Neurophysiology of CSWS-associated cognitive dysfunction

The phenomenon of continuous spikes and waves during slow-wave sleep (CSWS) is associated with a number of epileptic syndromes, which share a behavioral phenotype characterized by deterioration of cognitive, behavioral, or sensorimotor functions. Available evidence seems to suggest that spike-wave activity is a result of a complex interaction between cortical and subcortical inhibitory networks and can "per se" produce a transient loss of underlying cortical functions. Syndromes like Landau-Kleffner syndrome, CSWS, and phenomena such as negative myoclonus could share in common--at least at the neurophysiological level--some similarities. Differences in behavioral phenotypes could be explained in term of maturational and genetic differences, as well as by the functional specificity of the involved areas.

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.

Is neuropathological heterogeneity in Alzheimer’s disease related to apolipoprotein genotype?

The abundance of senile plaques (SP) and neurofibrillary tangles (NFT) was studied in cortical and subcortical regions from 30 patients with Alzheimer’s disease (AD) expressing different apolipoprotein E (apoE) genotypes. Principal components analysis (PCA) was used to identify the most important neuropathological variations between individual patients and to determine whether these variations were related to apoE genotype. The first two principal components (PC) accounted for 60% and 40% of the total variance of the SP and NFT data respectively. The abundance of SP in the frontal and occipital cortex and NFT in the frontal cortex, amygdala and substantia nigra were positively correlated with the first principal component (PC1). Analysis of the SP data revealed that the apoE score of the patient (the sum of the two alleles) was positively correlated with PC1 while analysis of the NFT data revealed no significant correlations between apoE score and the PC. The data suggest that apoE genotype was more closely related to variations in the distribution and abundance of SP than of NFT. In addition, a more rapid spread of SP into the frontal and occipital cortex may occur in patients with a high apoE score.

DNA Mutation of the progranulin (GRN) gene in familial frontotemporal lobar degeneration (FTLD):a study of the pathology of nine cases

Frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP) is a neurodegenerative disease characterized by variable neocortical and allocortical atrophy principally affecting the frontal and temporal lobes. Histologically, there is neuronal loss, microvacuolation in the superficial cortical laminae, and a reactive astrocytosis. A variety of TDP-43 immunoreactive changes are present in FTLD-TDP including neuronal cytoplasmic inclusions (NCI), neuronal intranuclear inclusions (NII), dystrophic neurites (DN) and, oligodendroglial inclusions (GI). Many cases of familial FTLD-TDP are caused by DNA mutations of the progranulin (GRN) gene. Hence, the density, spatial patterns, and laminar distribution of the pathological changes were studied in nine cases of FLTD-TDP with GRN mutation. The densities of NCI and DN were greater in cases caused by GRN mutation compared with sporadic cases. In cortical regions, the commonest spatial pattern exhibited by the TDP-43 immunoreactive lesions was the presence of clusters of inclusions regularly distributed parallel to the pia mater. In approximately 50% of cortical gyri, the NCI exhibited a peak of density in the upper cortical laminae while the GI were commonly distributed across all laminae. The distribution of the NII and DN was variable, the most common pattern being a peak of NII density in the lower cortical laminae and DN in the upper cortical laminae. These results suggest in FTLD-TDP caused by GRN mutation: 1) there are greater densities of NCI and DN than in sporadic cases of the disease, 2) there is degeneration of the cortico-cortical and cortico-hippocampal pathways, and 3) cortical degeneration occurs across the cortical laminae, the various TDP-43 immunoreactive inclusions often being distributed in different cortical laminae.

A spatial pattern analysis of beta-amyloid (Abeta) deposition in the temporal lobe in Alzheimer's disease

To determine the factors influencing the distribution of -amyloid (Abeta) deposits in Alzheimer's disease (AD), the spatial patterns of the diffuse, primitive, and classic A deposits were studied from the superior temporal gyrus (STG) to sector CA4 of the hippocampus in six sporadic cases of the disease. In cortical gyri and in the CA sectors of the hippocampus, the Abeta deposits were distributed either in clusters 200-6400 microm in diameter that were regularly distributed parallel to the tissue boundary or in larger clusters greater than 6400 microm in diameter. In some regions, smaller clusters of Abeta deposits were aggregated into larger 'superclusters'. In many cortical gyri, the density of Abeta deposits was positively correlated with distance below the gyral crest. In the majority of regions, clusters of the diffuse, primitive, and classic deposits were not spatially correlated with each other. In two cases, double immunolabelled to reveal the Abeta deposits and blood vessels, the classic Abeta deposits were clustered around the larger diameter vessels. These results suggest a complex pattern of Abeta deposition in the temporal lobe in sporadic AD. A regular distribution of Abeta deposit clusters may reflect the degeneration of specific cortico-cortical and cortico-hippocampal pathways and the influence of the cerebral blood vessels. Large-scale clustering may reflect the aggregation of deposits in the depths of the sulci and the coalescence of smaller clusters.

