Recovery from early cortical damage in rats. I. Differential behavioral and anatomical effects of frontal lesions at different ages of neural maturation

Rats with complete removal of the cortex anterior to bregma in adulthood (frontal cortex) were compared behaviorally and neuroanatomically to rats with similar removals at 1, 5, or 10 days of age. The age at which animals received the cortical excision made a significant difference with respect to the development of the thalamus and the remaining cortex as well as the behavioral outcome in adulthood. There was a direct relationship between cortical thickness in adulthood and the age at surgery: the earlier the lesion the thinner the cortex. Part of this anatomical effect was acute, and could be observed within 24 h of surgery, but the major reduction in thickness was not observed until adolescence. Behaviorally, the animals were administered several tests including tongue extension, grooming, beam walking, swimming, and a spatial navigation task. Like the cortical measurements, the behavioral measurements showed a clear relationship between age at surgery and behavioral outcome: the earlier the lesion in infancy, the greater the behavioral impairments. Thus, whereas rats with lesions at 10 days of age showed behavioral sparing, relative to adult operates, on every measure, rats with lesions at 5 days of age performed at about the level of adult operates on most tests and rats with lesions at 1 day had more extensive behavioral impairments than all other groups. These results imply that the effects of cortical injury in infancy are tightly correlated with the precise level of neural maturation at the time of lesion.     

Recovery from early cortical lesions in rats. III. Neonatal removal of posterior parietal cortex has greater behavioral and anatomical effects than similar removals in adulthood

The behavioral, anatomical, and electrophysiological effects of posterior parietal cortex lesions (Krieg's area 7) were compared in rats with removals at 1, 5, or 10 days of age or in adulthood. Behaviorally, the animals were administered several tests including grooming, beam walking, swimming, the Morris water task and a radial arm maze. Lesions at 10 days of age permitted behavioral sparing on most behavioral tasks, whereas lesions at 1 or 5 days of age allowed little sparing and even produced larger deficits than observed in adult operates on some tasks. Anatomical measures showed a direct relationship between cortical thickness and age of lesion: the earlier the lesion, the thinner the cortex. An analysis of postsurgical changes in cortical thickness showed only a small reduction in cortical thickness shortly after the lesions, with the major reduction occurring during adolescence. Electrophysiological recordings of cortical activity showed that rats with 1-day lesions had abnormal neocortical atropine-resistant activity and had an increased incidence of seizures. The results suggest that the neocortex of the rat may be particularly sensitive to perinatal injury.     

Earlier is not always better: behavioral dysfunction and abnormal cerebral morphogenesis following neonatal cortical lesions in the rat

Rats with lesions of the medial frontal, ventral frontal or posterior parietal cortex in adulthood were compared behaviorally and neuroanatomically in adulthood with rats with similar removals at 7 days of age. The neonatal lesions altered cortical morphogenesis, especially in the ventral frontal and parietal groups, in which there was a marked thinning of remaining cortex distal to the lesion site. Behavior was assessed on an extensive battery of sensorimotor and maze-learning tests. Although there was sparing of function on some tests, the overall result was very little sparing on sensorimotor tests and only partial sparing on tests of maze learning in the frontal groups. The parietal neonates showed sparing on only one sensorimotor task and, in addition, showed unexpected deficits on sensorimotor and maze-learning tasks that were not observed in the adult operates. The results suggest that there may be more localization of function in the infant cortex than is generally believed and that early cortical damage may produce different behavioral effects than similar damage in adulthood.     

