Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model

Previous studies have suggested that intravenous transplantation of mesenchymal stem cells (MSCs) in rat ischemia models reduces ischemia‐induced brain damage. Here, we analyzed the expression of neurotrophic factors in transplanted human MSCs and host brain tissue in rat middle cerebral artery occlusion (MCAO) ischemia model. At 1 day after transient MCAO, 3 × 10⁶ immortalized human MSC line (B10) cells or PBS was intravenously transplanted. Behavioral tests, infarction volume, and B10 cell migration were investigated at 1, 3, 7, and 14 days after MCAO. The expression of endogenous (rat origin) and exogenous (human origin) neurotorphic factors and cytokines was evaluated by quantitative real‐time RT‐PCR and Western blot analysis. Compared with PBS controls, rats receiving MSC transplantation showed improved functional recovery and reduced brain infarction volume at 7 and 14 days after MCAO. In MSC‐transplanted brain, among many neurotrofic factors, only human insulin‐like growth factor 1 (IGF‐1) was detected in the core and ischemic border zone at 3 days after MCAO, whereas host cells expressed markedly higher neurotrophic factors (rat origin) than control rats, especially vascular endothelial growth factor (VEGF) at 3 days and epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) at 7 days after MCAO. Intravenously transplanted human MSCs induced functional improvement, reduced infarct volume, and neuroprotection in ischemic rats, possibly by providing IGF‐1 and inducing VEGF, EGF, and bFGF neurotrophic factors in host brain. © 2009 Wiley‐Liss, Inc.     

Cilostazol enhances neovascularization in the mouse hippocampus after transient forebrain ischemia

Cilostazol is known to be a specific type III phosphodiesterase inhibitor, which promotes increased intracellular cAMP levels. We assessed the effect of cilostazol on production of angioneurins and chemokines and recruitment of new endothelial cells for vasculogenesis in a mouse model of transient forebrain ischemia. Pyramidal cell loss was prominently evident 3–28 days postischemia, which was markedly ameliorated by cilostazol treatment. Expression of angioneurins, including endothelial nitric oxide synthase, vascular endothelial growth factor, and brain‐derived neurotrophic factor, was up‐regulated by cilostazol treatment in the postischemic hippocampus. Cilostazol also increased Sca‐1/vascular endothelial growth factor receptor‐2 positive cells in the bone marrow and circulating peripheral blood and the number of stromal cell‐derived factor‐1α‐positive cells in the molecular layer of the hippocampus, which colocalized with CD31. CXCR4 chemokine receptors were up‐regulated by cilostazol in mouse bone marrow‐derived endothelial progenitor cells, suggesting that cilostazol may be important in targeting or homing in of bone marrow‐derived stem cells to areas of injured tissues. CD31‐positive cells were colocalized with almost all bromodeoxyuridine‐positive cells in the molecular layer, indicating stimulation of endothelial cell proliferation by cilostazol. These data suggest that cilostazol markedly enhances neovascularization in the hippocampus CA1 area in a mouse model of transient forebrain ischemia, providing a beneficial interface in which both bone marrow‐derived endothelial progenitor cells and angioneurins influence neurogenesis in injured tissue. © 2010 Wiley‐Liss, Inc.     

Analysis of Complications Following Decompressive Craniectomy for Traumatic Brain Injury

Objective

Adequate management of increased intracranial pressure (ICP) is critical in patients with traumatic brain injury (TBI), and decompressive craniectomy is widely used to treat refractory increased ICP. The authors reviewed and analyzed complications following decompressive craniectomy for the management of TBI.

Methods

A total of 89 consecutive patients who underwent decompressive craniectomy for TBI between February 2004 and February 2009 were reviewed retrospectively. Incidence rates of complications secondary to decompressive craniectomy were determined, and analyses were performed to identify clinical factors associated with the development of complications and the poor outcome.

Results

Complications secondary to decompressive craniectomy occurred in 48 of the 89 (53.9%) patients. Furthermore, these complications occurred in a sequential fashion at specific times after surgical intervention; cerebral contusion expansion (2.2 ± 1.2 days), newly appearing subdural or epidural hematoma contralateral to the craniectomy defect (1.5 ± 0.9 days), epilepsy (2.7 ± 1.5 days), cerebrospinal fluid leakage through the scalp incision (7.0 ± 4.2 days), and external cerebral herniation (5.5 ± 3.3 days). Subdural effusion (10.8 ± 5.2 days) and postoperative infection (9.8 ± 3.1 days) developed between one and four weeks postoperatively. Trephined and post-traumatic hydrocephalus syndromes developed after one month postoperatively (at 79.5 ± 23.6 and 49.2 ± 14.1 days, respectively).

Conclusion

A poor GCS score (≤ 8) and an age of ≥ 65 were found to be related to the occurrence of one of the above-mentioned complications. These results should help neurosurgeons anticipate these complications, to adopt management strategies that reduce the risks of complications, and to improve clinical outcomes.     

