Developmental neuropathology and impact of perinatal brain damage. III: gray matter lesions of the neocortex.

The evolving neuropathology of primarily undamaged cortical regions adjacent to the injured site has been studied in 36 infants who survived a variety of perinatally acquired encephalopathies (microgyrias, ulegyrias, multicystic encephalopathies, porencephalies, and hydranencephalies) and later died of unrelated causes. Their survival times range from hours, days, weeks, or months, to several years. Ten of these children developed epilepsy, 2 developed cerebral palsy, and several were neurologically and mentally impaired. In all cases studied, the undamaged cortex adjacent to the injured site survives, retains its intrinsic vasculature, and is capable of continuing differentiation. However, its postinjury development is characterized by progressive alterations compatible with acquired cortical dysplasia that affects the structural and functional differentiation of its neurons, synaptic profiles, fiber distribution, glial elements, and vasculature. The synaptic profiles of many neurons are transformed by an increased number of intrinsic loci that replace extrinsic ones vacated by the destruction of afferent fibers. The intrinsic fibers of layer I and some Cajal-Retzius cells survive even in severe lesions and may be capable of interconnecting cortical regions that have lost other type of connections. Some intrinsic neurons undergo postinjury structural and functional hypertrophy, acquire new morphologic and functional features, and achieve a large size (meganeurons). Probably, these meganeurons acquire their structural and functional hypertrophy by partial endomitotic DNA and/or RNA reduplication (polyploidy). These postinjury alterations are not static but ongoing processes that continue to affect the structural and functional differentiation of the still developing cortex and may eventually influence the neurologic and cognitive maturation of affected children. This study proposes that, in acquired encephalopathies, the progressive postinjury reorganization of the undamaged cortex and its consequences (acquired cortical dysplasia), rather than the original lesion, represent the main underlying mechanism in the pathogenesis of ensuing neurological sequelae, such as, epilepsy, cerebral palsy, dyslexia, cognitive impairment, and/or poor school performance.     

Recovery of forepaw gripping ability and reorganization of cortical motor control following cervical spinal cord injuries in mice

Previous studies using a grip strength meter (GSM) revealed a loss of gripping ability following cervical hemisection injuries in mice, followed by partial recovery. Here, we assess whether normal gripping ability and the recovered gripping ability after cervical hemisection depend on the cerebral cortex. First, we assessed grip strength of both forepaws of 18-week-old C57Bl/6 mice before and after a left sensorimotor cortex lesion or right lateral hemisection at C5. Both lesions led to a complete loss of gripping ability by the right forepaw and caused only minor deficits in the left. After cortical lesions, gripping ability re-appeared at about 17 days post-injury, and grip strength recovered to near-normal levels by 24 days post-injury. After C5 hemisections, gripping ability re-appeared after 31 days post-injury in 50% of the mice. Follow-up experiments were then carried out in which 10-week-old mice received C4 hemisection injuries and were tested for 28 days; then mice received secondary lesions of the sensorimotor cortex ipsi- or contralateral to the hemisection. Younger mice with cervical hemisections recovered gripping ability between 12 and 28 days post-hemisection. Cortical lesions on the side contralateral to the hemisection led to a complete loss of recovered gripping ability in all mice; cortical lesions on the side ipsilateral to the hemisection also disrupted recovered gripping ability in some animals. Surprisingly, lesions of the cortex ipsilateral to the hemisection did not impair gripping ability of the contralateral (left) forepaw. Finally, we assessed the effects of a third lesion of whichever side of the sensorimotor cortex remained, so that the sensorimotor cortex was ablated bilaterally. Remarkably, gripping function by the forepaw contralateral to the original hemisection was completely unaffected, and the recovered gripping function by the forepaw ipsilateral to the hemisection was disrupted in only some of the animals. These results indicate a substantial reorganization of motor control of gripping function after cervical injuries in mice so that gripping ability by both forepaws becomes largely independent of cortical control.     