Recovery from early cortical damage in rats. II. Effects of experience on anatomy and behavior following frontal lesions at 1 or 5 days of age

Perinatal cortical damage is often associated with significant overall shrinkage of the remaining cortex and severe behavioral impairments. Environmental experience was manipulated in order to determine if the anatomical and behavioral effects of neonatal frontal decortication might be attenuated by rearing in a complex environment. Rats received frontal decortication on the day of birth or 5 days later and were subsequently raised, along with littermate controls, in a complex environment or in standard laboratory cages. In adulthood, the animals were tested on a battery of behavioral tests which showed that enrichment markedly attenuated the effects of the early lesions, especially for the 5-day operates, even on tests such as tongue extension that would not be expected to benefit from specific practice in the complex environment. Analysis of the remaining cortex revealed that all groups raised in the complex environment developed thicker cortex, the increase being most dramatic in the rats given lesions at 5 days of age.     

Remote lateralized changes in cortical [3H]spiperone binding following focal frontal cortex lesions in the rat

Positron emission tomography (PET) studies in stroke patients have shown that right hemisphere lesions lead to increases in ipsilateral (compared to contralateral) cortical S2-serotonin receptors, while left hemisphere lesions do not. To assess whether similar lateralized changes in cortical S2-receptors could be demonstrated in response to brain injury in the rat, [3H]spiperone (SP) autoradiography was performed 30 days after unilateral cortical suction lesions. Right lesions produced bilateral increases in total SP binding in frontal cortex (excluding the lesion site): 48% greater than after left lesions, and 23% greater than shams. Left lesions led to bilateral decreases in S2-receptors in the frontal and perirhinal cortex and these decreases were asymmetric. There was a greater decrease in the hemisphere contralateral to the lesion than in the side with the lesion. Frontal S2-receptor binding was positively correlated with running wheel activity in all animals with lesions, regardless of lesion side. These results suggest that there is a lateralized receptor and behavioral response to focal injury in rats, analogous to that previously observed in humans.     

Cognitive outcome of children with epilepsy and malformations of cortical development

OBJECTIVE: To assess intellectual functioning (IQ) in 54 children and adolescents with intractable epilepsy who later underwent cortical resection due to unilateral malformations of cortical development acquired in utero. METHODS: Lesion type was classified into circumscribed mass lesions and diffuse cortical dysplasia based on histopathologic analysis of surgical tissue. Cortical dysplastic lesions were further graded as mild, moderate, or severe according to specific microscopic features. Laterality of lesion was determined through neurologic examination and electrophysiologic and neuroradiologic procedures. Classification of lesion type was corroborated by its significant relationship with other disease-related variables known to be related to clinical severity (age at seizure onset, age at resection, and extent of lesion). RESULTS: Analyses of covariance revealed that circumscribed lesions had a less deleterious effect on nonverbal IQ than did diffuse cortical dysplasia, after controlling for age at seizure onset and extent of lesion. This effect was also found on verbal IQ measures, but only in subjects with right-sided lesions. Subjects with left-sided lesions performed significantly more poorly on verbal IQ measures than those with right-sided lesions. Additionally, younger age at onset and greater extent of lesion were associated with poorer cognitive outcome. CONCLUSIONS: Cortical dysplasia and early left hemisphere lesions have a significantly worse impact on cognitive functioning than circumscribed lesions or right hemisphere developmental lesions in children with epilepsy.     

Comparison of the effects of neonatal and adult medial prefrontal cortex lesions on food hoarding and spatial delayed alternation

Performance in food hoarding, a species-typical task, and spatial delayed alternation, a learning task, was investigated in male rats with bilateral medial prefrontal cortex (mPFC) lesions sustained in adulthood or at the age of 6 days. Animals with adult mPFC lesions hoarded significantly fewer food pellets than their controls. The mPFC lesion effect on hoarding behaviour of the neonatally operated rats was unclear because of the unexpectedly low hoarding score of their controls. In the spatial delayed alternation task, the animals with mPFC lesions in adulthood exhibited a permanent deficit, while the animals with neonatal mPFC lesions showed no significant deficits. It is concluded that a bilateral lesion in adulthood, mainly affecting the frontal area 2 and the dorsal anterior cingulate area of the mPFC, results in a permanent deficit in food hoarding and spatial delayed alternation performance, whereas a similarly restricted mPFC lesion at the age of 6 days shows a complete sparing of the spatial delayed alternation task performance.     