A morphometric study of the spatial patterns of TDP-43 immunoreactive neuronal inclusions in frontotemporal lobar degeneration (FTLD) with progranulin (GRN) mutation

Mutations of the progranulin (GRN) gene are a major cause of familial frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). We studied the spatial patterns of TDP-43 immunoreactive neuronal cytoplasmic inclusions (NCI) and neuronal intranuclear inclusions (NII) in histological sections of the frontal and temporal lobe in eight cases of FTLD-TDP with GRN mutation using morphometric methods and spatial pattern analysis. In neocortical regions, the NCI were clustered and the clusters were regularly distributed parallel to the pia mater; 58% of regions analysed exhibiting this pattern. The NII were present in regularly distributed clusters in 35% of regions but also randomly distributed in many areas. In neocortical regions, the sizes of the regular clusters of NCI and NII were 400-800 µm, approximating to the size of the modular columns of the cortico-cortical projections, in 31% and 36% of regions respectively. The NCI and NII also exhibited regularly spaced clustering in sectors CA1/2 of the hippocampus and in the dentate gyrus. The clusters of NCI and NII were not spatially correlated. The data suggest degeneration of the cortico-cortical and cortico-hippocampal pathways in FTLD-TDP with GRN mutation, the NCI and NII affecting different clusters of neurons.

Multiple frequency functional connectivity in the hand somatosensory network:an EEG study

Objective: To investigate the dynamics of communication within the primary somatosensory neuronal network. Methods: Multichannel EEG responses evoked by median nerve stimulation were recorded from six healthy participants. We investigated the directional connectivity of the evoked responses by assessing the Partial Directed Coherence (PDC) among five neuronal nodes (brainstem, thalamus and three in the primary sensorimotor cortex), which had been identified by using the Functional Source Separation (FSS) algorithm. We analyzed directional connectivity separately in the low (1-200. Hz, LF) and high (450-750. Hz, HF) frequency ranges. Results: LF forward connectivity showed peaks at 16, 20, 30 and 50. ms post-stimulus. An estimate of the strength of connectivity was modulated by feedback involving cortical and subcortical nodes. In HF, forward connectivity showed peaks at 20, 30 and 50. ms, with no apparent feedback-related strength changes. Conclusions: In this first non-invasive study in humans, we documented directional connectivity across subcortical and cortical somatosensory pathway, discriminating transmission properties within LF and HF ranges. Significance: The combined use of FSS and PDC in a simple protocol such as median nerve stimulation sheds light on how high and low frequency components of the somatosensory evoked response are functionally interrelated in sustaining somatosensory perception in healthy individuals. Thus, these components may potentially be explored as biomarkers of pathological conditions. © 2012 International Federation of Clinical Neurophysiology.

Spatial patterns of the tau pathology in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is characterized neuropathologically by neuronal loss, gliosis, and the presence of tau-immunoreactive neuronal and glial cell inclusions affecting subcortical and some cortical regions. The objectives of this study were to determine (1) the spatial patterns of the tau-immunoreactive pathology, viz., neurofibrillary tangles (NFT), oligodendroglial inclusions (GI), tufted astrocytes (TA), and Alzheimer's disease-type neuritic plaques (NP) in PSP and (2) to investigate the spatial correlations between the histological features. Post-mortem material of cortical and subcortical regions of eight PSP cases was studied. Spatial pattern analysis was applied to the NFT, GI, TA, NP, abnormally enlarged neurons (EN), surviving neurons, and glial cells. NFT, GI, and TA were distributed either at random or in regularly distributed clusters. The EN and NP were mainly randomly distributed. Clustering of NFT and EN was more frequent in the cortex and subcortical regions, respectively. Variations in NFT density were not spatially correlated with the densities of either GI or TA, but were positively correlated with the densities of EN and surviving neurons in some regions. (1) NFT were the most widespread tau-immunoreactive pathology in PSP being distributed randomly in subcortical regions and in regular clusters in cortical regions, (2) GI and TA were more localized and exhibited a regular pattern of clustering in subcortical regions, and (3) neuronal and glial cell pathologies were not spatially correlated. © 2012 Springer-Verlag.

