Imaging of early brain injury and cortical plasticity

The human brain undergoes complex organizational changes during development in and ex utero. Pathogenic events affecting the developing brain cause abnormalities or lesions, the patterns of which depend on the stage of brain development. During the first and second trimester, cortical neurogenesis predominantly takes place, characterized by proliferation, migration, and organization of neuronal cells. Brain pathology is characterized by maldevelopments. During the third trimester, growth and differentiation events are predominant, which persist into postnatal life. Disturbances of brain development during this period mainly cause lesions. During the early third trimester, periventricular white matter is especially affected, whereas toward the end of the third trimester, gray matter, either cortical or deep gray matter, appears to be more vulnerable. These patterns of brain maldevelopments or lesions offer excellent models to study mechanisms of organization and reorganization in the developing brain. Evidence for superior brain plasticity is well established for language function after early left-sided lesions. Some evidence exists for higher compensatory potential within in the motor system; maintenance of ipsilateral tracts seems to play a certain, but only incomplete functional role after unilateral lesions in early and mid gestation. The visual system seems to have limited compensatory potential.     

Language disorder in a child with early left thalamic lesion

In this paper we present the case of a child with early left thalamic vascular damage who subsequently developed a language disorder. At 3 years and 8 months, her language was poor and unintelligible and showed phonetic, phonological and morpho-syntactic disorders. She did not exhibit any signs of mental retardation. After specific speech therapy, she improved in all linguistic skills. Given the lack of reports on thalamic lesions in children, this paper describes the effect of a thalamic injury in the earliest phases of language acquisition in a child who showed consistent phonological disorders. This case seems to confirm early hemispheric specialisation and the importance of a timely therapy.     

Behavioral recovery and anatomical plasticity in adult rats after cortical lesion and treatment with monoclonal antibody IN-1

We have previously reported that monoclonal antibody (mAb) IN-1 treatment after ischemic infarct in adult rats results in significant recovery of skilled forelimb use. Such recovery was correlated with axonal outgrowth from the intact, opposite motor cortex into deafferented subcortical motor areas. In the present study, we investigated the effects of mAb IN-1 treatment after adult sensorimotor cortex (SMC) aspiration lesion on behavioral recovery and neuroanatomical plasticity in the corticospinal tract. Adult rats underwent unilateral SMC aspiration lesion and treatment with either mAb IN-1 or a control Ab, or no treatment. Animals were then tested over a 6-week period in the skilled forelimb use task and the skilled ladder rung walking task. We found that animals treated with mAb IN-1 after SMC lesion fully recovered the use of forelimb reaching, but showed no improvement in digit grasping as tested in the skilled forelimb use task. The mAb IN-1 treatment group was also significantly improved as compared to control groups in the skilled ladder rung walking test. Furthermore, neuroanatomical tracing revealed a significant increase in the corticospinal projections into the deafferented motor areas of the spinal cord after mAb IN-1 treatment. These results indicate that treatment with mAb IN-1 after cortical aspiration lesion induces remodeling of motor pathways resulting in recovery in only certain behavioral tasks, suggesting that the cause of brain damage influences behavioral recovery after mAb IN-1 treatment.     

Repeated measurements of contrast sensitivity reveal limits to visual plasticity after early binocular deprivation in humans

Contrast sensitivity improves in visually normal children until 7 years of age and is impaired in children who experienced early visual deprivation from bilateral congenital cataracts. Here, we investigated whether the deficits after early visual deprivation change during childhood by retesting the contrast sensitivity of seven patients treated for bilateral congenital cataract who had been first tested before 7.5 years of age, and of two patients first tested after 11 years of age. For the younger group, contrast sensitivity at low spatial frequencies improved after 1- and 2-year intervals, while their sensitivity at mid and high spatial frequencies did not change. There was no systematic change in the two older patients. The results indicate that early visual input sets up the neural substrate for later improvement in contrast sensitivity at mid and high spatial frequencies. However, there is sufficient plasticity during middle childhood to allow some recovery at low spatial frequencies. The results shed new light on the role of early visual experience and the nature of developmental plasticity.     

Electrophysiological analysis of motor cortical plasticity after cortical lesions in newborn rats

Intracortical microstimulation of the motor cortex in normal adult rats evoked low threshold contralateral forelimb movements and high threshold ipsilateral movements. Ablation of the opposite sensorimotor cortex in adult animals did not alter these thresholds. However, stimulation of the unablated hemisphere in adult rats that sustained unilateral sensorimotor cortical lesions as neonates elicited low threshold ipsilateral forelimb movements that were similar to contralateral movements. These low threshold ipsilateral movements may be mediated via aberrant corticofugal pathways which are known to develop following neonatal cortical lesions.     