Hyperexcitability of intact neurons underlies acute development of trauma-related electrographic seizures in cats in vivo

Cortical trauma can lead to development of electrographic paroxysmal activities. Current views of trauma-induced epileptogenesis suggest that chronic neuronal hyperexcitability and extensive morphological reorganization of the traumatized cortex are required for the generation of electrographic seizures. However, the mechanisms responsible for the initiation of electrographic seizures shortly after cortical injury are poorly understood. Here we show that, in the experimental model of partially deafferented (undercut) cortex, an increase in intrinsic and synaptic excitability of neurons in areas adjacent to the undercut cortex is sufficient for the generation of electrographic paroxysmal activity within few hours after partial cortical deafferentation. Locally increased and spatially restricted neuronal excitability arose from the increased incidence of intrinsically bursting neurons, enhanced intrinsic and synaptic neuronal responsiveness, and slight disinhibition. These mechanisms only operate in neurons located in the vicinity of partially deafferented sites because, after the cortical injury, partially deafferented neurons are mostly silent and hypoexcitable. Our results suggest that trauma-induced electrographic seizures first arise in cortical fields that are closest to the site of injury and such seizures do not require long-term neuronal reorganization.     

Intracellular calcium signals in the surround of rat visual cortex lesions

Focal lesions of the visual cortex induce deafferentiation, excitotoxic cell death as well as functional reorganization in the surrounding tissue. The intracellular second messenger calcium is involved in a wide range of cellular responses including excitotoxicity and functional reorganization following cortical injuries. We investigated the intracellular calcium concentration [Ca2+]i in neurons of the visual cortex using fluorescence imaging of fura-2 signals in a slice preparation obtained from lesioned and sham-operated cortices. We observed an increase in resting and stimulus evoked [Ca2+]i in the surround of the lesion, which were mediated by NMDA and non-NMDA ionotropic glutamate receptors. This increase in [Ca2+]i might be an important factor for lesion-induced functional reorganization in the rat visual cortex.     

Evidence for the inhibitory neurotransmitter gamma-aminobutyric acid in aspiny and sparsely spiny nonpyramidal neurons of the turtle dorsal cortex

In order to learn more about the anatomical substrate for gamma-aminobutyric acid (GABA)-mediated inhibition in cortical structures, the intrinsic neuronal organization of turtle dorsal cortex was studied by using Golgi impregnation, immunohistochemical localization of GABA and its synthetic enzyme glutamic acid decarboxylase (GAD), and histochemical localization of the presynaptic GABA-degrading enzyme GABA-transaminase (GABA-T). GABAergic markers are found in neurons identical in morphology and distribution to Golgi-impregnated aspiny and sparsely spiny nonpyramidal neurons with locally arborizing axons and appear to label most if not all of the nonpyramidal neurons. In addition, the GABAergic markers are found in punctate structures in a distribution characteristic of presumed inhibitory terminals. The spine-laden pyramidal neurons, the principal projecting cell type in the dorsal cortex, are devoid of labelling for GABAergic markers but are surrounded by presumed GABAergic terminals. The data complement previous physiological and ultrastructural studies that implicate aspiny and sparsely spiny nonpyramidal neurons as mediators of intrinsic inhibition of pyramidal neurons in turtle cortex. The results also suggest similarities in the functional organization of intrinsic inhibitory elements in turtle and mammalian cortex.     

Abnormal development of the human cerebral cortex: genetics, functional consequences and treatment options

Genetic studies have identified several of the genes associated with malformations of cortical development which might disrupt each of the main stages of cell proliferation and specification, neuronal migration and late cortical organization. The largest malformation groups, focal cortical dysplasia, heterotopia and polymicrogyria, express different perturbations of these stages and carry a variable propensity for lacking activation, preservation or reorganization of cortical function and for atypical cortical organization. Some patients have obvious neurological impairment, whereas others show unexpected deficits that are detectable only by screening. Drug-resistant epilepsy is frequent but might be amenable to surgical treatment. However, the epileptogenic zone might include remote cortical and subcortical regions. Completeness of resection, a key factor for successful surgery, might be difficult, especially in proximity to eloquent cortex. Surgical planning should be based on assessments of structural imaging and of the major functions relevant to the area in question in any such patient.     

