamic astrocytes

Astrocytes in the somatosensory ventrobasal (VB) thalamus of rats respond to glutamatergic synaptic input with metabotropic glutamate receptor (mGluR) mediated intracellular calcium ([Ca²?](i)) elevations. Astrocytes in the VB thalamus also release the gliotransmitter (GT) glutamate in a Ca²?-dependent manner. The tripartite synapse hypothesis posits that astrocytic [Ca²?](i) elevations resulting from synaptic input releases gliotransmitters that then feedback to modify the synapse. Understanding the dynamics of this process and the conditions under which it occurs are therefore important steps in elucidating the potential roles and impact of GT release in particular brain activities. In this study, we investigated the relationship between VB thalamus afferent synaptic input and astrocytic glutamate release by recording N-methyl-D-aspartate (NMDA) receptor-mediated slow inward currents (SICs) elicited in neighboring neurons. We found that Lemniscal or cortical afferent stimulation, which can elicit astrocytic [Ca²?](i) elevations, do not typically result in the generation of SICs in thalamocortical (TC) neurons. Rather, we find that the spontaneous emergence of SICs is largely resistant to acute afferent input. The frequency of SICs, however, is correlated to long-lasting afferent activity. In contrast to short-term stimulus-evoked GT release effects reported in other brain areas, astrocytes in the VB thalamus do not express a straightforward input-output relationship for SIC generation but exhibit integrative characteristics.

A penny for your thoughts! Patterns of fMRI activity reveal the content and the spatial topography of visual mental images

Visual mental imagery is a complex process that may be influenced by the content of mental images. Neuropsychological evidence from patients with hemineglect suggests that in the imagery domain environments and objects may be represented separately and may be selectively affected by brain lesions. In the present study, we used functional magnetic resonance imaging (fMRI) to assess the possibility of neural segregation among mental images depicting parts of an object, of an environment (imagined from a first-person perspective), and of a geographical map, using both a mass univariate and a multivariate approach. Data show that different brain areas are involved in different types of mental images. Imagining an environment relies mainly on regions known to be involved in navigational skills, such as the retrosplenial complex and parahippocampal gyrus, whereas imagining a geographical map mainly requires activation of the left angular gyrus, known to be involved in the representation of categorical relations. Imagining a familiar object mainly requires activation of parietal areas involved in visual space analysis in both the imagery and the perceptual domain. We also found that the pattern of activity in most of these areas specifically codes for the spatial arrangement of the parts of the mental image. Our results clearly demonstrate a functional neural segregation for different contents of mental images and suggest that visuospatial information is coded by different patterns of activity in brain areas involved in visual mental imagery. Hum Brain Mapp 36:945-958, 2015.

Characteristics of motor resonance predict the pattern of flash-lag effects for biological motion

Background - When a moving stimulus and a briefly flashed static stimulus are physically aligned in space the static stimulus is perceived as lagging behind the moving stimulus. This vastly replicated phenomenon is known as the Flash-Lag Effect (FLE). For the first time we employed biological motion as the moving stimulus, which is important for two reasons. Firstly, biological motion is processed by visual as well as somatosensory brain areas, which makes it a prime candidate for elucidating the interplay between the two systems with respect to the FLE. Secondly, discussions about the mechanisms of the FLE tend to recur to evolutionary arguments, while most studies employ highly artificial stimuli with constant velocities. Methodology/Principal Finding - Since biological motion is ecologically valid it follows complex patterns with changing velocity. We therefore compared biological to symbolic motion with the same acceleration profile. Our results with 16 observers revealed a qualitatively different pattern for biological compared to symbolic motion and this pattern was predicted by the characteristics of motor resonance: The amount of anticipatory processing of perceived actions based on the induced perspective and agency modulated the FLE. Conclusions/Significance - Our study provides first evidence for an FLE with non-linear motion in general and with biological motion in particular. Our results suggest that predictive coding within the sensorimotor system alone cannot explain the FLE. Our findings are compatible with visual prediction (Nijhawan, 2008) which assumes that extrapolated motion representations within the visual system generate the FLE. These representations are modulated by sudden visual input (e.g. offset signals) or by input from other systems (e.g. sensorimotor) that can boost or attenuate overshooting representations in accordance with biased neural competition (Desimone & Duncan, 1995).