Radixin expression in microglia after cortical stroke lesion

Stroke induces extensive tissue remodeling, resulting in the activation of several cell types in the brain as well as recruitment of blood‐borne leucocytes. Radixin is part of a cytoskeleton linker protein family with the ability to connect transmembrane proteins to the actin cytoskeleton, promoting cell functions involving a dynamic cytoskeleton such as morphological changes, cell division and migration which are common events of different cell types after stroke. In the healthy adult brain radixin is expressed in Olig2⁺ cells throughout the brain and in neural progenitor cells in the subventricular zone. In the current study, we detected a 2.5 fold increase in the number of radixin positive cells in the peri‐infarct cortex two weeks after the induction of cortical stroke by photothrombosis. Similarly, the number of Olig2⁺ cells increased in the peri‐infarct area after stroke; however, the number of radixin⁺/Olig2⁺ cells was unchanged. Neural progenitor cells maintained radixin expression on their route to the infarct. More surprising however, was the expression of radixin in activated microglia in the peri‐infarct cortex. Seventy percent of Iba1⁺ cells expressed radixin after stroke, a population which was not present in the control brain. Furthermore, activation of radixin was predominantly detected in the peri‐infarct region of oligodendrocyte progenitors and microglia. The specific location of radixin⁺ cells in the peri‐infarct region and in microglia suggests a role for radixin in microglial activation after stroke.     

Temporal profile of ultrastructural changes in cortical neurons after a photochemical lesion

A photochemical lesion was induced in the right sensory motor cortex of rat brains. We examined at various time points the occurrence of different types of neuronal death with respect to a potential therapeutic window. The lesion appearance was documented by magnetic resonance imaging, and functional recovery was evaluated by behavioral tests showing recovery at 48 hr after lesioning. At 0.5, 1, 3, 6, 12, 24, 48, and 72 hr postlesion, cortical layers IV and V were examined by light and electron microscopy. Ultrastructural changes, which corresponded well to light microscopy findings, were found in both hemispheres. In the lesioned area, the neuropil appeared disorganized at 0.5 hr, and apoptotic and necrotic cell death was found at 0.5-3 hr. After 3 hr, the tissue was disintegrated. On the contralateral side, chromatin clumping appeared at 0.5-3 hr. At 3 hr, ruptured membranes were found, a sign of irreversible cell death. At 6-72 hr, the membranes were intact, and the chromatin was not clumped but heterogeneously distributed. The nuclei contained dispersed nucleoli at 48-72 hr. The morphology correlated well with magnetic resonance images and functional behavior. Our study demonstrates that a photochemical lesion is a useful model for studying morphological changes in injured cells. It results in a permanent infarction within 3 hr. In that the morphology on the contralateral side drastically changed between 3 and 6 hr, the cellular alterations at these time points might represent a break point at which cells either progress toward cell death or recover.     

Enlargement of cortical vibrissa representation in the surround of an ischemic cortical lesion

It has been shown that cortical lesions are associated with an increase of excitability in surrounding brain regions, and with a downregulation of GABA(A) receptors. In the present study we investigated whether this increased excitability affects the cortical map of inputs represented in areas surrounding the lesioned brain area. Focal lesions with a diameter of 2-2.5 mm were induced photochemically in the hindlimb area at the border of the primary somatosensory cortex of the rat. One week after lesioning, the cortical representation of the B3 vibrissa was studied using 14C-deoxyglucose (DG) autoradiography. In all animals mechanical stimulation of the B3 vibrissa produced a column-shaped DG-labeling in the somatosensory cortex, corresponding to the B3-barrel with a maximum of the glucose uptake in layer IV. In control animals without cortical lesions (n=6), stimulation increased the glucose uptake rate by 50.8+/-10.5% in layer IV. In lesioned animals (n=6) maximum DG-uptake in layer IV (54.8+/-8.6%) did not differ significantly from that in controls. However, as compared to control animals, lesioned animals showed also increased glucose uptake within the activated column in layers II/II (51.+/-11.1%, lesioned animals; 31.8+/-11.2%, controls; P<0.05, lesioned vs. control) and V (47.5+/-5.8%, lesioned animals, 28.8+/-10.5%, controls; P<0.05, lesioned vs. control). The diameter of the metabolically activated B3-barrel area of layer IV was expanded from 461.8+/-77.6 microm in control animals to 785.5+/-103.6 microm; P<0.01) in lesioned animals. Lesioned animals also showed expansion of the activated area in layers II/III (890.4+/-134.8 microm, lesioned animals; 430.6+/-95.1 microm, controls; P<0.01) and layer V (1117.5+/-163.6 microm, lesioned animals; 648.7+/-114.1 microm, controls; P<0.01). The depth profile of the activation columns showed a maximum in layer IV in control animals, which was expanded towards layers II/III and layer V in lesioned animals. It is concluded that cortical lesions alter the representational area of neighboring afferent inputs through disinhibition or 'unmasking' of pre-existing silent or ineffectual intracortical synapses. The present observations raise the possibility that the brain supports recovery from lesions by decreasing GABAergic inhibition, thereby facilitating a remapping of the cortical representation in neighboring brain areas.     

