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The organization of brain areas in functionally connected networks, their dynamic changes, and perturbations in disease states are subject of extensive investigations. Research on functional networks in humans predominantly uses functional magnetic resonance imaging (fMRI). However, adopting fMRI and other functional imaging methods to mice, the most widely used model to study brain physiology and disease, poses major technical challenges and faces important limitations. Hence, there is great demand for alternative imaging modalities for network characterization. Here, we present a refined protocol for in vivo widefield calcium imaging of both cerebral hemispheres in mice expressing a calcium sensor in excitatory neurons. We implemented a stringent protocol for minimizing anesthesia and excluding movement artifacts which both imposed problems in previous approaches. We further adopted a method for unbiased identification of functional cortical areas using independent component analysis (ICA) on resting-state imaging data. Biological relevance of identified components was confirmed using stimulus-dependent cortical activation. To explore this novel approach in a model of focal brain injury, we induced photothrombotic lesions of the motor cortex, determined changes in inter- and intrahemispheric connectivity at multiple time points up to 56 days post-stroke and correlated them with behavioral deficits. We observed a severe loss in interhemispheric connectivity after stroke, which was partially restored in the chronic phase and associated with corresponding behavioral motor deficits. Taken together, we present an improved widefield calcium imaging tool accounting for anesthesia and movement artifacts, adopting an advanced analysis pipeline based on human fMRI algorithms and with superior sensitivity to recovery mechanisms in mouse models compared to behavioral tests. This tool will enable new studies on interhemispheric connectivity in murine models with comparability to human imaging studies for a wide spectrum of neuroscience applications in health and disease., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Unilateral perinatal brain injury may result in recruitment of ipsilateral projections originating in the unaffected hemisphere and development of unilateral spastic cerebral palsy (USCP). The aim of this study was to assess the predictive value of neonatal neuroimaging following perinatal brain injury for recruitment of ipsilateral corticospinal tracts., Method: Neonatal magnetic resonance imaging (MRI) and cranial ultrasound scans of 37 children (20 males, 17 females; median [range] gestational age 36 wks(+4) [26(+6) -42wks(+5) ] and birthweight 2312 g ([770-5230g]) with unilateral perinatal arterial ischaemic stroke (n=23) or periventricular haemorrhagic infarction (n=14) were reviewed and scored for involvement of the corticospinal trajectory. Hand function was assessed using the Assisting Hand Assessment (AHA) and transcranial magnetic stimulation (TMS) was performed (age range 7y 4mo-18y and 7mo) to determine the type of cortical motor organization (normal, mixed or ipsilateral). Neuroimaging scores were used to predict TMS patterns., Results: Eighteen children developed USCP with ipsilateral corticospinal tract projections in 13 children (eight mixed, five ipsilateral). AHA scores decreased with increased ipsilateral projections. Asymmetry of the corticospinal tracts seen on neonatal MRI was predictive of development of USCP and recruitment of ipsilateral tracts (positive and negative predictive value of 73% and 91%)., Interpretation: Neonatal neuroimaging can predict recruitment of ipsilateral corticospinal tracts. Early knowledge of the expected pattern of cortical motor organization will allow early identification of children eligible for early therapy., (© 2013 Mac Keith Press.)

The present study establishes a new mouse model for traumatic brain injury (TBI), using an electromechanically driven linear motor impactor device to deliver a lateral controlled cortical impact (CCI) injury to the sensorimotor cortex. Lesion cavity size was measured, and inter-animal consistency demonstrated, at 14 days post injury. Qualitative information regarding damage progression over time was obtained by scanning with high field magnetic resonance imaging (MRI) at five time points following injury. Functional impairment and recovery were measured with the Rotarod, gridwalk and cylinder tests, and lesion cavity volume was measured post mortem with thionin-stained tissue sections. The study establishes the reliability of a linear-motor based device for producing repeatable damage in a CCI model, demonstrates the power of longitudinal MRI in studying damage evolution, and confirms that a simple battery of functional tests record sensorimotor impairment and recovery.