Alterations in GluR2 AMPA receptor phosphorylation at serine 880 following group I metabotropic glutamate receptor stimulation in the rat dorsal striatum

Phosphorylation of ionotropic glutamate receptors in the brain plays a crucial role in the regulation of synaptic plasticity. In this study, we investigated the regulation of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptor phosphorylation by thestimulation of group I metabotropic glutamate receptors (mGluRs) in the dorsal striatum in vivo. The results showed that intrastriatal infusion of the group I mGluR agonist, (RS)‐3,5‐dihydroxyphenylglycine (DHPG, 250 nmol), enhanced the sensitivity of GluR2 subunit in its phosphorylation at serine 880 (S880) in the dorsal striatum. This enhancement of the sensitivity of GluR2‐S880 phosphorylation was reduced by blocking group I mGluRs and N‐methyl‐D‐aspartate (NMDA) receptors. Similar reduction of the enhancement was also induced by inhibiting phospholipase C (PLC), calcium/calmodulin‐dependent protein kinase (CaMK), c‐Jun N‐terminal kinase (JNK), and protein kinase C (PKC). Inhibition of protein phosphatase (PP) 1/2A and calcineurin (PP2B) alone enhanced GluR2‐S880 phosphorylation in the dorsal striatum, whereas inhibition of these phosphatases did not further enhance the S880 phosphorylation by DHPG stimulation. In addition, inhibition of PP1/2A or PP2B also enhanced the phosphorylation of CaMKII, JNK and PKC. These data suggest that the phosphorylation of AMPA receptor GluR2 subunit at S880 is subject to the upregulation by the stimulation of group I mGluRs. Interactions among glutamate receptors, protein kinases, and PPs participate in this upregulation. © 2009 Wiley‐Liss, Inc.     

Clinical Utility of Interictal High-Frequency Oscillations Recorded with Subdural Macroelectrodes in Partial Epilepsy

Background and Purpose

There is growing interest in high-frequency oscillations (HFO) as electrophysiological biomarkers of the epileptic brain. We evaluated the clinical utility of interictal HFO events, especially their occurrence rates, by comparing the spatial distribution with a clinically determined epileptogenic zone by using subdural macroelectrodes.

Methods

We obtained intracranial electroencephalogram data with a high temporal resolution (2000 Hz sampling rate, 0.05-500 Hz band-pass filter) from seven patients with medically refractory epilepsy. Three epochs of 5-minute, artifact-free data were selected randomly from the interictal period. HFO candidates were first detected by an automated algorithm and subsequently screened to discard false detections. Validated events were further categorized as fast ripple (FR) and ripple (R) according to their spectral profiles. The occurrence rate of HFOs was calculated for each electrode contact. An HFO events distribution map (EDM) was constructed for each patient to allow visualization of the spatial distribution of their HFO events.

Results

The subdural macroelectrodes were capable of detecting both R and FR events from the epileptic neocortex. The occurrence rate of HFO events, both FR and R, was significantly higher in the seizure onset zone (SOZ) than in other brain regions. Patient-specific HFO EDMs can facilitate the identification of the location of HFO-generating tissue, and comparison with findings from ictal recordings can provide additional useful information regarding the epileptogenic zone.

Conclusions

The distribution of interictal HFOs was reasonably consistent with the SOZ. The detection of HFO events and construction of spatial distribution maps appears to be useful for the presurgical mapping of the epileptogenic zone.     

Early assessment of delirium in elderly patients after hip surgery

Objective

This study is intended to identify predictive factors of delirium, including risk factors and prodromal symptoms.

Methods

This study included sixty-five patients aged 65 years or older who had undergone hip surgery. Baseline assessments included age; gender; admission type (acute/elective); reason for surgery (fracture/replacement); C-reactive protein (CRP); Acute Physiology, Age, Chronic Health Evaluation (APACHE III); and the Mini-Mental State Examination (MMSE). The Korean version of the Delirium Rating Scale-Revised-98 (K-DRS-98) was used to assess prodromal symptoms daily before the onset of delirium.

Results

Almost 28% (n=18) of the 65 patients developed delirium after surgery. Delirium in elderly patients after hip surgery was observed more often in older patients and those with acute admission, hip fracture, higher APACHE III score, lower MMSE score, and higher CRP levels within early days after the operation. Sleep-wake cycle disturbances, thought process abnormalities, orientation, and long-term memory in symptom items of K-DRS-98 were showed significant difference on 4 days before delirium, lability of affect on 3 days before, perceptual disturbances and hallucination, and visuo-spatial ability on 2 days before, and delusion, motor agitation, and short-term memory on the day before the occurrence of delirium. CRP levels within 24 hours and 72 hours after hospitalization were significantly higher in the delirium group.

