Recovery of fine motor performance after ischemic damage to motor cortex is facilitated by cell therapy in the rhesus monkey

Abstract

We investigated the efficacy on recovery of function following controlled cortical ischemia in the monkey of the investigational cell drug product, CNTO 0007. This drug contains a cellular component, human umbilical tissue-derived cells, in a proprietary thaw and inject formulation. Results demonstrate significantly better recovery of motor function in the treatment group with no difference between groups in the volume or surface area of ischemic damage, suggesting that the cells stimulated plasticity.     

Dynamics of the activity of the postural asymmetry factor after unilateral damage to the motor area of the cortex

The authors studied the time-course of functional rearrangements of the segmental apparatus after unilateral injury of the rat motor cortex. It was found that one day after injury the postural asymmetry of the hind limbs was fixed by the lumbal region of the spinal cord. This functional state of the segmental apparatus lasted 10 days after injury in the presence of the maximal activity of postural asymmetry factor (PAF) in the CSF and increasing activity of the factor in the brain tissue. Recovery of the segmental apparatus to symmetrical function by the end of the third week following injury was accompanied by PAF inactivation.     

Recovery after damage to motor cortical areas

Until recently, the neural bases underlying recovery of function after damage to the cerebral cortex were largely unknown. Recent results from neuroanatomical and neurophysiological studies in animal models have demonstrated that after cortical damage, long-term and widespread structural and functional alterations take place in the spared cortical tissue. These presumably adaptive changes may play an important role in functional recovery.     

Correlation of the rat behavior after immobilization with structural reorganization in the motor cortex

Behavioral changes and accompanying morphological neuron-glia reorganization in the rat brain were compared after emotional stress. Wistar rats (n = 20) were stressed by the interrupted immobilization, which was carried out during one week 7-8 h daily. Behavioral immobilization of rats was accompanied by an increase in horizontal and vertical locomotors activity and in duration of the III and IV phases of grooming ("comfortable" grooming) in the "open field" test. The morphometric studies showed a statistically significant increase in the density of hypoxic neurons in the right neocortex of the experimental animals as compared with control. Hypoxic changes in neurons were of functional character. Experimental rats can be considered as a model of redistribution of functional brain activity with preferential intensification of the left brain hemisphere.     

Neuronal organization of field 4 of the motor cortex of the cat brain

By means of the silver nitrate impregnation method after Golgi-Kopsch in kittens and young cats the field 4 in the cerebral motor cortex has been studied. The motor cortex of the field 4 possesses certain heteromorphism. Besides usual stellate and pyramidal neurons, that differ from real ones by some morphological signs: their body is often round, the apical dendrite is much thinner than the corresponding dendrite of a pyramidal neuron, it does not produce oblique branches along the course, never gets into the I layer, the spines arrange less densely. According to the mode of dendrites setting off, the atypical pyramidal neurons can be divided into multipolar and spindle-like with horizontal or vertical branching of the dendrites. According to the spines distribution, the multipolar atypical neurons can be divided into spinous, rare-spinous and aspinous. With respect to various cellular forms and distribution of various types of neurons in layers, every of the areas (gamma, alpha, sfu, fu) possesses specific peculiarities. The greatest variability of the neurons have the field 4 gamma and 4 alpha, where, besides stellate and pyramidal, atypical neurons can be found. The stellate neurons of the field 4 gamma are characterized with a deep arrangement, their number is essentially less, than in other areas of the field 4. In the field 4 alpha they are situated in the layers II-III. Suprafundal and fundal parts of the field do not possess pyramidal atypical neurons and are characterized with presence of large amount of the stellate neurons. In respect to the axonal branching in the suprafundal part of the field 4, 2 types of the stellate cells are distinguished.     

Assembly organization of the motor region of the cerebral cortex in adult humans

Field IV and adjacent areas of fields VI, VI op, VI p of the human brain cortex were examined. Frontal, sagittal, tangential sections stained after the techniques of Nissle, Brachet, Klüver--Barer, Cajal and Peters demonstrated the motor cortex to contain a great number of local, with rare overlapping, groups of cellular columns, each of them being surrounded with a peculiar vessel-fibrillar capsule. A morphological unit resulted from topographic interdependens of neurons, vessels and fibres is considered as a neuronal assembly which occupies in the cortical space a figure of truncated upset cone or cylinder. Neuronal assemblies are distributed along radiate fibres and radial vessels, do not form regularly alternated raws, central axis of every assembly is perpendicular to the tangent line drawn in the given point of the cortical surface.     

Synchronization of electrical field potentials in neocortex of rat after isolation of a cortex island in the contralateral brain hemisphere

A correlation between the number of boutons and synchronization of electrical activity in two sites of the intact right somatosensory cortex of rats was anakyzed at different stages of axonal sprouting elicited by isolation of a cortex slab in the left cortex. Time delay between the development of epileptiform field potentials in two sites of intact cortex located at a distance of 4 mm from each other was determined as a parameter of synchronization. The analysis was carried out in 30 and 90 days after the complete isolation of the neural island in a symmetrical site of the contralateral cortex. Epileptiform activity was induced by penicillin. A significant increase in the number of boutons in the II and V layers of the intact cortex observed 90 days after the isolation of neural island in a symmetrical site of the cortex corresponded to a significant decrease in the delay of electrical activity development. Similar effects were observed in the V layer of the island 30 days after the isolation. The results suggest that the cortex lesion activates formation of new synaptic boutons in a contralateral site and increases a degree of synchronization of electrical activity, which may affect the epileptogenesis. The data suggest that pyramids of the III and, most probably, V layers form a neuronal network in the rat neocortex thus providing synchronization of epileptiform field potentials.     

