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Systems analysis of intracranial pressure

Comparison with volume-pressure test and CSF-pulse amplitude analysis

Michael Chopp and Harold D. Portnoy

✓ Systems analysis is explored as a method of evaluating intracranial pressure (ICP). The intracranial cavity is characterized by a transfer function that is evaluated by the blood pressure pulse acting as the system input and the ICP pulse acting as the output. A comparison is made of the ability of systems analysis, volume-pressure test (VPT), and cerebrospinal fluid-pulse amplitude analysis (CSFPAA) to distinguish between an epidural balloon inflation (EBI) and an intraventricular infusion (IVI) at various steady state levels of ICP. The VPT could not distinguish between EBI and IVI at any level of ICP, and above 30 mm Hg the volume-pressure response decreased. Spectral analysis was able to distinguish EBI from IVI above 30 mm Hg, and CSFPAA was demonstrated to be a simplified spectral analysis. Changes in ICP waveform generated during each cardiac cycle appear to be related to changes in vasomotor reactivity and may have value in the clinical monitoring of ICP.

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Harold D. Portnoy, Michael Chopp, Craig Branch, and Michael B. Shannon

✓ Systems analysis of the systemic arterial (SAPW), cerebrospinal fluid (CSFPW), and sagittal sinus (SSPW) pulse waves was carried out in 13 dogs during hypercapnia (5% CO2), intracranial normotension (inhalation of 100% O2), and intracranial hypertension (inhalation of 100% O2 plus an intraventricular infusion). Power amplitude and phase spectra were determined for each wave, and the power amplitude and phase transfer functions calculated between the cerebrospinal fluid (CSF) pressure and systemic arterial pressures, and between the sagittal sinus pressure and CSF pressure. The study indicates that the CSFPW and SSPW were virtually identical when impedance between the cerebral veins and sagittal sinus was minimal, which argues that the CSF pulse was derived from the cerebral venous bed. During inhalation of 100% O2, transmission of the SAPW across the precapillary resistance vessels into the cerebral venous pulse (as represented by the CSFPW) was nonlinear, while transmission across the lateral lacunae into the sagittal sinus was linear. During intracranial hypertension, wave transmission across the precapillary resistance vessels was linear, and across the lateral lacunae was nonlinear. During hypercapnia, wave transmission across the precapillary resistance vessels and the lateral lacunae was linear. When the wave transmission was nonlinear, there was also suppression in transmission of the lower harmonics, particularly the fundamental frequency, and a more positive phase transfer function, suggesting an inertial effect or decrease in acceleration of the pulse. Conversion from a nonlinear to linear transmission across the precapillary resistance vessels is evidence of loss of vasomotor tone, and is accompanied by rounding of the CSFPW. A vascular model which encompasses the above data and is based on flow in collapsible tubes and changes in vasomotor tone is posited to explain control of pulsatile flow and pulse waveform changes in the cerebrovascular bed. The model helps to clarify the strong interrelationship between intracranial pressure, cerebral blood flow, and cerebral autoregulation.

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Dunyue Lu, Asim Mahmood, Ruilan Zhang, Yi Li, and Michael Chopp

Object. Neurogenesis, which is upregulated by neural injury in the adult mammalian brain, may be involved in the repair of the injured brain and functional recovery. Therefore, the authors sought to identify agents that can enhance neurogenesis after brain injury, and they report that (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NONOate), a nitric oxide donor, upregulates neurogenesis and reduces functional deficits after traumatic brain injury (TBI) in rats.

Methods. The agent DETA/NONOate (0.4 mg/kg) was injected intraperitoneally into 16 rats daily for 7 days, starting 1 day after TBI induced by controlled cortical impact. Bromodeoxyuridine (100 mg/kg) was also injected intraperitoneally daily for 14 days after TBI to label the newly generated cells in the brain. A neurological functional evaluation was performed in all rats and the animals were killed at 14 or 42 days postinjury. Immunohistochemical staining was used to identify proliferating cells.

Conclusions. Compared with control rats, the proliferation, survival, migration and differentiation of neural progenitor cells were all significantly enhanced in the hippocampus, subventricular zone, striatum, corpus callosum, and the boundary zone of the injured cortex, as well as in the contralateral hemisphere in rats with TBI that received DETA/NONOate treatment. Neurological functional outcomes in the DETA/NONOate-treated group were also significantly improved compared with the untreated group. These data indicate that DETA/NONOate may be useful in the treatment of TBI.

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Yuxia Han, Don Seyfried, Yuling Meng, Dongmei Yang, Lonni Schultz, Michael Chopp, and Donald Seyfried


Previous studies have demonstrated that transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after experimental intracerebral hemorrhage (ICH). In this study the authors tested the hypothesis that administration of multipotent MSC-derived exosomes promotes functional recovery, neurovascular remodeling, and neurogenesis in a rat model of ICH.