Introduction: Neuroplasticity is a natural property of the nervous system to change its function and to reorganize due to a lesion or environmental changes. We review some of the main experimental and clinical experiences on cortical sensorimotor plasticity related to central nervous system (CNS) lesions., Development: In the last 10 years increasing interest in neuronal plasticity has been prompted by several important discoveries. Long term potentiation and depression have been described as basic synaptic mechanism mediating functional recovery after CNS lesions, modulated by the up-down regulation of inhibitory-excitatory activity related to GABA, acetylcholine and glutamate between other neurotransmitters. In humans there are evidences from functional reorganization in the affected hemisphere in patients with hemispheric lesions, and the activation of homologues areas in the contralateral healthy hemisphere. Significative changes in the topography of cortical somatosensory and motor maps have been demonstrated using non invasive mapping techniques as multichannel EEG, evoked potential, transcranial magnetic stimulation, functional magnetic resonance imaging and positron emission tomography. Axonal and dendritic sprouting take place in animal models of brain lesions; but effective neural regeneration in the CNS does not seem to be a plausible mechanism for functional restoring., Conclusions: Plastic changes after CNS lesions make it possible the restoration of neurological functions in a high number of patients. It is important now to understand which changes are related to the clinical improvement of patients, and what might be done to promote or facilitate this changes and to inhibit maladaptive phenomena, for the design of rationale therapeutics strategies with modulatory influence on this process.

In recent years, there has been increasing interest in studies of brain plasticity. Although still loosely defined, this term describes the ability of the brain to change. Cortical plasticity encompasses a wide variety of phenomena and mechanisms, including modifications in cortical properties such as strength of internal connections, representational patterns, or neuronal modifications, either morphological or functional (Donoghue et al., 1996). We focus on the description of different ways in which transcranial magnetic stimulation (TMS) can be used to study patterns of reorganization and some of the mechanisms involved in these changes. Correlation between TMS and neuroimaging studies in humans and animal studies addressing similar questions is discussed. It is important to identify in each situation whether plasticity plays a beneficial role or is maladaptive in terms of functional compensation. The understanding of patterns, mechanisms, and functional relevance of cortical plasticity will hopefully lead to the design of effective strategies to enhance plasticity when it is beneficial and to down-regulate it when it is maladaptive. An example of a possible strategy, using TMS, is discussed.

We transplanted the fresh and Iloprost or saline preserved (3 hours) embryonic rat cortical brain tissue into the rats in which the motor cortex had been injured and compared the neurobehavioral and morphological changes. The neurobehavior of the transplanted groups was more significantly improved than that in the injured, untransplanted group. The neurobehavior of the animals of the fresh tissue group and Iloprost preserved group recovered to the preinjurylevel. The survival rate of the Iloprost preserved grafts was 90%, which was higher than that of the saline preserved grafts (P < 0.05). In comparison with the fresh grafts, however, there was no significant difference (P > 0.05). In addition, the growth volume of the Iloprost preserved grafts was more markedly increased than that of the fresh grafts (P < 0.01). We conclude that injured brain may be repaired effectively by transplantation of fetal brain cortex. The Iloprost solution not only maintains of vitality the grafts, but also promotes its survival and growth in the host brain.

Traumatic brain injury (TBI) produces learning and memory impairments in humans. This study investigated the effects of TBI on memory and spatial localization strategies in rats. Prior to TBI, separate groups of rats were trained in an 8-arm radial maze with either all 8 arms baited (Expt. 1) or only 4 of the 8 arms baited (Expt. 2). TBI was produced by a controlled pneumatic impactor striking the entire right sensorimotor cortex of the anesthetized rat. Rats used in Expt. 1 were selected because they did not use a stereotypic response strategy (going to adjacent arms) in performing the maze before injury. After TBI the rats were not different from control rats in the number of working memory (WM) errors made. They did, however, display a distinct propensity to go to adjacent arms, i.e., exhibit stereotypic behavior, with a right-handed (ipsiversive) bias (P < 0.005). After TBI, rats which were trained with only 4 of 8 arms baited committed more reference memory (RM) errors than control rats (P < 0.05). They did not differ from controls on WM errors. Injured rats took longer to re-attain criteria than controls (P < 0.0001). Injured rats also initially displayed a propensity to enter the adjacent arm sequentially before re-attaining criteria. Further analysis indicated that injured rats re-learned the maze with a right-hand bias (P < 0.0001). The results of both experiments suggest that after TBI, rats shifted from an allocentric to an egocentric strategy to re-learn the maze. It was suggested that damage to the parietal cortex may have been responsible for both RM errors and the shift away from an allocentric strategy to an egocentric strategy. Possibly, the ipsiversive (right-hand) bias may be the result of a behaviorally or injury-induced neurochemical asymmetry within the motor system.

