γ-Aminobutyric Acid Type A Receptor Potentiation Inhibits Learning in a Computational Network Model.

BACKGROUND: Propofol produces memory impairment at concentrations well below those abolishing consciousness. Episodic memory, mediated by the hippocampus, is most sensitive. Two potentially overlapping scenarios may explain how γ-aminobutyric acid receptor type A (GABAA) potentiation by propofol disrupts episodic memory-the first mediated by shifting the balance from excitation to inhibition while the second involves disruption of rhythmic oscillations. We use a hippocampal network model to explore these scenarios. The basis for these experiments is the proposal that the brain represents memories as groups of anatomically dispersed strongly connected neurons. METHODS: A neuronal network with connections modified by synaptic plasticity was exposed to patterned stimuli, after which spiking output demonstrated evidence of stimulus-related neuronal group development analogous to memory formation. The effect of GABAA potentiation on this memory model was studied in 100 unique networks. RESULTS: GABAA potentiation consistent with moderate propofol effects reduced neuronal group size formed in response to a patterned stimulus by around 70%. Concurrently, accuracy of a Bayesian classifier in identifying learned patterns in the network output was reduced. Greater potentiation led to near total failure of group formation. Theta rhythm variations had no effect on group size or classifier accuracy. CONCLUSIONS: Memory formation is widely thought to depend on changes in neuronal connection strengths during learning that enable neuronal groups to respond with greater facility to familiar stimuli. This experiment suggests the ability to form such groups is sensitive to alteration in the balance between excitation and inhibition such as that resulting from administration of a γ-aminobutyric acid-mediated anesthetic agent.

γ-Aminobutyric acid receptor type A receptor potentiation reduces firing of neuronal assemblies in a computational cortical model.

BACKGROUND: The understanding of how general anesthetics act on individual cells and on global brain function has increased significantly during the last decade. What remains poorly understood is how anesthetics act at intermediate scales. Several major theories emphasize the importance of neuronal groups, sets of strongly connected neurons that fire in a time-locked fashion, in all aspects of brain function, particularly as a necessary substrate of consciousness. The authors have undertaken computer modeling to determine how ã-aminobutyric acid receptor type A (GABAA) receptor potentiating agents such as propofol may influence the dynamics of neuronal group formation and ongoing activity. METHODS: A computer model of a cortical network with connections modified by synaptic plasticity was examined. At baseline, the model spontaneously formed neuronal groups. Direct effects of GABAA receptor potentiation and indirect effects on input drive were then examined to study their effects on this process. RESULTS: Potentiation of GABAA inhibition and input drive reduction reduced the firing frequency of inhibitory and excitatory neurons in a dose-dependent manner. The diminution in spiking rates led to dramatic reductions in the firing frequency of neuronal groups. Simulated electroencephalographic output from the model at baseline exhibits gamma and theta rhythmicity. The direct and indirect GABAA effects reduce the amplitude of these underlying rhythms and modestly slow the gamma rhythm. CONCLUSIONS: GABAA facilitation both directly and indirectly inhibits the ability of neurons to form groups spontaneously. A lack of group formation is consistent with some theories of anesthetic-induced loss of memory formation and consciousness.

Endothelial molecular changes in a rodent model of arteriovenous malformation.

OBJECT: The cellular and molecular processes underlying arteriovenous malformation (AVM) development and response to radiosurgery are largely unknown. An animal model mimicking the molecular properties of AVMs is required to examine these processses. This study was performed to determine whether the endothelial molecular changes in an animal model of arteriovenous fistula (AVF) are similar to those in human AVMs. METHODS: Arteriovenous fistulas were created in 18 Sprague-Dawley rats by end-to-side anastomosis of the left jugular vein to the common carotid artery creating a model "nidus" of arterialized branching veins that coalesce into a "draining vein" (sigmoid sinus). Six control animals underwent sham operations. RESULTS: After 1 or 3 days, or 1, 3, 6, or 12 weeks, fresh-frozen sections of the fistula, nidus vessels, and contralateral vessels were studied immunohistochemically for thrombomodulin, von Willebrand factor, E-selectin, P-selectin, and vascular endothelial growth factor. CONCLUSIONS: The AVF model has a "nidus" with endothelial molecular changes similar to those observed in human AVMs, supporting its use as a model for studying the effects of radiosurgery on AVMs.

Inflammatory molecule expression in cerebral arteriovenous malformations.