Sixteen adult male Wistar rats were subjected to ICH via blood injection into the striatum, followed 24 hours later by tail vein injection of 100 μg protein of MSC-derived exosomes (treatment group, 8 rats) or an equal volume of vehicle (control group, 8 rats); an additional 8 rats that had identical surgery without blood infusion were used as a sham group. The modified Morris water maze (mMWM), modified Neurological Severity Score (mNSS), and social odor–based novelty recognition tests were performed to evaluate cognitive and sensorimotor functional recovery after ICH. All 24 animals were killed 28 days after ICH or sham procedure. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume and neurovascular and white matter remodeling.


Compared with the saline-treated controls, exosome-treated ICH rats showed significant improvement in the neurological function of spatial learning and motor recovery measured at 26–28 days by mMWM and starting at day 14 by mNSS (p < 0.05). Senorimotor functional improvement was measured by a social odor–based novelty recognition test (p < 0.05). Exosome treatment significantly increased newly generated endothelial cells in the hemorrhagic boundary zone, neuroblasts and mature neurons in the subventricular zone, and myelin in the striatum without altering the lesion volume.


MSC-derived exosomes effectively improve functional recovery after ICH, possibly by promoting endogenous angiogenesis and neurogenesis in rats after ICH. Thus, cell-free, MSC-derived exosomes may be a novel therapy for ICH.

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Donald Seyfried, Jennifer Ding, Yuxia Han, Yi Li, Jieli Chen, and Michael Chopp


The goal of this study was to investigate whether human bone marrow stromal cells (hBMSCs) administered by intravenous injection have a beneficial effect on outcome after intracerebral hemorrhage (ICH) in rats.


An ICH was induced in 54 adult male Wistar rats by a stereotactically guided injection of autologous blood into the right striatum. Intravenous infusion of the hBMSCs (3, 5, or 8 million cells) was performed 1 day after ICH, and for each dose group there was a control group that received injections of vehicle. Neurological function, which was evaluated using the Neurological Severity Score (NSS) and the corner turn test, was tested before and at 1, 7, and 14 days after ICH. After 14 days of survival, the area of encephalomalacia was calculated and histochemical labeling was performed.

For all three groups, there were no statistical differences in either the NSS or corner turn tests after 1 day. After 7 and 14 days, however, the three groups that received the hBMSCs showed significant improvement in functional scores compared with the control group. In addition, after 14 days there was significantly more striatal tissue loss in the placebo groups compared with each of the three treatment groups. The region of injury in the treated animals demonstrated a significantly increased presence of hBMSCs, immature neurons, neuronal migration, synaptogenesis, and newly formed DNA.


Intravenous administration of hBMSCs significantly improves neurological function in rats subjected to ICH. This improvement in the treated animals is associated with reduced tissue loss and increased local presence of the hBMSCs, mitotic activity, immature neurons, synaptogenesis, and neuronal migration.

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Dunyue Lu, Asim Mahmood, Changsheng Qu, Anton Goussev, Mei Lu, and Michael Chopp

Object. Atorvastatin, a β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitor, has pleiotropic effects such as improving thrombogenic profile, promoting angiogenesis, and reducing inflammatory responses and has shown promise in enhancing neurological functional improvement and promoting neuroplasticity in animal models of traumatic brain injury (TBI), stroke, and intracranial hemorrhage. The authors tested the effect of atorvastatin on intracranial hematoma after TBI.

Methods. Male Wistar rats were subjected to controlled cortical impact, and atorvastatin (1 mg/kg) was orally administered 1 day after TBI and daily for 7 days thereafter. Rats were killed at 1, 8, and 15 days post-TBI. The temporal profile of intraparenchymal hematoma was measured on brain tissue sections by using a MicroComputer Imaging Device and light microscopy.

Conclusions. Data in this study showed that intraparenchymal and intraventricular hemorrhages are present 1 day after TBI and are absorbed at 15 days after TBI. Furthermore, atorvastatin reduces the volume of intracranial hematoma 8 days after TBI.

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Donald Seyfried, Yuxia Han, Dunyue LU, Jieli Chen, Ali Bydon, and Michael Chopp

Object. Atorvastatin, a β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitor, improves neurological functional outcome, reduces cerebral cell loss, and promotes regional cellular plasticity when administered after intracerebral hemorrhage (ICH) in rats.

Methods. Autologous blood was stereotactically injected into the right striatum in rats, and atorvastatin was administered orally beginning 24 hours after ICH and continued daily for 1 week. At a dose of 2 mg/kg, atorvastatin significantly reduced the severity of neurological deficit from 2 to 4 weeks after ICH. The area of cell loss in the ipsilateral striatum was also significantly reduced in these animals. Consistent with previous study data, higher doses of atorvastatin (8 mg/kg) did not improve functional outcome or reduce the extent of injury. Histochemical stains for markers of synaptogenesis, immature neurons, and neuronal migration revealed increased labeling in the region of hemorrhage in the atorvastatin-treated rats.