Complete reorganization of the motor cortex of adult rats following long‐term spinal cord injuries

Understanding brain reorganization following long‐term spinal cord injuries is important for optimizing recoveries based on residual function as well as developing brain‐controlled assistive devices. Although it has been shown that the motor cortex undergoes partial reorganization within a few weeks after peripheral and spinal cord injuries, it is not known if the motor cortex of rats is capable of large‐scale reorganization after longer recovery periods. Here we determined the organization of the rat (Rattus norvegicus) motor cortex at 5 or more months after chronic lesions of the spinal cord at cervical levels using intracortical microstimulation. The results show that, in the rats with the lesions, stimulation of neurons in the de‐efferented forelimb motor cortex no longer evokes movements of the forelimb. Instead, movements of the body parts in the adjacent representations, namely the whiskers and neck were evoked. In addition, at many sites, movements of the ipsilateral forelimb were observed at threshold currents. The extent of representations of the eye, jaw and tongue movements was unaltered by the lesion. Thus, large‐scale reorganization of the motor cortex leads to complete filling‐in of the de‐efferented cortex by neighboring representations following long‐term partial spinal cord injuries at cervical levels in adult rats.     

Progress in clinical neurosciences: stroke recovery and rehabilitation

BACKGROUND: Recent literature has provided new insights into the role of rehabilitation in neurological recovery post-stroke. The present review combines results of animal and clinical research to provide a summary of published information regarding the mechanisms of neural recovery and impact of rehabilitation. METHODS: Plasticity of the uninjured and post-stroke brain is examined to provide a background for the examination of brain reorganization and recovery following stroke. SUMMARY AND CONCLUSIONS: Recent research has confirmed many of the basic underpinnings of rehabilitation and provided new insight into the role of rehabilitation in neurological recovery. Recovery post stroke is dependent upon cortical reorganization, and therefore, upon the presence of intact cortex, especially in areas adjacent to the infarct. Exposure to stimulating and complex environments and involvement in tasks or activities that are meaningful to the individual with stroke serves to increase cortical reorganization and enhance functional recovery. Additional factors associated with neurological recovery include size of stroke lesion, and the timing and intensity of therapy.     

Inhibitory dendrite dynamics as a general feature of the adult cortical microcircuit

The mammalian neocortex is functionally subdivided into architectonically distinct regions that process various types of information based on their source of afferent input. Yet, the modularity of neocortical organization in terms of cell type and intrinsic circuitry allows afferent drive to continuously reassign cortical map space. New aspects of cortical map plasticity include dynamic turnover of dendritic spines on pyramidal neurons and remodeling of interneuron dendritic arbors. While spine remodeling occurs in multiple cortical regions, it is not yet known whether interneuron dendrite remodeling is common across primary sensory and higher-level cortices. It is also unknown whether, like pyramidal dendrites, inhibitory dendrites respect functional domain boundaries. Given the importance of the inhibitory circuitry to adult cortical plasticity and the reorganization of cortical maps, we sought to address these questions by using two-photon microscopy to monitor interneuron dendritic arbors of thy1-GFP-S transgenic mice expressing GFP in neurons sparsely distributed across the superficial layers of the neocortex. We find that interneuron dendritic branch tip remodeling is a general feature of the adult cortical microcircuit, and that remodeling rates are similar across primary sensory regions of different modalities, but may differ in magnitude between primary sensory versus higher cortical areas. We also show that branch tip remodeling occurs in bursts and respects functional domain boundaries.     

Reduced somatostatin-like immunoreactivity in cerebral cortex in nonfamilial dysphasic dementia

A nonfamilial syndrome is described in two middle-aged men who presented with progressive aphasia without incipient signs of cognitive impairment. In each case, 2 years elapsed before progressive functional decline or behavioral disabilities supervened. Radiologic studies documented asymmetric left cerebral atrophy that was progressive. The structure of the language disintegration was distinctive and not like that in Alzheimer's disease. Pathologic studies performed at postmortem examination of one patient documented asymmetric cerebral atrophy with nonspecific histopathologic changes. Biochemical studies revealed normal tissue levels of choline acetyltransferase activity, but reduced somatostatin-like immunoreactivity. Since cerebral somatostatin is largely present in intrinsic cortical neurons, while cholinergic innervation is largely derived from the basal forebrain, these findings suggest that nonfamilial dysphasic dementia may be an example of a distinct class of dementia due to intrinsic cortical degeneration, with sparing of the basal forebrain.     