Functional recovery after brain damage has been described frequently and different mechanisms have been proposed to account for the observed recovery. One possible mechanism involves the capacity of one part of the brain to take over the function of another. A possible area for this to take place is in the cerebral cortex, where a variety of reorganizational processes have been described after different manipulations. We show in the present study that the forelimb force and response capacity of the rat, which becomes highly impaired after the bilateral ablation of the forelimb primary motor cortex, is recovered when the animals receive an electrical stimulation in the ventral tegmental nucleus contingent to each forelimb response in the task. Microstimulation mapping of the cortical areas adjacent to the forelimb primary motor cortex revealed the appearance of an area located caudolaterally to the forelimb primary motor cortex, where forelimb movements could be evoked in recovered animals but to a lesser extent in non-recovered animals. A positive and significant correlation was observed between the size of the reorganized forelimb area and the behavioral performance of the animals. Ablation of the forelimb reorganized area in recovered animals reinstated the forelimb behavioral impairment, while the same lesion in normal animals had no effect on the behavioral performance. The results indicate that recovery after bilateral forelimb primary motor cortex ablation may be due to the organization of specific adjacent areas in the cortex.

1. We used an in vitro model to explore critical aspects of chronic epileptogenesis. Partial neocortical isolations having intact blood supply were made in rat and guinea pig from postnatal day 7 to 34 and then examined 1 to 150 days later in standard brain slice preparations. 2. The epileptogenic potential of several different types of lesions was assessed. Slices containing transcortical (i.e., gray matter) lesions, with or without a contiguous white matter injury (i.e., "undercut"), developed chronic epileptogenesis after a latency of approximately 1-2 wk, manifested by evoked and spontaneous "interictal" discharges and evoked "ictal" events. The region of hyperexcitability did not extend beyond approximately 2 mm from the chronic transcortical lesion and was rarely observed in slices having only an apparent white matter injury. 3. Multiple recordings and current source density (CSD) analysis identified layer V as the source of the interictal discharge. 4. Significant differences in CSD profiles of the evoked interictal discharge occurred between chronically epileptogenic slices and control (noninjured) slices bathed in the convulsant, bicuculline methiodide, suggesting that mechanisms other than disinhibition must be involved in posttraumatic epileptogenesis. 5. Interictal events were blocked in most but not all chronically injured slices by application of the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonovalerate (D-AP5), suggesting that non-NMDA receptors were predominantly involved in some preparations. 6. This model of chronic epileptogenesis in vitro will be useful in studies relevant to mechanisms of posttraumatic epilepsy in man.

Unilateral damage to the forelimb representation area of the sensorimotor cortex in adult rats increases dendritic arborization of layer V pyramidal neurons of the contralateral homotopic cortex. Arbor size was maximum at approximately 18 d postlesion, following which there was a partial elimination, or pruning, of dendritic processes. These neural changes were closely associated with behavioral events. The overgrowth of dendrites was related in time to disuse of the contralateral (to the lesion) forelimb and over-reliance on the ipsilateral forelimb for postural and exploratory movements. The pruning of dendrites was related to a return to more symmetrical use of the forelimbs. To investigate the possibility that lesion-induced asymmetries in motor behavior contributed to dendritic arborization changes, movements of the forelimb ipsilateral to the lesion were restricted during the period of dendritic overgrowth through the use of one-holed vests. This interfered with the increase in dendritic arborization. In contrast, animals that were allowed to use both forelimbs, or only the forelimb ipsilateral to the lesion, showed the expected increases. When sham-operated rats were forced to use only one forelimb, no significant increases in arborization were found. Therefore, neither a lesion nor asymmetrical limb use alone could account for the dendritic overgrowth--it depended on a lesion-behavior interaction. Furthermore, greater sensorimotor impairments were found when the dendritic growth was blocked, suggesting that the neural growth and/or associated limb-use behavior were related to functional recovery from the cortical damage. Finally, in a second experiment, immobilization of the impaired limb during the pruning period did not prevent the elimination of processes. Thus, the pruning of neural processes was not related simply to the recovery of more symmetrical forelimb use. There may be a period early after brain damage during which marked neural structural changes can occur in the presence of adequate behavioral demand.