Is there an optimal age for recovery from motor cortex lesions? I. Behavioral and anatomical sequelae of bilateral motor cortex lesions in rats on postnatal days 1, 10, and in adulthood

Rats were given bilateral lesions of the motor cortex on the day of birth (P1), tenth day of life (P10), or in adulthood. They were trained on several motor tasks (skilled forelimb reaching, beam traversing, tongue extension), general motor activity, and a test of spatial learning (Morris water task). Although all lesion groups were impaired at skilled reaching, the P10 group was less impaired than either of the other two lesion groups. Furthermore, on the other motor tests the P10 group did not differ from controls whereas both P1 and adult groups were impaired. Only the P1 lesion group was impaired at the acquisition of the Morris water task. Anatomical analyses revealed that the P1 and P10 rats had smaller brains than the other two groups as well as having a generalized decrease in cortical thickness. Dendritic analysis of layer III pyramidal cells in the parietal cortex revealed a decrease in apical arbor in the lesion groups and an increase in the basilar arbor of the P1 and adult lesion animals. The P1 and adult operated groups showed an increase in spine density in the basilar dendrites of layer V pyramidal cells. Finally, analysis of the pattern of corticospinal projections revealed that the P1 animals had a markedly wider field of corticospinal projection neurons than any of the other groups. The widespread anatomical changes in all lesion groups versus the relatively better behavioral recovery after P10 lesions suggests that day 10 represents an optimal period for adapting to brain damage and subsequent brain reorganization.     

Some effects of commissurotomy on the reinstatement and potentiation of lesion deficits

Two experiments investigated in rats the effects of cutting the corpus callosum after recovery from unilateral cortical lesions that produce transient symptoms of neglect and circling. Side of lesion was also examined. In Expt. I, 60 rats received left or right lesions of parietal, medial frontal, or motor cortex. After one month of testing for visual, auditory and somatosensory responsiveness and for circling, the callosum was cut, and the sequence of measures was repeated. Callosotomy reinstated neglect after recovery from the lesions in the parietal and medial frontal groups, more severely and consistently in the frontal group. Side of lesion made no difference. Circling was predominantly ipsiversive after the cortical lesions, due entirely to the frontal group. Callosum section markedly potentiated contraversive circling in the left parietal group; right parietal animals showed no preference. This was the only hemisphere difference found. Circling remained ipsiversive in medial frontal animals after callosotomy. These circling biases did not diminish in the postcallosotomy period. Expt. II replicated the circling procedures with 58 animals that were given the same unilateral cortical lesions or were unoperated controls. Callosotomy was performed one month postlesion. Again, left parietal animals circled contraversively, and there was no bias in the right parietal group. A left-right difference was also evident in the motor cortex group, left lesions producing contraversive turning. We confirm the reinstatement of neglect from frontal lesions by callosum section previously found in the monkey and show that it also occurs with parietal lesions. While neglect symptoms do not differ after left or right lesions, circling does: left parietal lesions plus callosotomy produce a marked contraversive tendency that may reflect an elemental spatial lateralization.     

Pre- and postnatal FGF-2 both facilitate recovery and alter cortical morphology following early medial prefrontal cortical injury

Rats with either no treatment or administration of exogenous basic fibroblast growth factor (FGF-2) received bilateral medial prefrontal cortical (mPFC) aspiration or sham lesions at postnatal day 3 (P3). FGF-2 was administered either prenatally at embryonic day 15.5 (PreFGF) or, postnatally (PostFGF) for 7 consecutive days beginning 1 day following surgery. As adults, animals were tested behaviorally at spatial navigation (Morris water task), and skilled reaching (Whishaw tray reaching task). Early lesions of the mPFC produced a significant reduction in both brain weight and cortical thickness in adulthood. Behaviorally, mPFC lesions resulted in deficits in the water maze and reaching task. Both pre- and postnatal FGF-2 facilitated recovery in the spatial navigation task. In contrast, FGF-2 was only effective in reducing the deficits in skilled forelimb movements when the FGF was given postnatal (i.e., postsurgery). Prenatal FGF-2 increased brain weight in the lesion animals, whereas postnatal FGF-2 increased cortical thickness in the lesion animals. It thus appears that FGF-2 can facilitate recovery from perinatal cortical injury, whether it is given during the period of neurogeneration (prenatally) or after the injury, although the mechanism of action is likely different for the pre- and postnatal administration.     

