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OBJECTIVE: Our study is to investigate somatosensory dysfunction in children with spastic cerebral palsy (CP) using magnetoencephalography (MEG) and synthetic aperture magnetometry (SAM). METHODS: Six children with spastic CP and six age- and gender-matched typically developing children were studied using a 275-channel MEG system while their left and right index fingers were stimulated in random order. The latency and amplitude of somatosensory evoked magnetic fields were analyzed at sensor level. The patterns of high-gamma oscillations were investigated with SAM at source level. RESULTS: In comparison to the children with typical development, the latency of the first response of somatosensory evoked magnetic fields (SEFs) in the children with spastic CP was significantly delayed (p<0.05). High-gamma oscillations were identified in the somatosensory cortex in both children with CP and typical developing children. Interestingly, children with spastic CP had significantly higher incidence of ipsilateral activation in the somatosensory cortex following right and left finger stimulation, compared to typically developing children (p=0.05). CONCLUSION: The results suggest that children with spastic CP have a measurable delay of SEFs and high-gamma oscillations. The high rates of ipsilateral cortical activation imply the impairments of functional lateralization in the developing brain. This is the first MEG study to demonstrate abnormal high-gamma oscillations of somatosensory cortices representing the finger in children with spastic CP.

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Spontaneous episodes of spreading depression (SD) originating in multiple sources adjacent to a focal intracerebral hemorrhage (ICH) propagate into brain regions away from the lesion site soon after injury onset. Although these transient depolarizations have not been established in the opposite hemisphere of the swine ICH model, we have reported a diminishing of sensory responsiveness in this homotopic brain region following induction of a unilateral hemorrhage lesion. This study examined whether transient depolarizations exist in this distant brain region contralateral to the ICH site. Electrocorticographic (ECoG) recordings of brain activity were collected bilaterally from the primary somatosensory (SI) cortices of the swine brain prior to and immediately after an intracerebral injection of collagenase or saline or the insertion of the infusion pipette into the SI cortex of the right hemisphere. Transient depolarizations were present in both hemispheres of all the experimental groups. The earliest negative DC potential shifts were observed in the injured SI cortex within the first hour after collagenase injection, as compared to T = 3 h in the saline-injected group and T = 4 h in the infusion pipette only group. In contrast, transient depolarizations were first detected in the left SI cortex contralateral to the lesioned hemisphere within 2 h after collagenase infusion, by T = 4 h after saline infusion and by T = 3 h in the pipette only group. Propagating waves of negative DC potential shifts continued in both brain hemispheres, particularly in the ICH group, throughout the 11-h recording period. This novel finding of recurrent depolarizing waves in the hemisphere contralateral to the injury site prompted us to examine whether corpus callosal connections may play a role in this transhemispheric phenomenon. In a separate group of animals, the corpus callosum was transected prior to acquiring DC potential recordings and collagenase injection. The onset pattern of negative DC shifts in the callosotomized + collagenase-injected group was similar to the collagenase group with an intact corpus callosum. Initial generation of SD in the callosotomized + collagenase-injected group occurred by T = 1 h in the ICH injured right hemisphere and T = 2 h in the contralateral hemisphere. These transient depolarizations also persisted throughout 11-h recording period indicating that the corpus callosal transection did not hinder these remote propagating waves of depolarization. The presence of SD in the SI cortices of both hemispheres in all experimental groups of this study suggests that a focal mechanical or hemorrhagic injury increases the susceptibility of distant ipsilateral and contralateral brain regions to depolarizing perturbations. The mechanism for these transient depolarizations in the contralateral hemisphere apparently does not involve transhemispheric propagation along corpus callosal fibers.