PET measures of benzodiazepine receptors in progressive supranuclear palsy

OBJECTIVE: To evaluate the integrity of neurons containing benzodiazepine receptors in metabolically affected regions of the brain in patients with clinically diagnosed progressive supranuclear palsy (PSP). METHODS: The cerebral distribution of [11C]flumazenil (FMZ), a ligand that binds to the gamma-aminobutyric acid A (GABAA) receptor, and [18F]fluorodeoxyglucose (FDG), a measure of local cerebral glucose metabolism, was determined with PET in 12 patients with PSP and 10 normal control subjects. Tracer kinetic analysis was applied to quantify data and analysis was performed using three-dimensional stereotactic surface projections and stereotactically determined volumes of interest. RESULTS: There was a global reduction in FMZ binding of 13%, with a reduction in the anterior cingulate gyrus of 20% (p = 0.004), where glucose metabolic rates also showed the greatest reduction. CONCLUSIONS: PSP causes loss of benzodiazepine receptors in the cerebral cortex. Consistent with postmortem studies, the authors did not find significant changes in FMZ binding in subcortical nuclei that exhibit the most pathologic change. This study suggests that both loss of intrinsic neurons containing benzodiazepine receptors and deafferentation of the cerebral cortex from distant brain regions contribute to cerebral cortical hypometabolism in PSP.     

Organization of corticospinal neurons in the monkey

The retrograde axonal transport method has been employed to identify the cell bodies of cortical neurons projecting directly to the spinal cord in the monkey. The investigation has focused on aspects of the laminar, columnar, and somatotopic organization of corticospinal neurons within each of the cytoarchitectural and functional subdivisions of the sensorimotor cortex. The principle findings of these experiments are that: (i) cortical regions containing cell bodies of corticospinal neurons are the first motor cortex (area 4), the first somatic sensory cortex (areas 3a, 3b, 1, and 2), and part of the immediately adjacent posterior parietal cortex (area 5), the second somatic sensory cortex, the supplementary motor cortex (the medial aspect of area 6), and the medial part of the posterior parietal cortex in a region termed the supplementary sensory area; (ii) corticospinal neurons display a somatotopic organization within each of these functional subdivisions of the sensorimotor cortex; (iii) all corticospinal neurons arise from layer V of the cortex; and (iv) corticospinal neurons within the first motor and first somatic sensory cortex oftern occur in clusters, perhaps reflecting a columnar organization in the sensorimotor cortex. These findings demonstrate the origins of the corticospinal system to be more extensive than previously recognized and show that a number of common features characterize the organization of corticospinal neurons in all cortical areas. Across cortical subdivisions, however, major differences exist in the extent of spinal segmental representations, in the manner in which corticospinal neurons occur in groups, and in the numerical density and sizes of corticospinal neurons. These aspects of the organization of the corticospinal system presumably reflect specialization of the different cortical areas in spinal cord sensory and motor control.     

Reorganization of visual cortical maps after focal ischemic lesions.

Plasticity after central lesions may result in the reorganization of cortical representations of the sensory input. Visual cortex reorganization has been extensively studied after peripheral (retinal) lesions, but focal cortical lesions have received less attention. In this study, we investigated the organization of retinotopic and orientation preference maps at different time points after a focal ischemic lesion in the primary visual cortex (V1). We induced a focal photochemical lesion in V1 of kittens and assessed, through optical imaging of intrinsic signals, the functional cortical layout immediately afterwards and at 4, 13, 33, and 40 days after lesion. We analyzed histologic sections and evaluated temporal changes of functional maps. Histological analysis showed a clear lesion at all time points, which shrank over time. Imaging results showed that the retinotopic and orientation preference maps reorganize to some extent after the lesion. Near the lesion, the cortical retinotopic representation of one degree of visual space expands over time, while at the same time the area of some orientation domains also increases. These results show that different cortical representations can reorganize after a lesion process and suggest a mechanism through which filling-in of a cortical scotoma can occur in cortically damaged patients.     