Genetic associations between intelligence and cortical thickness emerge at the start of puberty

Cognitive abilities are related to (changes in) brain structure during adolescence and adulthood. Previous studies suggest that associations between cortical thickness and intelligence may be different at different ages. As both intelligence and cortical thickness are heritable traits, the question arises whether the association between cortical thickness development and intelligence is due to genes influencing both traits. We study this association in a longitudinal sample of young twins. Intelligence was assessed by standard IQ tests at age 9 in 224 twins, 190 of whom also underwent structural magnetic resonance imaging (MRI). Three years later at age 12, 177/125 twins returned for a follow‐up measurement of intelligence/MRI scanning, respectively. We investigated whether cortical thickness was associated with intelligence and if so, whether this association was driven by genes. At age 9, there were no associations between cortical thickness and intelligence. At age 12, a negative relationship emerged. This association was mainly driven by verbal intelligence, and manifested itself most prominently in the left hemisphere. Cortical thickness and intelligence were explained by the same genes. As a post hoc analysis, we tested whether a specific allele (rs6265; Val66Met in the BDNF gene) contributed to this association. Met carriers showed lower intelligence and a thicker cortex, but only the association between the BDNF genotype and cortical thickness in the left superior parietal gyrus reached significance. In conclusion, it seems that brain areas contributing to (verbal) intellectual performance are specializing under the influence of genes around the onset of puberty. Hum Brain Mapp 35:3760–3773, 2014. © 2013 Wiley Periodicals, Inc .     

Effects of caudate nuclei or frontal cortical ablations in kittens: Neurology and gross behavior

Kittens with a one-stage ablation by aspiration of the caudate nuclei were compared to kittens with bilateral removal of the frontal cortical regions, sham-operated animals, and intact littermates. Surgery was done between 9 and 36 days of age and more than 50% of the subjects were studied through adulthood. After surgery, most caudate-ablated kittens showed a visual and auditory stereotyped “compulsory approaching syndrome” with exaggerated visual tracking and motor activity. This was similar to, but less marked, than that seen in adults. Other components of the adult syndrome, such as exaggerated forelimb treading, marked purring, rooting, exaggerated tactile approach, and sexual changes, began to appear when the kittens were 3 to 4 months of age and peaked at puberty. Kittens with frontal or sham operations did not significantly show these changes. All subjects with lesions were remarkably free of gross neurologic deficits except for defective paw usage and, in the kittens with the caudate lesion, impoverishment of movement. Both groups with lesions showed a significant delay in the development of the limb contact placing reactions with acaudate kittens showing a longer delay than those with frontal cortex ablations. In brief, neonatal caudatectomy produced qualitative effects similar to those after caudate ablation in adults and, as in the adults, these were different from those resulting from frontal removals. However, there were marked differences in the time course and the magnitude of the effects. At least three variables were found to influence the consequences of neonatal brain damage demonstrated here: Age at surgery, age at testing, and cortical versus subcortical site of the lesion.     

Prefrontal lesion reverses abnormal mesoaccumbens response in an animal model of schizophrenia.