Examination of the predictive value of structural magnetic resonance scans in bipolar disorder:a pattern classification approach

Background - Bipolar disorder (BD) is one of the leading causes of disability worldwide. Patients are further disadvantaged by delays in accurate diagnosis ranging between 5 and 10 years. We applied Gaussian process classifiers (GPCs) to structural magnetic resonance imaging (sMRI) data to evaluate the feasibility of using pattern recognition techniques for the diagnostic classification of patients with BD. Method - GPCs were applied to gray (GM) and white matter (WM) sMRI data derived from two independent samples of patients with BD (cohort 1: n = 26; cohort 2: n = 14). Within each cohort patients were matched on age, sex and IQ to an equal number of healthy controls. Results - The diagnostic accuracy of the GPC for GM was 73% in cohort 1 and 72% in cohort 2; the sensitivity and specificity of the GM classification were respectively 69% and 77% in cohort 1 and 64% and 99% in cohort 2. The diagnostic accuracy of the GPC for WM was 69% in cohort 1 and 78% in cohort 2; the sensitivity and specificity of the WM classification were both 69% in cohort 1 and 71% and 86% respectively in cohort 2. In both samples, GM and WM clusters discriminating between patients and controls were localized within cortical and subcortical structures implicated in BD. Conclusions - Our results demonstrate the predictive value of neuroanatomical data in discriminating patients with BD from healthy individuals. The overlap between discriminative networks and regions implicated in the pathophysiology of BD supports the biological plausibility of the classifiers.

Spatial patterns of phosphorylation-dependent TDP-43-immunoreactive neuronal cytoplasmic inclusions (NCI) in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP)

The transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) is an RNA binding protein encoded by the TARDPB gene. Abnormal aggregations of TDP-43 in neurons in the form of neuronal cytoplasmic inclusions (NCI) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of TDP-43 in FTLD-TDP, the spatial patterns of the NCI were studied in frontal and temporal cortex of FTLD-TDP cases using a phosphorylation dependent anti-TDP-43 antibody (pTDP-43). In many regions, the NCI formed clusters and the clusters were distributed regularly parallel to the tissue boundary. In about 35% of cortical regions, cluster size of the NCI was within the size range of the modular columns of the cortex. The spatial patterns of the pTDP-immunoreactive inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody and also similar to inclusions characterized by other molecular pathologies such as tau, ?-synuclein and ‘fused in sarcoma’ (FUS). In conclusion, the data suggest degeneration of cortical and hippocampal anatomical pathways associated with accumulation of cellular pTDP-43 is characteristic of FTLD-TDP. In addition, the data are consistent with the hypothesis of cell to cell transfer of pTDP-43 within the brain.

Dementia with Lewy bodies

Dementia with Lewy bodies (‘Lewy body dementia' or ‘diffuse Lewy body disease') (DLB) is the second commonest form of dementia after Alzheimer’s disease (AD). Characteristic of DLB are: (1) fluctuating cognitive ability with variations in attention and alertness, (2) recurrent visual hallucinations, and (3) motor features including akinesia, rigidity, and tremor. Various brain regions are affected in DLD including cortical and limbic regions. Histopathologically, alpha-synuclein-immunoreactive Lewy bodies (LB) are observed in the substantia nigra and in the cerebral cortex. DLB has affinities both with the parkinsonian syndromes including Parkinson’s disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA), and with AD, which can make differential diagnosis difficult. The presence of visual hallucinations may aid differential diagnosis of the parkinsononian syndromes and occipital hypometabolism may be a useful potential method of distinguishing DLB from AD. Treatment of CBD involves managing and reducing the effect of symptoms.