Inflammatory proteins may play a role in the pathophysiology of cerebral arteriovenous malformations and their response to radiosurgery. The aim of this study was to compare the expression of inflammatory molecules in arteriovenous malformations (AVMs) with that in normal cerebral vessels. Fresh-frozen surgical specimens from 15 AVMs and three control specimens were studied. The expression of P- and E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule (PECAM-1) and von Willebrand factor were examined using immunohistochemistry. AVMs had significant upregulation of E-selectin. VCAM-1 and ICAM-1 upregulation was also observed in AVMs. Pre-operative embolization was associated with increased expression of E-selectin and VCAM-1. This study has provided further evidence that the endothelium of AVMs has different molecular properties than the endothelium of normal cerebral vasculature. Inflammatory molecules may be biologically relevant in the response of vascular malformations to radiosurgery and embolization.

Thrombotic molecule expression in cerebral vascular malformations.

Thrombosis is an important end-point in the obliteration of vascular malformations after radiosurgery. The aim of this study was to investigate the expression of thrombotic molecules in arteriovenous malformations (AVMs) and cavernous malformations (CMs), and in AVMs after radiosurgery. Fresh-frozen surgical specimens from 18 AVMs (including three that had previously been treated with radiosurgery), seven CMs, and three control specimens were studied. The expression of tissue factor, thrombomodulin and von Willebrand factor (vWF) were examined using immunofluorescence. Thrombomodulin and vWF were expressed in the endothelium of all specimens, while tissue factor was predominately found in the perivascular region and vascular adventitia. Previous treatment of AVMs with either radiation or embolisation did not significantly alter the intensity of expression. In some irradiated lesions, vessels were found with absent endothelial vWF staining and exposed tissue factor. This study has demonstrated that loss of the endothelium and exposure of underlying tissue factor occurs in irradiated AVMs. There were no significant differences in the expression of these thrombotic molecules in vascular malformations when compared to control vessels. While no long-term alterations in antigen expression were observed after radiosurgery, further work may elucidate the nature of the immediate response to irradiation.

Ultrastructural characteristics of hemorrhagic, nonhemorrhagic, and recurrent cavernous malformations.

OBJECT: Ultrastructural characteristics of hemorrhagic, nonhemorrhagic, primary, and recurrent central nervous system cavernous malformations (CMs) were examined in an attempt to clarify their pathological mechanisms. METHODS: Thirteen specimens (nine from samples of CMs and four from healthy control tissue) were processed for ultrastructural study immediately after surgical or postmortem removal, by fixation in glutaraldehyde/formalin and postfixation in OsO4. Transmission electron microscopy was used to examine the vascular walls, endothelium, subendothelium, and cytoplasmic organelles. The vascular walls in CMs demonstrated abnormal ultrastructure with no basement membranes and astrocytic foot processes. Pericytes were rarely seen. Single-layer lining endothelial cells showed fenestrated luminal surfaces. Large gaps were observed at intercellular junctions between endothelial cells, and large vesicles with extremely thin plasma membranes bordering the lumen were common in the lesions that had previously hemorrhaged. Endothelial cells of recurrent CMs had more Weibel-Palade bodies, filopodia, cytoplasmic processes, micropinocytotic vesicles, and filaments than those in primary lesions and normal control tissues. CONCLUSIONS: The absence of the blood-brain barrier, normal supporting wall structure, and large vesicles bordering the lumen of CM vessels may explain leakage of red blood cells into surrounding brain in the absence of major hemorrhage. Proliferation of residual abnormal endothelial cells may contribute to the recurrence of surgically removed CMs.

Expression of endothelial adhesion molecules after radiosurgery in an animal model of arteriovenous malformation.

