Spatial patterns of the pathological changes in the temporal lobe of patients with neuronal intermediate filament inclusion disease

Neuronal intermediate filament inclusion disease (NIFID) is a new neurodegenerative disease characterized histologically by the presence of neuronal cytoplasmic inclusions (NI) immunopositive for intermediate filament proteins, neuronal loss, swollen achromatic neurons (SN), and gliosis. We studied the spatial patterns of these pathological changes parallel to the pia mater in gyri of the temporal lobe in four cases of NIFID. Both the NI and SN occurred in clusters that were regularly distributed parallel to the pia mater, the cluster sizes of the SN being significantly greater than those of the NI. In a significant proportion of areas studied, there was a spatial correlation between the clusters of NI and those of the SN and with the density of the surviving neurons. In addition, the clusters of surviving neurons were negatively correlated (out of phase) with the clusters of glial cell nuclei. The pattern of clustering of these histological features suggests that there is degeneration of the cortico-cortical projections in NIFID leading to the formation of NI and SN within the same vertical columns of cells. The glial cell reaction may be a response to the loss of neurons rather than to the appearance of the NI or SN.

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.

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.

Spatial patterns of FUS-immunoreactive neuronal cytoplasmic inclusions (NCI) in neuronal intermediate filament inclusion disease (NIFID)

Neuronal intermediate filament inclusion disease (NIFID), a rare form of frontotemporal lobar degeneration (FTLD), is characterized neuropathologically by focal atrophy of the frontal and temporal lobes, neuronal loss, gliosis, and neuronal cytoplasmic inclusions (NCI) containing epitopes of ubiquitin and neuronal intermediate filament (IF) proteins. Recently, the 'fused in sarcoma' (FUS) protein (encoded by the FUS gene) has been shown to be a component of the inclusions of NIFID. To further characterize FUS proteinopathy in NIFID, we studied the spatial patterns of the FUS-immunoreactive NCI in frontal and temporal cortex of 10 cases. In the cerebral cortex, sectors CA1/2 of the hippocampus, and the dentate gyrus (DG), the FUS-immunoreactive NCI were frequently clustered and the clusters were regularly distributed parallel to the tissue boundary. In a proportion of cortical gyri, cluster size of the NCI approximated to those of the columns of cells was associated with the cortico-cortical projections. There were no significant differences in the frequency of different types of spatial patterns with disease duration or disease stage. Clusters of NCI in the upper and lower cortex were significantly larger using FUS compared with phosphorylated, neurofilament heavy polypeptide (NEFH) or a-internexin (INA) immunohistochemistry (IHC). We concluded: (1) FUS-immunoreactive NCI exhibit similar spatial patterns to analogous inclusions in the tauopathies and synucleinopathies, (2) clusters of FUS-immunoreactive NCI are larger than those revealed by NEFH or ???, and (3) the spatial patterns of the FUS-immunoreactive NCI suggest the degeneration of the cortico-cortical projections in NIFID.

Spatial patterns of TDP-43 neuronal cytoplasmic inclusions (NCI) in fifteen cases of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP)

Neuronal cytoplasmic inclusions (NCI) immunoreactive for transactive response DNA-binding protein (TDP-43) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). We studied the spatial patterns of the TDP-43 immunoreactive NCI in the frontal and temporal cortex of 15 cases of FTLD-TDP. The NCI were distributed parallel to the tissue boundary predominantly in regular clusters 50-400 µm in diameter. In five cortical areas, the size of the clusters approximated to the cells of the cortico-cortical pathways. In most regions, cluster size was smaller than 400 µm. There were no significant differences in spatial patterns between familial and sporadic cases. Cluster size of the NCI was not correlated with disease duration, brain weight, Braak stage, or disease subtype. The spatial pattern of the NCI was similar to that of neuronal inclusions in other neurodegenerative diseases and may reflect a common pattern of degeneration involving the cortico-cortical projections.