MHC class I expression and synaptic plasticity after nerve lesion

An axon lesion to a bulbar or spinal motoneuron is followed by a typical retrograde response at the cell body level, including the removal or 'stripping' of synapses from the perikaryon and dendrites of affected cells. Both activated microglia and astrocytes have been attributed roles in this process. The signalling pathways for this 'synaptic stripping' have so far been unknown, but recently a classical set of immune recognition molecules, the MHC class I molecules, have been shown to have a strong influence on the strength and pattern of the synapse elimination response. Thus, when MHC class I signalling is severely impaired in mice lacking the MHC class I subunit beta2-microglobulin (beta2m) and transporter associated with antigen processing 1 (TAP 1) genes, both of which are necessary for surface expression of MHC class I, there is a stronger elimination of synapses from injured neurons, with the surplus elimination directed towards clusters of putatively inhibitory synapses. Moreover, the regenerative capacity of motoneurons in such mice is lower than in wild-type animals. The expression of MHC class I, as well as MHC class I-related receptors in both neurons and glia, lend support to a hypothesis that classical immune recognition signalling between neurons and glia underlie part of the 'stripping' response.     

Developmental plasticity after right hemispherectomy in an epileptic adolescent with early brain injury

Objectives The authors present the case of an adolescent affected with refractory epilepsy due to a neonatal ischemic infarction of the right medial cerebral artery. Hemiplegic since the first months of life, she began presenting motor partial seizures associated with drop attacks at 4.5 years; these were initially well controlled by antiepileptic drugs, but at 10 years seizures appeared again and became refractory. Thus, at 14 years and 10 months, she was submitted to a right hemispherectomy that made her rapidly seizure free. In the post-surgical follow-up lasting 5 years, neuropsychological serial assessments showed an impressive progressive improvement of cognitive skills, namely, visuospatial abilities. This case seems to challenge the widely spread feeling that functional catch-up in brain-injured children could only occur early in life. In effect, the astonishing recovery especially of visuospatial skills in our case occurred in adolescence after a late surgical intervention of right hemispherectomy.Methods Different neuropsychological aspects are discussed. The reorganisation process recovered the spatial and linguistic abilities as well as the verbal and visuospatial memory; however, there was a persistent impairment of complex spatial and perceptual skills as well as recall abilities. Despite the deficit of complex visual stimuli processing, the patient showed a good performance in the recognition of unknown faces.Conclusions Probably, the absence of seizures in the first 4 years of life could have allowed a generally adequate compensatory reorganisation, successively masked by the persistent and diffuse epileptic disorder. The seizure control produced by surgery eventually made evident the effectiveness of the brain reorganisation.     

What's to lose and what's to learn: development under auditory deprivation, cochlear implants and limits of cortical plasticity

Sensory and environmental manipulations affect the development of sensory systems. Higher-order auditory representations (auditory categories or “objects”) evolve with experience and via top–down influences modify representations in early auditory areas. During development of a functional auditory system, the capacity for bottom–up reorganizations is successively less well expressed due to a molecular change in synaptic properties. It is, however, complemented by top–down influences that direct and modulate the residual (adult) capacity for circuit reorganization. In a deprived condition, this developmental step is substantially affected. As higher-order representations cannot be established in absence of auditory experience, the developmental decrease in capacity for “bottom–up regulated” reorganizations (as repeatedly demonstrated in also in deprived sensory systems) cannot be complemented by an increasing influence of top–down modulations. In consequence, the ability to learn is compromised in sensory deprivation, resulting in a sensitive period for recovery.     

Effect of early cortical lesion on the acute model of epilepsy

The experiments were performed in order to investigate the sparing of function following early postnatal cortical lesion in the acute rat model of epilepsy. Sensomotor cortex was unilaterally removed at 9 and 10 days of postnatal age in lesioned animals, while control animals were only sham operated (at the same early stage of life) or non-operated (before implantation of the electrodes). Seizure activity was recorded by means of electroencephalograms at adult stage of life induced by parenteral administration of penicillin (1 000 000 I.U./kg, i.p.). Our results showed that when the cortical lesion was performed in infancy (on the contrary to the lesion performed in adulthood) there was no prolongation of seizure activity in an acute model of epilepsy.     