Afferent and efferent connections of the transplant, implanted in the previously damaged sensorimotor area of the mature rat cerebral cortex have been studied by means of axonal transport of horseradish peroxidase. For 5 months after transplantation neural axons of the transplant are capable to reach the caudo-putamen and thalamic structures, while connections with the spinal cord are absent. The afferent connections of the transplant are minimal and belong only to the neighbouring areas of the cortex and the caudo-putamen of the recipient brain. Presence of efferent projections to the striate and thalamic structures demonstrates specificity of the projections formed; this can be a morphological base for restoration of the functions lost after the damage of the sensorimotor area of the cortex in mature animals.

Effects of S-adenosyl-L-methionine (SAMe) on deficits in a trained delayed response task or trained hand movement tasks after lesions in bilateral dorsolateral prefrontal cortices or the hand-arm area of the unilateral motor cortex in monkeys were studied. Lesions disturbed the delayed response task or hand movement tasks moderately or severely for 1 week to several months depending on the extent of the lesion and nature of the task. Although treatment with small doses of SAMe (10 mg/kg/day, i.m.) had no effect on these disturbances, treatment with moderate doses of SAMe (20 or 30 mg/kg/day, i.m.) reduced impairments and promoted recovery from both disturbances. Pretreatment with SAMe (30 mg/kg/day, i.m.) facilitated recovery from delayed response task deficits due to administration of reserpine (0.3 mg/kg, i.m.) in monkey with bilateral prefrontal cortical lesions, but not in intact monkey. The data suggest that SAMe improves recovery from behavioral disturbances due to brain damage, and this is partly due to increased monoamine turnover rate.

The distribution of corticopontine projections was studied, primarily with the Fink-Heimer technique, in adult rats which at 2-3 days of age had sustained unilateral sensorimotor (SMC) or occipital (OC) cortical lesions and in animal that had received neonatal hemocerebellar (HCb) lesions singly or in combination with the neonatal SMC or OC lesions. Neonatal left SMC or left HCb lesions induced an anomalous increase in crossed sensorimotor corticopontine (SMP) projections originating from the right SMC. This increase appeared more dense after cortical lesions as compared to cerebellar lesions and appeared more dense in those animals receiving the combined SMC plus HCb lesions. No alterations in the distribution of SMP fibers were observed after neonatal OC lesions nor were any alterations of occipital corticopontine (OP) fibers observed in any of the neonatal lesion groups. The remodelling of right SMP projections after neonatal left SMC lesions demonstrates an interaction between corresponding pathways originating from opposite sides of the brain and which occurs in response to the partial removal of afferents to pontine gray neurons as a result of the SMC lesions. In contrast, the absence of SMP plasticity after OC lesions, and vice versa, demonstrates the absence of plasticity between pathways which differ anatomically and functionally. The substantial neuronal loss which occurs within the right PG after neonatal left HCb lesions is believed to influence the increase in crossed SMP fibers coursing from the right hemisphere to the larger left PG. No increase in crossed OP fibers from the right hemisphere was observed in these animals. The increase in crossed SMP fibers after neonatal SMC lesions combined with neonatal HCb lesions is more dense than found in the single lesion groups. These findings suggest that separate mechanisms of plasticity might be operational for each lesion and that these mechanisms may be additive.

Structural characteristics (survival, growth, connections) have been studied in the transplant of the cerebral cortex tissue in Wistar rat embryos (18-day-old), implanted into the brain of mature rats of the same line at various time after a partial lesion of the sensomotor cortex. In 3-5 months after transplantation the light microscopy methods demonstrate that spatial interconnections of the transplant and the injured brain of the recipient depend on time interval between the cerebral lesion and transplantation of the embryonal nervous tissue. Horseradish peroxidase (HP) is ionophoretically injected into the recipient's cerebral tissue away from the place of transplantation. In the transplant retrogradely labelled HP neurons are revealed. This demonstrates efferent connections of the implanted tissue with the host's brain. Presence of the anterogradely labelled nervous terminals in the transplant tissue demonstrates existence of afferent connections of the transplant with the recipient's tissue. Possible mechanisms of survival, growth and formation of connections of the transplant in the injured brain of the mature animal are discussed.