Cortical plasticity and motor activity studied with transcranial magnetic stimulation

For decades cortical representations of the parts of the body have been considered to be unchangeable. This view has changed radically during the past 20 years using new tools designed to study plasticity in the adult human brain. Transcranial magnetic stimulation (TMS) is a valuable non-invasive technique for exploring the ability of the motor cortex to change during motor skill acquisition. Results obtained with TMS in neurological patients as well as in normal subjects demonstrate that cortical plasticity is a necessity for correct adaptation to the continuously changing environment. Topographical reorganization of the motor cortex depends on the types of movements performed by the subjects. During simple training, the cortical representation is enlarged, and it returns to its initial size when the task is overlearned. These transient modifications characterize simple motor training. Motor skills in which coordination of distal and proximal muscles, precision of the task and spatio-temporal constraints are associated, has a different impact on cortical reorganization. We propose that years of practice of a complex motor skill induces a new cortical topography that must be interpreted as structural plasticity which provides the capacity to execute a plastic behaviour instead of a stereotypical movement. We review the neuronal mechanisms underlying plasticity in different types of movement. We stress new emerging notions, such as overlap of cortical maps, and system dynamics at single neuron and network levels, to explain the reorganization of movement representations that encode motor skill. Dendritic arborizations as functional computing elements, newly generated neurons in adult brain, and plastic architectures of cortical networks operating as distributed functional modules are new hypotheses for structural plasticity.     

Is essential tremor a Purkinjopathy? The role of the cerebellar cortex in its pathogenesis

Essential tremor (ET) encompasses a group of progressive neurological diseases in which the primary clinical feature is kinetic tremor of the arms. There is accumulating evidence to suggest that the cerebellum is involved in the pathogenesis of ET; the clinical presentation, neurophysiological data, and functional and metabolic abnormalities revealed by neuroimaging studies all point toward the dysregulation of cerebellar circuits. Recent neuropathological findings at postmortem demonstrate that Purkinje neurons, and some brainstem neurons, play an integral role in the pathogenesis of this common neurological disorder. The assessment of Purkinje cell linear density shows that Purkinje density is abnormal in ET brains. Specific efforts need be devoted to understanding the molecular and cellular events occurring in the Purkinje neurons of the cerebellar cortex, which are emerging as being of particular importance in the pathogenesis of ET in a subgroup of patients. © 2013 International Parkinson and Movement Disorder Society.     

A novel phosphodiesterase type 4 inhibitor, HT-0712, enhances rehabilitation-dependent motor recovery and cortical reorganization after focal cortical ischemia

Rehabilitation-dependent motor recovery after cerebral ischemia is associated with functional reorganization of residual cortical tissue. Recovery is thought to occur when remaining circuitry surrounding the lesion is "retrained" to assume some of the lost function. This reorganization is in turn supported by synaptic plasticity within cortical circuitry and manipulations that promote plasticity may enhance recovery. Activation of the cAMP/CREB pathway is a key step for experience-dependent neural plasticity. Here we examined the effects of the prototypical phosphodiesterase inhibitor 4 (PDE4) rolipram and a novel PDE inhibitor (HT-0712), known to enhance cAMP/CREB signaling and cognitive function, on restoration of motor skill and cortical function after focal cerebral ischemia. Adult male rats were trained on a skilled reaching task to establish a baseline level of motor performance. Intracortical microstimulation was then used to derive high-resolution maps of forelimb movement representations within the caudal forelimb area of motor cortex contralateral to the trained paw. A focal ischemic infarct was created within approximately 30% of the caudal forelimb area. The effects of administering either rolipram or the novel PDE4 inhibitor HT-0712 during rehabilitation on motor recovery and restoration of movement representations within residual motor cortex were examined. Both compounds significantly enhanced motor recovery and induced an expansion of distal movement representations that extended beyond residual motor cortex. The expansion beyond the initial residual cortex was not observed in vehicle injected controls. Furthermore, the motor recovery seen in the HT-0712 animals was dose dependent. Our results suggest that PDE4 inhibitors during motor rehabilitation facilitate behavioral recovery and cortical reorganization after ischemic insult to levels significantly greater than that observed with rehabilitation alone.     