Modulation of long-range neural synchrony reflects temporal limitations of visual attention in humans

Because of attentional limitations, the human visual system can process for awareness and response only a fraction of the input received. Lesion and functional imaging studies have identified frontal, temporal, and parietal areas as playing a major role in the attentional control of visual processing, but very little is known about how these areas interact to form a dynamic attentional network. We hypothesized that the network communicates by means of neural phase synchronization, and we used magnetoencephalography to study transient long-range interarea phase coupling in a well studied attentionally taxing dual-target task (attentional blink). Our results reveal that communication within the fronto-parieto-temporal attentional network proceeds via transient long-range phase synchronization in the beta band. Changes in synchronization reflect changes in the attentional demands of the task and are directly related to behavioral performance. Thus, we show how attentional limitations arise from the way in which the subsystems of the attentional network interact. The human brain faces an inestimable task of reducing a potentially overloading amount of input into a manageable flow of information that reflects both the current needs of the organism and the external demands placed on it. This task is accomplished via a ubiquitous construct known as “attention,” whose mechanism, although well characterized behaviorally, is far from understood at the neurophysiological level. Whereas attempts to identify particular neural structures involved in the operation of attention have met with considerable success (1-5) and have resulted in the identification of frontal, parietal, and temporal regions, far less is known about the interaction among these structures in a way that can account for the task-dependent successes and failures of attention. The goal of the present research was, thus, to unravel the means by which the subsystems making up the human attentional network communicate and to relate the temporal dynamics of their communication to observed attentional limitations in humans. A prime candidate for communication among distributed systems in the human brain is neural synchronization (for review, see ref. 6). Indeed, a number of studies provide converging evidence that long-range interarea communication is related to synchronized oscillatory activity (refs. 7-14; for review, see ref. 15). To determine whether neural synchronization plays a role in attentional control, we placed humans in an attentionally demanding task and used magnetoencephalography (MEG) to track interarea communication by means of neural synchronization. In particular, we presented 10 healthy subjects with two visual target letters embedded in streams of 13 distractor letters, appearing at a rate of seven per second. The targets were separated in time by a single distractor. This condition leads to the “attentional blink” (AB), a well studied dual-task phenomenon showing the reduced ability to report the second of two targets when an interval <500 ms separates them (16-18). Importantly, the AB does not prevent perceptual processing of missed target stimuli but only their conscious report (19), demonstrating the attentional nature of this effect and making it a good candidate for the purpose of our investigation. Although numerous studies have investigated factors, e.g., stimulus and timing parameters, that manipulate the magnitude of a particular AB outcome, few have sought to characterize the neural state under which “standard” AB parameters produce an inability to report the second target on some trials but not others. We hypothesized that the different attentional states leading to different behavioral outcomes (second target reported correctly or not) are characterized by specific patterns of transient long-range synchronization between brain areas involved in target processing. Showing the hypothesized correspondence between states of neural synchronization and human behavior in an attentional task entails two demonstrations. First, it needs to be demonstrated that cortical areas that are suspected to be involved in visual-attention tasks, and the AB in particular, interact by means of neural synchronization. This demonstration is particularly important because previous brain-imaging studies (e.g., ref. 5) only showed that the respective areas are active within a rather large time window in the same task and not that they are concurrently active and actually create an interactive network. Second, it needs to be demonstrated that the pattern of neural synchronization is sensitive to the behavioral outcome; specifically, the ability to correctly identify the second of two rapidly succeeding visual targets