The spatial patterns of β-amyloid (Aβ) deposits and neurofibrillary tangles (NFT) in late-onset sporadic Alzheimer's disease

The spatial patterns of β-amyloid (Aβ) deposits and neurofibrillary tangles (NFT) were studied in areas of the cerebral cortex in 16 patients with the late-onset, sporadic form of Alzheimer's disease (AD). Diffuse, primitive, and classic Aβ deposits and NFT were aggregated into clusters; the clusters being regularly distributed parallel to the pia mater in many areas. In a significant proportion of regions, the sizes of the regularly distributed clusters approximated to those of the cells of origin of the cortico-cortical projections. The diffuse and primitive Aβ deposits exhibited a similar range of spatial patterns but the classic Aβ deposits occurred less frequently in large clusters >6400m. In addition, the NFT often occurred in larger regularly distributed clusters than the Aβ deposits. The location, size, and distribution of the clusters of Aβ deposits and NFT supports the hypothesis that AD is a 'disconnection syndrome' in which degeneration of specific cortico-cortical and cortico-hippocampal pathways results in synaptic disconnection and the formation of clusters of NFT and Aβ deposits. © 2011 Nova Science Publishers, Inc.

Cortical 3D face and object recognition using 2D projections

Empirical studies concerning face recognition suggest that faces may be stored in memory by a few canonical representations. In cortical area V1 exist double-opponent colour blobs, also simple, complex and end-stopped cells which provide input for a multiscale line/edge representation, keypoints for dynamic feature routine, and saliency maps for Focus-of-Attention.

Astrocytes refine cortical connectivity at dendritic spines.

During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines.

Anticipatory Planning Reveals Segmentation of Cortical Motor Output During Action Observation

It has been argued that the variation in brain activity that occurs when observing another person reflects a representation of actions that is indivisible, and which plays out in full once the intent of the actor can be discerned. We used transcranial magnetic stimulation to probe the excitability of corticospinal projections to 2 intrinsic hand muscles while motions to reach and grasp an object were observed. A symbolic cue either faithfully indicated the required final orientation of the object and thus the nature of the grasp that was required, or was in conflict with the movement subsequently displayed. When the cue was veridical, modulation of excitability was in accordance with the functional role of the muscles in the action observed. If however the cue had indicated that the alternative grasp would be required, modulation of output to first dorsal interosseus was consistent with the action specified, rather than the action observed-until the terminal phase of the motion sequence during which the object was seen lifted. Modulation of corticospinal output during observation is thus segmented-it progresses initially in accordance with the action anticipated, and if discrepancies are revealed by visual input, coincides thereafter with that of the action seen.

Paired associative transcranial alternating current stimulation increases the excitability of corticospinal projections in humans

Many types of non-invasive brain stimulation alter corticospinal excitability (CSE). Paired associative stimulation (PAS) has attracted particular attention as its effects ostensibly adhere to Hebbian principles of neural plasticity. In prototypical form, a single electrical stimulus is directed to a peripheral nerve in close temporal contiguity with transcranial magnetic stimulation delivered to the contralateral primary motor cortex (M1). Repeated pairing of the two discrete stimulus events (i.e. association) over an extended period either increases or decreases the excitability of corticospinal projections from M1, contingent on the interstimulus interval. We studied a novel form of associative stimulation, consisting of brief trains of peripheral afferent stimulation paired with short bursts of high frequency (≥80 Hz) transcranial alternating current stimulation (tACS) over contralateral M1. Elevations in the excitability of corticospinal projections to the forearm were observed for a range of tACS frequency (80, 140 and 250 Hz), current (1, 2 and 3 mA) and duration (500 and 1000 ms) parameters. The effects were at least as reliable as those brought about by PAS or transcranial direct current stimulation. When paired with tACS, muscle tendon vibration also induced elevations of CSE. No such changes were brought about by the tACS or peripheral afferent stimulation alone. In demonstrating that associative effects are expressed when the timing of the peripheral and cortical events is not precisely circumscribed, these findings suggest that multiple cellular pathways may contribute to a long term potentiation-type response. Their relative contributions will differ depending on the nature of the induction protocol that is used.