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Injury to the cerebral cortex results in functional deficits not only within the vicinity of the lesion but also in remote brain regions sharing neuronal connections with the injured site. To understand the electrophysiological basis of this phenomenon, we evaluated the effects of a focal intracerebral hemorrhage (ICH) on cortical excitability in a remote, functionally connected brain region. Cortical excitability was assessed by measuring the somatic evoked potential (SEP) elicited by electrical stimulation of the swine snout, which is somatotopically represented in the rostrum area of the primary somatosensory (SI) cortex. The SEP was measured on the SI cortex ipsilateral to the site of ICH and on the contralateral SI cortex during the acute period (< or =11 h) after collagenase-induced ICH. The ICH rapidly attenuated the SEP on the ipsilateral cortex as we reported earlier. Interestingly, the ICH also attenuated the SEP on the contralateral SI cortex. Evoked potentials in the contralateral SI cortex showed a gradual decrease in amplitude during this acute period of ICH. We then investigated whether the interhemispheric connections shared by the contralateral SI and the lesion cortex were responsible for the diminished evoked potentials in the uninjured hemisphere after ICH. A separate group of animals underwent corpus callosal transection prior to electrocorticography (ECoG) recordings and ICH injury. Within hours of hemorrhagic injury, a gradual but marked increase in evoked potential amplitude was observed in the homotopic SI cortex of callosotomized animals as compared to pre-injection recordings. The enhancement suggests that there are additional effects of ICH on remote areas functionally connected to the site of injury. Functional deficits were present in both SI cortices within the first several hours of a unilateral injury indicating that the cessation of brain activity in the lesioned SI is mirrored in the contralateral hemisphere. This electrophysiological depression in the uninjured SI cortex is mediated in part by the interhemispheric connections of the corpus callosum.

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The absence of cortical responses to external stimuli is a dubious clinical sign during the first 1-2 days of brain injury. We previously showed that the amplitude of the somatic evoked potential (SEP) in the swine is diminished at the infarct site and perihematomal surround within the first 6 h of collagenase-induced intracerebral hemorrhage (ICH). We now report that this depressed SEP persists during the subchronic (48 h) period of ICH in the swine not only within the injured primary somatosensory (SI) cortex, but also in the contralateral homotopic SI cortex. This impairment of sensory responsiveness was accompanied by increases in various matrix metalloproteinases (MMPs) in different brain regions. By 24 h, a marked rise in MMP-9, an inflammatory marker, was detected in the white matter of the ipsilesional SI and secondary somatosensory cortex (SII), and in the contralesional SI gray matter, as compared to saline-injected controls. A subsequent increase in MMP-9 level was found in the ipsilesional SI and SII gray matter, and in the contralesional SI white matter by 48 h (P<0.05). By 7 days, significant levels of MMP-9 were detected only in the ipsilesional SI white and gray matter tissues. In contrast, the elevation of MMP-2, a marker of degeneration, was delayed until 7 days post-ICH in the ipsilesional SII gray matter. A significant rise in MMP-9 was also noted in CA1 of the ipsilesional and contralesional hemispheres during 1-2 days. Our MMP assay shows that the depressed cortical excitability seen in the contralateral SI cortex is a manifestation of the broad effect of a focal ICH that produces inflammatory and degenerative processes not only in the region adjacent to the focal ICH site, but also in remote regions that are functionally connected to the site of focal ICH.

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Neuroinflammation induces a complex molecular cascade that leads to the proteolysis of cells. Matrix metalloproteinases (MMPs) attack all components of the extracellular matrix in a number of neuroinflammatory diseases and cause a delayed opening of the blood-brain barrier (BBB). Earlier, we showed that lipopolysaccharide (LPS) disrupted the BBB through the action of gelatinase B (MMP-9). In a study of cerebral ischemia, gelatinase A (MMP-2) was seen in astrocytic end-feet and stromelysin-1 (MMP-3) in microglia. Since other MMPs may be important in LPS-induced injury, we studied the gene transcription and cellular localization of several MMPs and an inflammatory mediator, tumor necrosis factor (TNF-alpha), using competitive polymerase chain reaction (PCR) and immunohistochemical methods. Significantly elevated levels of MMP-2 and -3 mRNA were observed in LPS-injected brains by 2 h after injection as compared to non-injected brain tissue (P<0.05). By 8 h post-LPS injection, gene expression of MMP-2 and -3 had declined in both saline- and LPS-injected tissue, while TNF-alpha mRNA levels rose significantly. Immunohistochemistry of control brains confirmed the earlier observation of MMP-2 immunoreactivity in processes abutting cerebral blood vessels, which increased after LPS injection. The expression of MMP-9 and MMP-3 was localized mainly to the cerebrovasculature in LPS-stimulated brain tissue, predominantly in the perivascular cells of the basal lamina near the site of injection. Both of these proteinases were present at the site of LPS injection at 8 h, but MMP-2 was absent. Our results show that MMP genes are up-regulated prior to the induction of cytokines such as TNF-alpha, and that MMP proteins are prominent around blood vessels in LPS-induced neuroinflammation.

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