GABAB receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid

The gamma-aminobutyric acid (GABA) metabolite gamma-hydroxybutyric acid (GHB) shows a variety of behavioural effects when administered to animals and humans, including reward/addiction properties and absence seizures. At the cellular level, these actions of GHB are mediated by activation of neuronal GABAB receptors (GABABRs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABAA and GABABRs, here we investigated the action of GHB on astrocytes on the ventral tegmental area (VTA) and the ventrobasal (VB) thalamic nucleus, two brain areas involved in the reward and proepileptic action of GHB, respectively, and compared it with that of the potent GABABR agonist baclofen. We found that GHB and baclofen elicited dose-dependent (ED50: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca2+ in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABABRs and mediated by Ca2+ release from intracellular store release. In contrast, prolonged GHB and baclofen exposure caused a reduction in spontaneous astrocyte activity and glutamate release from VTA astrocytes. These findings have key (patho)physiological implications for our understanding of the addictive and proepileptic actions of GHB.

Novel neuronal and astrocytic mechanisms in thalamocortical loop dynamics

In this review, we summarize three sets of findings that have recently been observed in thalamic astrocytes and neurons, and discuss their significance for thalamocortical loop dynamics. (i) A physiologically relevant ‘window’ component of the low–voltage–activated, T–type Ca2+ current (ITwindow) plays an essential part in the slow (less than 1 Hz) sleep oscillation in adult thalamocortical (TC) neurons, indicating that the expression of this fundamental sleep rhythm in these neurons is not a simple reflection of cortical network activity. It is also likely that ITwindow underlies one of the cellular mechanisms enabling TC neurons to produce burst firing in response to novel sensory stimuli. (ii) Both electrophysiological and dye–injection experiments support the existence of gap junction–mediated coupling among young and adult TC neurons. This finding indicates that electrical coupling–mediated synchronization might be implicated in the high and low frequency oscillatory activities expressed by this type of thalamic neuron. (iii) Spontaneous intracellular Ca2+ ([Ca2+]i) waves propagating among thalamic astrocytes are able to elicit large and long–lasting N–methyl–D–aspartate–mediated currents in TC neurons. The peculiar developmental profile within the first two postnatal weeks of these astrocytic [Ca2+]i transients and the selective activation of these glutamate receptors point to a role for this astrocyte–to–neuron signalling mechanism in the topographic wiring of the thalamocortical loop. As some of these novel cellular and intracellular properties are not restricted to thalamic astrocytes and neurons, their significance may well apply to (patho)physiological functions of glial and neuronal elements in other brain areas.

Dyslexia research at the turn of the 21st century:behavioural, neuroimaging and genetic findings

Behavioural studies have shown that dyslexics are a heterogeneous population and between-group comparisons are thus inadequate. Some subjects do not develop dyslexia despite having a deficit implicated in this disorder, which points to protective factors. Dyslexia co-occurs with ADHD, DCD, SLI, and SSD, so that future behavioural studies will need to screen and/or statistically control for other disorders. Studies of multiple cases of DPs with other developmental disorders are necessary. Neuroimaging findings show structural and/or functional brain abnormalities in language areas, V5/MT and the cerebellum. Future neuroimaging studies need to investigate the whole reading network and multiple cases. Six dyslexia risk genes have been found, mostly involved in neural migration, which may suggest dyslexia is a deficit of neuronal migration. However, it is not clear how these genes can restrict migration to specific brain areas. As a complex and heterogeneous disorder, dyslexia is likely to be associated with several mutated genes. ADHD and SSD are characterised by genetic risk factors which are partially shared with dyslexia, resulting in comorbidity. Future genetic studies need to focus on identifying other risk genes and pleiotropic genes involved in comorbidities, and linking genotypes implicated in dyslexia with brain structure. Any theory of dyslexia needs to take into account a multitude of risk and protective factors across behavioural, neural and genetic domains.