BACKGROUND: A neonatal hippocampal lesion induces postpubertal behavioral alterations resembling phenomena observed in schizophrenia. We have recently reported that nucleus accumbens neurons exhibit altered response to ventral tegmental area activation, but only when animals with this lesion reach adulthood. Because a prefrontal cortical lesion eliminates postpubertal abnormal behaviors in these animals, we investigated whether altered accumbens responses were reversed with this manipulation. METHODS: In vivo intracellular recordings were conducted in accumbens neurons in rats that had received neonatal hippocampal lesions combined with either adult prefrontal cortical lesion or sham treatment. Accumbens response to mesolimbic pathway activation was recorded in these animals. RESULTS: Accumbens neurons from animals with a neonatal hippocampal lesion and an adult prefrontal sham operation still showed altered accumbens response to mesolimbic stimulation. On the other hand, most animals with combined neonatal hippocampal and adult prefrontal lesions exhibited responses similar to those of na?ve animals. CONCLUSIONS: This result suggests that abnormal behaviors in these animals might be related to excessive prefrontal drive of accumbens neurons upon dopamine activation.     

Induction of bilateral plasticity in sensory cortical maps by small unilateral cortical infarcts in rats

Behavioural impairments caused by brain lesions show a considerable, though often incomplete, recovery. It is hypothesized that cortical and subcortical plasticity of sensory representations contribute to this recovery. In the hindpaw representation of somatosensory cortex of adult rats we investigated the effects of focal unilateral cortical lesions on remote areas. Cortical lesions with a diameter of approximately 2 mm were induced in the parietal cortex by photothrombosis with the photosensitive dye Rose Bengal. Subsequently, animals were kept in standard cages for 7 days. On day seven, animals were anaesthetized and cutaneous receptive fields in the cortical hindpaw representations ipsi- and contralateral to the lesion were constructed from extracellular recordings of neurons in layer IV using glass microelectrodes. Receptive fields in the lesioned animals were compared to receptive fields measured in nonlesioned animals serving as controls. Quantitative analysis of receptive fields revealed a significant increase in size in the lesioned animals. This doubling in receptive field size was observed equally in the hemispheres ipsi- and contralateral to the lesion. The results indicate that the functional consequences of restricted cortical lesions are not limited to the area surrounding the lesion, but affect the cortical maps on the contralateral, nonlesioned hemisphere.     

Is there an optimal age for recovery from motor cortex lesions? II. behavioural and anatomical consequences of unilateral motor cortex lesions in perinatal, infant, and adult rats

Purpose: The purpose of this study was to compare the behavioural and anatomical effects of unilateral motor cortex ablation in neonatal, infant, and adult rats. Methods: Rats were given unilateral lesions of the motor cortex on the day of birth (P1), at ten days of age (P10), or in adulthood. They were trained on several motor tasks (skilled forelimb reaching, beam traversing, tongue extension), general motor activity, and a test of spatial learning (Morris water task). Results: Although all lesion groups were equally impaired at skilled reaching with the forelimb contralateral to the lesion, rats with P1 lesions also were impaired at traversing a narrow beam and at learning the Morris task. Gross anatomical analyses revealed that the P1 rats had smaller brains than the other groups, a result that may account for the larger behavioural deficits in the P1 group. Analysis of Golgi-Cox stained neurons showed that relative to control groups, all lesion groups showed an increase in dendritic length in the basilar dendrites of layer III pyramidal cells and, paradoxically a decrease in length of the apical dendrites of the same cells. Conclusions: The bilateral alterations in dendritic organization following the motor cortex lesions suggest that there has been a bilateral reor-ganization of intrinsic cortical connectivity following motor cortex lesions at any age. These alterations in connectivity are likely not identical in the young and adult animals, however, because relative to controls, both the young operated groups, but not the adult group, showed a bilat-eral drop in spine density in the basilar dendrites of layer V pyramidal cells. These findings are discussed with respect to the idea that there may be critical ages in development in which animals can use anatomical modifications to compensate for deficits produced by cortical injury.     