Assessment of social cognition in bipolar disorder

Background: Impairment in social cognition may contribute to deficits in social functioning in patients with bipolar disorder (BD). In this study, a complex social cognition task was administered during a neuroimaging session. The behavioral and neural correlates of social cogniton in patients with BD were compared to healthy comparison (HC) subjects. Methods: The task was administered to 25 HC and 25 patients with depression scores ranging from euthymic to depressed at the time of assessment. The task required participants to evaluate situations that were “enhancing” or “threatening” to self-esteem, directed at both oneself, and at other people. For instance, self-esteem enhancing scenarios involved vignettes of activities such as receiving praise during a sports game, while a threatening scenario involved, for example, receiving criticism at a party. Participants were then required to evaluate characters in the scenarios on the basis of positive (“kind”) or negative (“mean”) descriptors. Evaluations were classified from extremely negative to extremely positive. The frequencies of behavioral responses were analyzed using chi-square tests and fMRI data were analyzed using Statistical Parametric Mapping software. Results: Patients differed significantly from HCs in their evaluation of threatening scenarios, directed at both oneself and at other people (p<0.001). Patients had a lower proportion of responses in the neutral category, and more responses in the positive and negative categories, relative to HCs. Neuroimaging results reveal differential patterns of prefrontal-cortical and limbic-subcortical activation in BDs throughout the task [p<0.05 (unc.)]. Conclusions: Findings will contribute to understanding difficulty in interpersonal functioning in patients with BD.

A spatial pattern analysis of β-amyloid (Aβ) deposition in the temporal lobe in Alzheimer's disease

To determine the factors influencing the distribution of β-amyloid (Aβ) deposits in Alzheimer's disease (AD), the spatial patterns of the diffuse, primitive, and classic Aβ deposits were studied from the superior temporal gyrus (STG) to sector CA4 of the hippocampus in six sporadic cases of the disease. In cortical gyri and in the CA sectors of the hippocampus, the Aβ deposits were distributed either in clusters 200-6400 μm in diameter that were regularly distributed parallel to the tissue boundary or in larger clusters greater than 6400 μm in diameter. In some regions, smaller clusters of Aβ deposits were aggregated into larger 'superclusters'. In many cortical gyri, the density of Aβ deposits was positively correlated with distance below the gyral crest. In the majority of regions, clusters of the diffuse, primitive, and classic deposits were not spatially correlated with each other. In two cases, double immunolabelled to reveal the Aβ deposits and blood vessels, the classic Aβ deposits were clustered around the larger diameter vessels. These results suggest a complex pattern of Aβ deposition in the temporal lobe in sporadic AD. A regular distribution of Aβ deposit clusters may reflect the degeneration of specific cortico-cortical and cortico-hippocampal pathways and the influence of the cerebral blood vessels. Large-scale clustering may reflect the aggregation of deposits in the depths of the sulci and the coalescence of smaller clusters.

Hebbian and homeostatic plasticity mechanisms in regular spiking and intrinsic bursting cells of cortical layer 5

Layer 5 contains the major projection neurons of the neocortex and is composed of two major cell types: regular spiking (RS) cells, which have cortico-cortical projections, and intrinsic bursting cells (IB), which have subcortical projections. Little is known about the plasticity processes and specifically the molecular mechanisms by which these two cell classes develop and maintain their unique integrative properties. In this study, we find that RS and IB cells show fundementally different experience-dependent plasticity processes and integrate Hebbian and homeostatic components of plasticity differently. Both RS and IB cells showed TNFα-dependent homeostatic plasticity in response to sensory deprivation, but IB cells were capable of a much faster synaptic depression and homeostatic rebound than RS cells. Only IB cells showed input-specific potentiation that depended on CaMKII autophosphorylation. Our findings demonstrate that plasticity mechanisms are not uniform within the neocortex, even within a cortical layer, but are specialized within subcircuits.

Cortical oscillatory activity associated with the perception of illusory and real visual contours

We used magnetoencephalography (MEG) to examine the nature of oscillatory brain rhythms when passively viewing both illusory and real visual contours. Three stimuli were employed: a Kanizsa triangle; a Kanizsa triangle with a real triangular contour superimposed; and a control figure in which the corner elements used to form the Kanizsa triangle were rotated to negate the formation of illusory contours. The MEG data were analysed using synthetic aperture magnetometry (SAM) to enable the spatial localisation of task-related oscillatory power changes within specific frequency bands, and the time-course of activity within given locations-of-interest was determined by calculating time-frequency plots using a Morlet wavelet transform. In contrast to earlier studies, we did not find increases in gamma activity (> 30 Hz) to illusory shapes, but instead a decrease in 10–30 Hz activity approximately 200 ms after stimulus presentation. The reduction in oscillatory activity was primarily evident within extrastriate areas, including the lateral occipital complex (LOC). Importantly, this same pattern of results was evident for each stimulus type. Our results further highlight the importance of the LOC and a network of posterior brain regions in processing visual contours, be they illusory or real in nature. The similarity of the results for both real and illusory contours, however, leads us to conclude that the broadband (< 30 Hz) decrease in power we observed is more likely to reflect general changes in visual attention than neural computations specific to processing visual contours.