BACKGROUND: Endothelial adhesion molecules may be important in the response of brain arteriovenous malformations (AVMs) to radiosurgery. In addition to a putative role in the occlusive process after radiosurgery, they may serve as potential targets for biological strategies to accelerate intravascular thrombosis. OBJECTIVE: To determine the temporal expression of E-selectin and vascular cell adhesion molecule-1 in an animal model of AVMs. METHODS: Forty-one Sprague-Dawley rats underwent surgical creation of a carotid-to-jugular anastomosis. Radiosurgery (25 Gy) was delivered to the model "nidus" after 6 weeks, and the tissue was harvested 1 to 84 days after radiosurgery. Control groups received sham irradiation. Immunofluorescence was used to study the expression of E-selectin and vascular cell adhesion molecule-1. RESULTS: Endothelial E-selectin expression was limited to regions receiving radiosurgery. E-selectin expression reached maximal expression at 24 hours after radiosurgery and was sustained for another 24 hours before gradually reducing to baseline at 84 days post-radiosurgery (P < .01). Vascular cell adhesion molecule-1 expression remained at the baseline level for the first week; a 50% increase was observed at 21 days after radiosurgery, which was sustained for another 3 weeks before returning to the baseline at 84 days after radiosurgery (P < .05). CONCLUSION: Radiosurgery stimulates early expression of E-selectin and delayed up-regulation of vascular cell adhesion molecule-1 on the endothelial surface of the AVM model nidus. Cell adhesion molecule expression may play an important role in the process leading to vascular obliteration after irradiation. These molecular alterations may be harnessed to promote thrombosis in the irradiated vasculature using a vascular targeting agent.

Ultrastructure of perinidal capillaries in cerebral arteriovenous malformations.

OBJECTIVE: The ultrastructure of perinidal capillaries in cerebral arteriovenous malformations (AVMs) was examined to clarify their pathomorphological features. METHODS: Fifteen AVM specimens were dissected and divided into perinidal and intranidal groups and processed for ultrastructural study immediately after surgical removal. Eleven of the patients had presented with hemorrhage. Tissue from four normal controls was also studied. Electron microscopy was used to compare features of the blood-brain barrier and endothelial cells (ECs) of capillaries in perinidal, intranidal, and controls. RESULTS: Perinidal capillaries demonstrated abnormal ultrastructure of the blood-brain barrier with no basement membranes and astrocytic foot processes. ECs had fenestrated luminal surfaces. Large gaps were observed at endothelial intercellular junctions. ECs contained numerous filopodia, large numbers of cytoplasmic processes, numerous micropinocytotic vesicles, and the cytoplasm contained more filaments than those observed in controls. Pericytes were rich in pinocytotic vesicles, vacuoles, and filaments. Their processes were in close contact with ECs. Weibel-Palade bodies were present in perinidal ECs. CONCLUSION: The absence of blood-brain barrier components in perinidal capillaries may contribute to extravasation of red blood cells into the surrounding brain in the absence of major hemorrhage and explain the gliosis and hemosiderin occasionally seen around AVMs. Cellular differentiation and proliferation in perinidal capillaries should be included in a systematic study aimed at a better understanding of the mechanisms underlying the recurrence of surgically removed AVMs.

Responses of arteriovenous malformations to radiosurgery: ultrastructural changes.

OBJECTIVE: To examine the ultrastructural changes in arteriovenous malformations (AVMs) after radiosurgery and to explore the possible mechanisms of posttreatment obliteration and hemorrhage. METHODS: Twenty-two specimens, among them three irradiated AVMs (size, 3-6 cm), 15 nonirradiated AVMs, and four normal controls were processed for ultrastructural study immediately after removal. Transmission electron microscopy was used to compare the vasculature of irradiated AVMs with nonirradiated AVMs and normal controls. RESULTS: Thirty-three months postradiosurgery, partial vaso-occlusion (36-74% lumen) occurred by coagulation of cytoplasmic debris and proteinaceous material leaking from the endothelium. Forty-eight months postradiosurgery, heterogeneous thrombus formation (86-96% lumen) with fibrinoid and proteinaceous materials was observed. Sixty-four months postradiosurgery, complete luminal closure (90-100% lumen) by a fibrin thrombus was seen in vessels with diameters up to 5.5 mm including feeding arteries and draining veins. In occluded vessels, there was extensive degeneration of endothelial cells, subendothelial fibroblasts, and myofibroblasts. Neoproliferation and endothelialization of smooth muscle cells with Weibel-Palade bodies was observed in arteries. CONCLUSION: Radiosurgery causes irreversible cellular damage of the vascular wall. Partial vaso-occlusion that increases blood flow in remaining vessels and degenerative changes on the blood-brain barrier may contribute to hemorrhage at early stage postradiosurgery. Radiosurgery stimulates neoproliferating and endothelializing smooth muscle cells in vessel walls, which might lead to narrowing of the vessel lumina. Complete vaso-occlusion achieved 64 months postradiosurgery suggested a minimum follow-up duration of 5 years to determine final outcome of radiosurgery. Histological end point of vaso-occlusion of AVMs takes longer time than neuroimaging endpoint of complete obliteration.