Conclusions. Analysis of the data in this study indicates that atorvastatin improves neurological recovery after experimental ICH and may do so in part by increasing neuronal plasticity.

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Asim Mahmood, Dunyue Lu, Changsheng Qu, Anton Goussev, and Michael Chopp


This study was designed to follow the effects of bone marrow stromal cell (BMSC) administration in rats after traumatic brain injury (TBI) for a 3-month period.


Forty adult female Wistar rats were injured by a controlled cortical impact and, 1 week later, were injected intravenously with one of three different doses of BMSCs (2 × 106, 4 × 106, or 8 × 106 cells per animal) obtained in male rats. Control rats received phosphate-buffered saline (PBS). Neurological function in these rats was studied using a neurological severity scale (NSS). The rats were killed 3 months after injury, and immunohistochemical stains were applied to brain samples to study the distribution of the BMSCs. Additional brain samples were analyzed by quantitative enzyme-linked immunosorbent assays to measure the expression of the growth factors brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF).

Three months after injury, BMSCs were present in the injured brain and their number was significantly greater in animals that received 4 × 106 or 8 × 106 BMSCs than in animals that received 2 × 106 BMSCs. The cells were primarily distributed around the lesion boundary zone. Functional outcome was significantly better in rats that received 4 × 106 or 8 × 106 BMSCs, compared with control animals, although no improvement was seen in animals that received 2 × 106 BMSCs. All doses of BMSCs significantly increased the expression of BDNF but not that of NGF; however, this increase was significantly larger in animals that received 4 × 106 or 8 × 106 BMSCs than in controls or animals that received 2 × 106 BMSCs.


In summary, when injected in rats after TBI, BMSCs are present in the brain 3 months later and significantly improve functional outcome.

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Asim Mahmood, Hongtao Wu, Changsheng Qu, Ye Xiong, and Michael Chopp


This study was designed to investigate how transplantation into injured brain of human bone marrow stromal cells (hMSCs) impregnated in collagen scaffolds affects axonal sprouting in the spinal cord after traumatic brain injury (TBI) in rats. Also investigated was the relationship of axonal sprouting to sensorimotor functional recovery after treatment.


Adult male Wistar rats (n = 24) underwent a controlled cortical impact injury and were divided into three equal groups (8 rats/group). The two treatment groups received either hMSCs (3 × 106) alone or hMSC (3 × 106)–impregnated collagen scaffolds transplanted into the lesion cavity. In the control group, saline was injected into the lesion cavity. All treatments were performed 7 days after TBI. On Day 21 after TBI, a 10% solution of biotinylated dextran amine (10,000 MW) was stereotactically injected into the contralateral motor cortex to label the corticospinal tract (CST) originating from this area. Sensorimotor function was tested using the modified neurological severity score (mNSS) and foot-fault tests performed on Days 1, 7, 14, 21, 28, and 35 after TBI. Spatial learning was tested with Morris water maze test on Days 31–35 after TBI. All rats were sacrificed on Day 35 after TBI, and brain and spinal cord (cervical and lumbar) sections were stained immunohistochemically for histological analysis.


Few biotinylated dextran amine–labeled CST fibers crossing over the midline were found in the contralateral spinal cord transverse sections at both cervical and lumbar levels in saline-treated (control) rats. However, hMSC-alone treatment significantly increased axonal sprouting from the intact CST into the denervated side of the gray matter of both cervical and lumbar levels of the spinal cord (p < 0.05). Also, this axonal sprouting was significantly more in the scaffold+hMSC group compared with the hMSC-alone group (p < 0.05). Sensorimotor functional analysis showed significant improvement of mNSS (p < 0.05) and foot-fault tests (p < 0.05) in hMSC-alone and scaffold+hMSC-treated rats compared with controls (p < 0.05). Functional improvement, however, was significantly greater in the scaffold+hMSC group compared with the hMSC-alone group (p < 0.05). Morris water maze testing also showed significant improvement in spatial learning in scaffold+hMSC and hMSC-alone groups compared with the control group (p < 0.05), with rats in the scaffold+hMSC group performing significantly better than those in the hMSC-alone group (p < 0.05). Pearson correlation data showed significant correlation between the number of crossing CST fibers detected and sensorimotor recovery (p < 0.05).


Axonal plasticity plays an important role in neurorestoration after TBI. Transplanting hMSCs with scaffolds enhances the effect of hMSCs on axonal sprouting of CST fibers from the contralateral intact cortex into the denervated side of spinal cord after TBI. This enhanced axonal regeneration may at least partially contribute to the therapeutic benefits of treating TBI with hMSCs.