Is there an optimal age for recovery from motor cortex lesions? II. behavioural and anatomical consequences of unilateral motor cortex lesions in perinatal, infant, and adult rats

Purpose: The purpose of this study was to compare the behavioural and anatomical effects of unilateral motor cortex ablation in neonatal, infant, and adult rats. Methods: Rats were given unilateral lesions of the motor cortex on the day of birth (P1), at ten days of age (P10), or in adulthood. They were trained on several motor tasks (skilled forelimb reaching, beam traversing, tongue extension), general motor activity, and a test of spatial learning (Morris water task). Results: Although all lesion groups were equally impaired at skilled reaching with the forelimb contralateral to the lesion, rats with P1 lesions also were impaired at traversing a narrow beam and at learning the Morris task. Gross anatomical analyses revealed that the P1 rats had smaller brains than the other groups, a result that may account for the larger behavioural deficits in the P1 group. Analysis of Golgi-Cox stained neurons showed that relative to control groups, all lesion groups showed an increase in dendritic length in the basilar dendrites of layer III pyramidal cells and, paradoxically a decrease in length of the apical dendrites of the same cells. Conclusions: The bilateral alterations in dendritic organization following the motor cortex lesions suggest that there has been a bilateral reor-ganization of intrinsic cortical connectivity following motor cortex lesions at any age. These alterations in connectivity are likely not identical in the young and adult animals, however, because relative to controls, both the young operated groups, but not the adult group, showed a bilat-eral drop in spine density in the basilar dendrites of layer V pyramidal cells. These findings are discussed with respect to the idea that there may be critical ages in development in which animals can use anatomical modifications to compensate for deficits produced by cortical injury.     

The restricted effects of right-hemisphere lesions after age one; Wechsler test data

The late effects of early and later lateralized brain lesions were studied with the Wechsler intelligence test in 50 patients with unilateral nonprogressive cerebral lesions incurred in infancy or in childhood. Results differed according to age at lesion for right but not left hemisphere patients; patients with right hemisphere lesions after age one had normal Verbal ratings impaired Performance ratings; patients with earlier right hemisphere lesions were impaired on both ratings.     

Effects of one- and two-stage lesions of the posterior hypothalamus on temperature regulation in the rat

Rats received 1-stage bilateral or sequential unilateral (serial) lesions of the posterior hypothalamus and were tested for the ability to regulate body temperature after a lengthy recovery period. The groups with lesion differed from the sham-operated groups in the cold, although not under ambient or warm conditions. The fact that the serial lesion group performed the same as the 1-stage lesion groups in the cold is significant because earlier tests on these same animals revealed much better recovery after serial lesions in swimming, and a partial serial lesion effect in open field performance.     

The behavioral and dendritic growth effects of focal sensorimotor cortical damage depend on the method of lesion induction

Using different models of focal cortical injury in adult rats, the neural structural and behavioral outcomes of unilateral lesions of the forelimb representation of the sensorimotor cortex (SMC) were assessed. Lesions were produced using either electrolytic, aspiration, or combined ('electroaspiration') techniques. Measurements of dendritic arborization in layer V of the motor cortex opposite the lesion revealed a growth of pyramidal neuron dendritic processes following electrolytic lesions in comparison to shams. This effect was not found in either the aspiration or electroaspiration lesion groups. Behaviorally, animals in all lesion groups developed a hyper-reliance on the forelimb ipsilateral to the lesion and proportionate disuse of the contralateral (impaired) forelimb for postural support behaviors. In comparison to sham-operated animals, the initial asymmetries in behaviors expressed during movement were similar between lesion groups, but were less enduring following electrolytic lesions than following aspiration and electroaspiration lesions. Furthermore, both aspiration lesion groups had more prevalent adduction of the impaired forelimb than the electrolytic-only lesion rats. Thus, cortical aspiration resulted in more severe and enduring forelimb impairments than the electrolytic lesions, despite similar lesion sizes, as assessed using cortical volume measures. These findings suggest that the aspiration lesion procedures, at least as performed in the present study, exacerbate the behavioral effects of focal cortical injury and limit compensatory plasticity in the contralateral cortex.     

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.