Effect of damage to the parietal associative cortex on the function of acquired motor coordination in dogs

The effect of ablation of the parietal associative cortex on the performance of a complex food instrumental reaction was studied in dogs. The reaction consisted in two movements of the forelimb which were of similar pattern, but differed by their coordination. The first one was the lifting and holding of the paw at a required level for a required time, with the head in natural position (lifted), and the second one was the same movement of the paw with the head bent down for feeding, i.e. a new coordination, for the natural coordination consists in lowering of the forelimb associated with lowering of the head. During two sessions after the lesion, both reactions became irregular (so that the dogs performed only one of two movements or none). In the course of four months, the precision of the first movement was reduced, the amplitude of lifting the paw and duration of holding it were diminished. The new coordination persisted after ablation of the parietal associative cortex, though the holding (fixation) of the paw was less perfect. As was shown before by one of the present authors (M. E. Ioffe), lesion of the sensorimotor cortex resulted in profound disturbance of acquired coordination.     

Tangential organization of the infragranular fiber plexus in rat cerebral cortex

Cylindrical lesions (diameter 300-500 microns) were formed by poking needles into various parts of the cerebral cortex of adult albino rats. Degenerating axons were visualized in horizontal sections through the 'flattened' cortex using the silver impregnation method of Gallyas et al. [Stain Technol. 55: 291-297 (1980)] which stains degenerating axoplasm. The density and distribution of tangentially oriented axons were evaluated in the infragranular layers by TV image analysis. The sampling fields were concentrically arranged around the lesion at distances of 200, 400, 700 and 1,100 microns. The results indicate that the distribution patterns of degenerating (associational) axons covary with the cytoarchitectonic regions into which the lesions were placed. In the motor cortex, the majority of axons run in the antero-posterior direction. The density is generally lower around lesions in frontal regions than in parietal regions. The most extended degeneration was found around lesions near the border of or within the retrosplenial cortex, indicating an exceptionally strong internal connectivity in this area. Since only few degenerating axons were seen around lesions in the center of area 17, the high density of myelinated axons in the primary visual cortex seems to be due to fibers that originate in peristrate areas. It is concluded that the number and extension of fibers that degenerate tends to covary with some aspects of cortical architecture, but it is not area-specific.     

Functional organization of adult motor cortex is dependent upon continued protein synthesis

The functional organization of adult cerebral cortex is characterized by the presence of highly ordered sensory and motor maps. Despite their archetypical organization, the maps maintain the capacity to rapidly reorganize, suggesting that the neural circuitry underlying cortical representations is inherently plastic. Here we show that the circuitry supporting motor maps is dependent upon continued protein synthesis. Injections of two different protein synthesis inhibitors into adult rat forelimb motor cortex caused an immediate and enduring loss of movement representations. The disappearance of the motor map was accompanied by a significant reduction in synapse number, synapse size, and cortical field potentials and caused skilled forelimb movement impairments. Further, motor skill training led to a reappearance of movement representations. We propose that the circuitry of adult motor cortex is perpetually labile and requires continued protein synthesis in order to maintain its functional organization.     

Neurons and their synaptic organization in the visual cortex of the rat

Summary Cells in the visual cortex (area 17) of adult rats were impregnated by the rapid Golgi method and characterized by light microscopy. Selected cells were then sectioned for electron microscopy and their cytological characteristics and the pattern of synapses on their cell bodies and dendrites were studied Twelve classical pyramidal cells from layers II–VI, two pyramid-like cells from layer VI, two inverted pyramidal cells from layers V and VI, ten spine-free non-pyramidal cells from layers II–VI and two spinous non-pyramidal cells from layer IV were examined.The cytoplasmic features of the identified cells, where these could be discerned, corresponded to those previously reported for the different cell types in conventionally prepared tissue. Pyramidal Cells received exclusively type 2 synaptic contacts on their cell bodies, type 1 contacts on their dendritic spines and a mixture of synaptic types (type II predominating) on their shafts, where synaptic density was relatively low. This pattern of synaptic contacts was consistent for all portions of the dendritic tree; inverted pyramidal cells and pyramid-like cells showed the same synaptic organization as classical pyramids. The axon collaterals of pyramidal cells established type I contacts with dendritic spines (or, rarely, shafts) of unknown origin. Non-Pyramidal Cells received both type 1 and type 2 contacts (the former predominating) on their cell bodies and dendrites. The spinous variety also received type I contacts on their dendritic spines. Axon terminal of spine-free non-pyramidal cells established type II synaptic contacts with dendritic shafts of unknown origin. The similarity in synaptic organization between the spine-free and spinous non-pyramidal cells examined in this study suggest that the latter correspond to the sparsely spinous stellate cells rather than to the spinous stellate cells of cat and monkey visual cortex.We thank the Medical Research Council for financial support