The role of visual experience in the cortical topographic map reorganization following retinal lesions

The mature visual cortex is capable of reorganizing its functional connections in response to retinal injuries. Although this phenomenon is well established, there are a number of unresolved issues. This paper will review some of the more critical aspects of adult plasticity including those based on our most recent findings. Our preliminary data indicate that a large-scale reorganization of cortical maps following retinal injuries may require an increase in synaptic strengths at key cortical sites promoted by long-term, repeated use.     

Reductions in corticotropin releasing factor-like immunoreactivity in cerebral cortex in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy

Dementias occurring in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy are associated with dysfunction and death of neurons in a variety of cell populations, including cholinergic, monoaminergic, and peptidergic systems. In the present investigation of these three disorders, we demonstrated decreased levels of corticotropin releasing factor (CRF)-like immunoreactivity in the frontal, temporal, and occipital poles of the neocortex. Moreover, reductions in peptidergic immunoreactivity correlated with reductions in the activity of choline acetyltransferase, the enzyme that catalyzes the formation of acetylcholine. The reduction in cortical CRF levels may be due to abnormalities of intrinsic cortical neurons or to dysfunction in neurons that contain CRF and innervate cortex.     

Neuronal populations stained with the monoclonal antibody Cat-301 in the mammalian cerebral cortex and thalamus

The monoclonal antibody Cat-301 was used to examine neurons in the cerebral cortex and dorsal thalamus of several mammalian species, including Old World monkeys, cats, bush babies, guinea pigs, and rats. In each species, subpopulations of cortical and thalamic neurons are stained along the surfaces of their somata and proximal dendrites. Cat-301-positive cortical neurons include specific groups of pyramidal cells (e.g., corticospinal but not corticobulbar or callosal neurons in the monkey sensory-motor areas) and certain GABA-immunoreactive nonpyramidal cells. In the thalamus, the relay neurons projecting to the cortex and not the intrinsic neurons are stained. The Cat-301-positive neurons are nonhomogeneously distributed in the cat and monkey cortex and thalamus. In the cortex, they are densely packed in 2 bands that in most areas include layers III and V, but that in primary sensory areas include layers IV and VI. Because the density of stained neurons, their distribution, and the intensity of their staining vary among cortical areas, the borders between neighboring areas can often be detected by the differences in Cat-301 staining. Broader, regional differences are also readily apparent, for areas in the parietal and occipital lobes contain large numbers of intensely stained cells, but most areas in the frontal and temporal lobes contain fewer, more lightly stained neurons. The same broad differences are seen within the thalamus: only those nuclei reciprocally connected with intensely stained cortical areas contain large numbers of Cat-301-positive neurons. Differences among species include variations in cell density and distribution when a given cortical area or thalamic nucleus is compared between cats and monkeys. Greater differences are seen among the other species. Immunoreactive neurons in the cerebral cortex are sparse and lightly stained in guinea pigs, are restricted to the hippocampal formation in rats, and are very rare and isolated in bush babies. Similarly, Cat-301-positive thalamic neurons are restricted to only one or 2 nuclei in the guinea pig and rat and are extremely rare in the bush baby. Cat-301 stains organized groups of neurons in the cat and monkey cortex and thalamus. In addition to the laminar organization of stained cells in all cortical areas (see above), the Cat-301-positive neurons of monkey areas 17 and 18 are grouped into radial arrays. In area 17, clusters of stained cells are present in layers above and below layer IVC. These clusters lie at the centers of ocular dominance columns, within patches stained for cytochrome oxidase (CO). Most of these cells are also GABA-immunoreactive.(ABSTRACT TRUNCATED AT 400 WORDS)