Interhemispheric inhibition of corticospinal projections to forearm muscles

OBJECTIVE: Interhemispheric inhibition (IHI) is typically examined via responses elicited in intrinsic hand muscles. As the cortical representations of proximal and distal muscles in the upper limb are distinguished in terms of their inter-hemispheric projections, we sought to determine whether the IHI parameters established for the hand apply more generally.

METHODS: We investigated IHI at 5 different conditioning stimulus (CS) intensities and a range of short-latency inter-stimulus intervals (ISIs) in healthy participants. Conditioning and test stimuli were delivered over the M1 representation of the right and left flexor carpi radialis respectively.

RESULTS: IHI increased as a function of CS intensity, and was present for ISIs between 7 and 15ms. Inhibition was most pronounced for the 10ms ISI at all CS intensities.

CONCLUSIONS: The range of parameters for which IHI is elicited in projections to the forearm is similar to that reported for the hand. The specific utility lies in delineation of stimulus parameters that permit both potentiation and attenuation of IHI to be assessed.

SIGNIFICANCE: In light of evidence that there is a greater density of callosal projections between cortical areas that represent proximal muscles than between those corresponding to distal limb muscles, and in view of the assumption that variations in functional connectivity to which such differences give rise may have important implications for motor behavior, it is critical to determine whether processes mediating the expression of IHI depend on the effector that is studied. This issue is of further broad significance given the practical utility of movements generated by muscles proximal to the wrist in the context of upper limb rehabilitation.

Characteristics of Corticospinal Projections to the Intrinsic Hand Muscles in Skilled Harpists.

The process of learning to play a musical instrument necessarily alters the functional organisation of the cortical motor areas that are involved in generating the required movements. In the case of the harp, the demands placed on the motor system are quite specific. During performance, all digits with the sole exception of the little finger are used to pluck the strings. With a view to elucidating the impact of having acquired this highly specialized musical skill on the characteristics of corticospinal projections to the intrinsic hand muscles, focal transcranial magnetic stimulation (TMS) was used to elicit motor evoked potentials (MEPs) in three muscles (of the left hand): abductor pollicis brevis (APB); first dorsal interosseous (FDI); and abductor digiti minimi (ADM) in seven harpists. Seven non-musicians served as controls. With respect to the FDI muscle–which moves the index finger, the harpists exhibited reliably larger MEP amplitudes than those in the control group. In contrast, MEPs evoked in the ADM muscle–which activates the little finger, were smaller in the harpists than in the non-musicians. The locations on the scalp over which magnetic stimulation elicited discriminable responses in ADM also differed between the harpists and the non-musicians. This specific pattern of variation in the excitability of corticospinal projections to these intrinsic hand muscles exhibited by harpists is in accordance with the idiosyncratic functional demands that are imposed in playing this instrument.

Cortical origin of functional recovery in the somatosensory cortex of the adult mouse after thalamic lesion