Conclusion

Medical professionals must pay attention to behavioral, cognitive changes and risk factors in elderly patients undergoing hip surgery and to the prodromal phase of delirium. K-DRS-98 may help in identifying the prodromal symptoms of delirium in elderly patients after hip surgery.     

Disrupted functional connectivity for controlled visual processing as a basis for impaired spatial working memory in schizophrenia

Although regional brain abnormalities underlying spatial working memory (SWM) deficits in schizophrenia have been identified, little is known about which brain circuits are functionally disrupted in the SWM network in schizophrenia. We investigated SWM-related interregional functional connectivity in schizophrenia using functional magnetic resonance imaging (fMRI) data collected during a memory task that required analysis of spatial information in object structure. Twelve schizophrenia patients and 11 normal control subjects participated. Patients had SWM performance deficits and deficient neural activation in various brain areas, especially in the high SWM load condition. Examination of the covariation of regional brain activations elicited by the SWM task revealed evidence of functional disconnection between prefrontal and posterior visual association areas in schizophrenia. Under low SMW load, we found reduced functional associations between dorsolateral prefrontal cortex (DLPFC) and inferior temporal cortex (ITC) in the right hemisphere in patients. Under high SWM load, we found evidence for further functional disconnection in patients, including additional reduced functional associations between left DLPFC and right visual areas, including the posterior parietal cortex (PPC), fusiform gyrus, and V1, as well as between right inferior frontal cortex and right PPC. Greater prefrontal-posterior cortical functional connectivity was associated with better SWM performance in controls, but not in patients. These results suggest that prefrontal-posterior functional connectivity associated with the maintenance and control of visual information is central to SWM, and that disruption of this functional network underlies SWM deficits in schizophrenia.     

The cortical neuroanatomy of neuropsychological deficits in mild cognitive impairment and Alzheimer's disease: a surface-based morphometric analysis

Patients with probable Alzheimer's disease (AD) and the amnesic form of mild cognitive impairment (aMCI) often demonstrate several types of neuropsychological deficits. These deficits are often related to cortical atrophy, induced by neuronal degradation. The purpose of this study is to investigate whether different anatomic patterns of cortical atrophy are associated with specific neuropsychological deficits. The participants were 170 patients with AD and 99 patients with aMCI. All participants underwent the Seoul Neuropsychological Screening Battery (SNSB), which includes tests that assess attention, language, visuospatial functions, verbal and visual memory, and frontal/executive functions. Cortical atrophy (thinning) was quantified by measuring the thickness of the cortical mantle across the entire brain using automated, three-dimensional magnetic resonance imaging. The relationship between cortical thickness and neuropsychological performance was analysed using stepwise multiple linear regression analyses. These analyses (corrected P < .001) showed that several specific brain regions with cortical thinning were associated with cognitive dysfunction including: digit span backward, verbal and picture recall, naming and fluency, drawing–copying, response inhibition and selective attention. Some of the other functions, however, were not associated with specific foci of cortical atrophy (digit span forward, the word reading portion of the Stroop test, word and picture recognition). Our study, involving a large sample of participants with aMCI and AD, provides support for the postulate that cortical thinning-atrophy in specific anatomic loci are pathological markers for specific forms of cognitive dysfunction.     

Patterns of cardiorespiratory coordination in young women with recurrent major depressive disorder treated with escitalopram or venlafaxine

Evidence from previous studies suggests autonomic dysregulation in patients with major depressive disorder (MDD). Antidepressant treatment may also affect central autonomic function. We investigated whether the type of antidepressant might be associated with the pattern of cardiorespiratory coordination in non-depressed women with recurrent MDD. Resting electrocardiograms and respiratory signals were simultaneously recorded from 38 euthymic women with recurrent MDD who were treated with either escitalopram (n=19) or venlafaxine (n=19) monotherapy and from 38 healthy women. Linear measures of heart rate variability were extracted to assess cardiac autonomic control. Sample entropy (SampEn) was computed to assess the complexity of heart rate and respiratory signals, and cross-SampEn was calculated to measure the nonlinear interaction of both signals. Significant decreases in the cardiovagal tone and cardiorespiratory coupling of women with recurrent MDD receiving venlafaxine, and tendencies toward lower cardiovagal tone and cardiorespiratory coupling in women with recurrent MDD receiving escitalopram were observed when compared with healthy controls. Effect sizes for these differences were large between women receiving venlafaxine and healthy controls. We found a positive association between cardiorespiratory decoupling and venlafaxine dose. Norepinephrine-enhancement, within a therapeutic dose range, seems to be closely associated with decreased vagal tone and reduced nonlinear coupling between heart rate and respiration in euthymic women with recurrent MDD. However, the effects of serotonin enhancement on cardiovagal tone should be considered. Our results suggest that the pharmacodynamic properties of antidepressants may affect autonomic regulation of women with recurrent MDD even in euthymic state.