Compensatory and transneuronal plasticity after early collicular ablation

Plasticity within the visual system was assessed in the quokka wallaby following unilateral superior collicular (SC) ablation at postnatal days (P) 8-10, prior to the arrival of retinal ganglion cell (RGC) axons. At maturity (P100), projections were traced from the eye opposite the ablation, and total RGC numbers were estimated for both eyes. Ablations were partial (28-89% of SC remaining) or complete (0-5% of SC remaining). Projections to the visual centers showed significant bilateral (P < 0.05) increases in absolute volume. Minor anomalous projections also formed within the deep, surviving non-retino-recipient layers of the ablated SC and via a small bundle of RGC axons recrossing the midline to innervate discrete patches in the SC contralateral to the lesion. Total absolute volume of projections did not differ between partial and complete ablations; moreover, values did not differ from normal (P > 0.05). Compared with normal, total RGC numbers were significantly (P < 0.05) reduced in the eye opposite the ablation but increased (P < 0.05) in the other eye. Consequently, the sum of the two RGC populations did not differ from normal (P > 0.05). As in rodents, the visual system in quokka compensates following injury by maintaining a set volume of arborization but does so by forming only minor anomalous projections. Furthermore, increased RGC numbers in the eye ipsilateral to the lesion indicate that compensation occurs transneuronally, thus maintaining total numbers of projecting neurons. The implication is that the visual system acts in concert following unilateral injury to maintain set values for RGC terminal arbors as well as their cell bodies.     

Discourse plasticity in children after stroke: age at injury and lesion effects

Studies of children with stroke indicate remarkable recovery of language after some initial delay. However, complex language abilities as measured by discourse (connected language) may be required to detect the full impact of stroke on subsequent cognitive-linguistic development. This study examined discourse ability in children with stroke as compared with orthopedic controls, age-at-injury, and lesion effects. Discourse between two groups of children was compared [stroke (n = 17) vs orthopedic control (n = 17)]. The stroke group was subdivided into early age at stroke (<1 year) and late age at stroke (>1 year). The discourse samples were analyzed along two dimensions: language and information structure. Results revealed that the stroke group performed at significantly lower levels than the orthopedic control group across discourse measures. The most important finding was a poorer outcome for early age at stroke as compared with later age at stroke. These findings alter the widespread belief of optimistic language outcomes after childhood stroke. Interestingly, no site or size-of-lesion effects, common to adult stroke, were identified. These findings identify poor long-term outcome with early brain insults at stages far removed from the onset of injury. The implication is that childhood stroke management should be revised to provide protracted follow-up and treatment.     

Adaptive cortical plasticity in higher visual areas after acute optic neuritis

The ability to distinguish adaptive cortical reorganization may help to target future therapeutic strategies after neurological insult. We investigated cortical plasticity by prospectively applying visual functional magnetic resonance imaging (fMRI) and optic nerve MRI to 20 patients with acute optic neuritis at baseline, 1, 3, 6, and 12 months. We performed three types of correlation analyses to investigate the relationships between fMRI activity, clinical function, and optic nerve structure. The first analysis directly correlated the fMRI response to clinical function or optic nerve structure and found dynamic relations especially within the first 3 months. The second analysis used a novel technique that modeled the fMRI response and optic nerve structure together with clinical function, to determine the contribution fMRI made to clinical function after accounting for structural factors. Significant effects were found at baseline only, within the right peristriate cortex, and bilaterally in the lateral occipital complexes, which are normally involved in higher order visual processing. The third analysis investigated the relation between the modeled visual recovery rate and fMRI response but found no significant effects. The key findings of this study are from the second analysis and suggest a genuine adaptive role for cortical reorganization within extrastriate visual areas early after optic neuritis.     

Reduced plasticity of cortical whisker representation in adult tenascin-C-deficient mice after vibrissectomy

The effect of the extracellular matrix recognition molecule tenascin-C on cerebral plasticity induced by vibrissectomy was investigated with 2-deoxyglucose (2DG) brain mapping in tenascin-C-deficient mice. Unilateral vibrissectomy sparing row C of vibrissae was performed in young adult mice. Two months later, cortical representations of spared row C vibrissae and control row C on the other side of the snout were visualized by [(14)C]2DG autoradiography. In both wild-type and tenascin-C-deficient mice, cortical representation of the spared row was expanded in all layers of the barrel cortex. However, the effect was significantly more extensive in wild-type animals than in the mutant. Elimination of tenascin-C by genetic manipulation thus reduces the effect of vibrissectomy observed in the somatosensory cortex. No increase in number of fibres in the vibrissal nerve of spared vibrissae was seen, and occurrence of additional nerve to the spared follicle was very rare. Thus, in tenascin-C-deficient mice functional plasticity seems to be impaired within the CNS.