Résumé L'accident vasculaire cérébral sensoriel pur est un des syndromes lacunaires, dû à l'occlusion de petits vaisseaux cérébraux, souvent dans le cadre d'une lésion intéressant le noyau ventro-caudal du thalamus. Il produit un hémisyndrome sensitif pur, et parfois un syndrome douloureux se développe à distance de l'événement aigu. Afin d'étudier la récupération fonctionnelle dans le cortex somatosensoriel (SI) après une telle lésion dans le thalamus, un modèle de lésion excitotoxique a été développé dans le système somatosensoriel de la souris adulte, caractérisé par la présence de formations cytoarchitectoniques dans SI appelées "tonneaux". Chacun de ces tonneaux correspond à la représentation corticale d'une vibrisse du museau. L'activité métabolique a été mesurée dans SI à différents intervalles après la lésion, à l'aide de déoxyglucose marqué radioactivement. Dans les deux premiers jours suivant celle-ci, l'activité métabolique diminue de manière importante dans toutes les couches corticales, avec une atteinte plus marquée dans la couche IV, principale projection des axones thalamo-corticaux. Une récupération de l'activité métabolique se produit ensuite, d'autant plus marquée que le délai après la lésion est grand. Cette récupération s'observe dans toutes les couches coticales, les couches I et Vb récupérant plus rapidement que les couches II, III, IV, Va et VI. Cinq semaines après la lésion, l'absence des vibrisses correspondant à la partie déafférentée de SI diminue l'activité métabolique corticale de 32% et démontre l'activation par la périphérie de cette partie de l'écorce, malgré la perte des axones thalamo-corticaux provenant du noyau ventro-caudal. Des expériences de traçage rétrograde ont montré une augmentation des projections intracorticales sur la partie déafférentée de l'écorce, en particulier de longue distance, ainsi que des projections interhémisphériques, mais n'ont pas permis de mettre en évidence de nouvelle projection thalamique, indiquant une origine corticale à la récupération fonctionnelle observée. Abstract To study the degree and time course of the functional recovery in the somatosensory cortex (SI) after an excitotoxic lesion in the adult mouse thalamus, metabolic activity was determined in SI at various times points post lesion. Immediately after the lesion, metabolic activity in the thalamically deafferented part of SI was at its lowest value but increased progressively at subsequent time points. This was seen in all cortical layers, however, layers I and Vb recover more rapidly than layers II, III, IV, Va and VI. Removal of the mystacial whiskers corresponding to the deafferented area, 5 weeks after cortical recovery, produced a subsequent 32% drop in metabolic activity, demonstrating peripheral sensory activation of this part of the cortex. Tracing experiments revealed that the deafferented cortex did not receive a novel thalamic input, but cortico-cortical and contralateral barrel cortex projections to this area were reinforced. We conclude that the cortical functional recovery after a thalamic lesion is, at least partially, due to modified cortico-cortical and callosal projections to the deafferented cortical area.

Origine des projections sensorimotrices dans des sous-régions du cortex moteur primaire chez le singe capucin.

Certaines études ont démontrés que les connexions entre l’aire prémotrice ventrale (PMv) et la région de la main du cortex moteur primaire (M1) sont distribuées non-uniformément, ciblant des sous-régions spécifiques dans M1. Dans la présente étude nous avons voulu développer ces résultats en étudiant la distribution au sein de M1 des projections corticales issues de PMv, l’aire prémotrice dorsale (PMd), l’aire motrice supplémentaire (SMA) et les aires pariétales 1, 2 et 5. Pour se faire, nous avons combiné des approches électrophysiologiques et anatomiques chez trois singes naïfs du Nouveau Monde (Cebus apella) pour examiner l’organisation et la spécificité topographique des projections corticales dans M1. Nos résultats indiquent que quatre sous-régions à l’intérieur de la région dédiée à la main reçoivent des inputs prédominants de différentes aires sensorimotrices. Ces résultats suggèrent que des sous-régions de M1 puissent avoir des fonctions spécifiques pour le contrôle moteur de la main et des doigts.

Horizontal projections of area 17 in Cebus monkeys: metric features, and modular and laminar distribution

Metric features and modular and laminar distributions of intrinsic projections of area 17 were studied in Cebus apella. Anterogradely and retrogradely labeled cell appendages were obtained using both saturated pellets and iontophoretic injections of biocytin into the operculum. Laminar and modular distributions of the labeled processes were analyzed using Nissl counterstaining, and/or cytochrome oxidase and/or NADPH-diaphorase histochemistry. We distinguished three labeled cell types: pyramidal, star pyramidal and stellate cells located in supragranular cortical layers (principally in layers IIIa, IIIb α, IIIb ß and IIIc). Three distinct axon terminal morphologies were found, i.e., Ia, Ib and II located in granular and supragranular layers. Both complete and partial segregation of group I axon terminals relative to the limits of the blobs of V1 were found. The results are compatible with recent evidence of incomplete segregation of visual information flow in V1 of Old and New World primates.