A Case of Long-Term Exposure to Valproic Acid Mimicking Tremor-Dominant Parkinson's Disease.

Background: Valproic acid is associated with increased risks of tremor and parkinsonism. Case Report: A 67-year-old man with a diagnosis of epilepsy who had been treated with valproic acid (VPA) for 32 years noticed right-dominant upper-limb resting tremor accompanied by mild rigidity and bradykinesia. He was initially diagnosed with tremor-dominant Parkinson's disease (TDPD), but dopamine transporter single-photon emission computed tomography demonstrated no nigrostriatal degeneration. At 3 months after discontinuing VPA, his symptoms dramatically improved. Discussion: VPA-induced tremor usually consists of postural or kinetic tremor without asymmetry. Our case indicated that careful evaluation is needed, even in cases of asymmetrical resting tremor and mild parkinsonism resembling TDPD after long term exposure to VPA. Highlights: We report an atypical case of valproic acid-induced tremor and parkinsonism that mimics tremor-dominant Parkinson's disease. Physicians should not exclude the possible relation to valproic acid in patients presenting unilateral resting tremor and parkinsonism even in the absence of long-term side effects.

Preoperative simulation of a middle cerebral artery aneurysm clipping using a rotational three-dimensional digital subtraction angiography.

BACKGROUND: In recent years, young neurosurgeons have had few opportunities to gain experience with clipping surgeries. The first author was sometimes surprised that she could not predict the anatomical relationships between the aneurysm and vessels during actual surgery. This study investigated the differences between the expected and actual operative findings during clipping surgery for aneurysms of the middle cerebral artery. METHODS: Medical records for 15 patients who underwent rotational three-dimensional (3D) digital subtraction angiography (3D-DSA) before the clipping surgery were analyzed after the surgery. The anatomical relationships between the aneurysm and parent arteries were defined by the intraoperative findings just before clipping. The viewing direction to obtain this definitive perspective (virtual viewing direction) was measured. The angle between this viewing direction and the coordinate axis was denoted as the "virtual angle for clipping (VAC)." RESULTS: The VAC between the X-axis and viewing direction on the XY-plane (VAC-XY) ranged from -43° to +73° (mean, +27°), and the angle between the XY-plane and viewing direction (VAC-Z) ranged from +25° to -34° (mean, 5.5°). The difference between the VAC-XY and mean angle was significantly larger in cases with hidden branches behind the aneurysm. In these cases, the virtual viewing direction visualized the neck of the aneurysm. There is no correlation between M1 length and VAC-XY or VAC-Z discrepancy. CONCLUSION: 3D-DSA or 3D computed tomography angiography images visualizing the neck of the aneurysm should be obtained in combination with images obtained from the standard oblique angle.

In Vitro Modeling of Human Brain Arteriovenous Malformation for Endovascular Simulation and Flow Analysis.

BACKGROUND: Current in vitro models for human brain arteriovenous malformation (AVM) analyzing the efficacy of embolic materials or flow conditions are limited by a lack of realistic anatomic features of complex AVM nidus. The purpose of this study was to evaluate a newly developed in vitro AVM model for embolic material testing, preclinical training, and flow analysis. METHODS: Three-dimensional (3D) images of the AVM nidus were extracted from 3D rotational angiography from a patient. Inner vascular mold was printed using a 3D printer, coated with polydimethylsiloxanes, and then was removed by acetone, leaving a hollow AVM model. Injections of liquid embolic material and 4-dimensional (4D) flow magnetic resonance imaging (MRI) were performed using the AVM models. Additionally, computational fluid dynamics analysis was performed to examine the flow volume rate as compared with 4D flow MRI. RESULTS: The manufacture of 3D in vitro AVM models delivers a realistic representation of human nidus vasculature and complexity derived from patients. The injection of liquid embolic agents performed in the in vitro model successfully replicated real-life treatment conditions. The model simulated the plug and push technique before penetration of the liquid embolic material into the AVM nidus. The 4D flow MRI results were comparable to computational fluid dynamics analysis. CONCLUSIONS: An in vitro human brain AVM model with realistic geometric complexities of nidus was successfully created using 3D printing technology. This AVM model offers a useful tool for training of embolization techniques and analysis of hemodynamics analysis, and development of new devices and materials.

Robot-assisted partial nephrectomy of initial cases using a 3D square-block type kidney model.

BACKGROUND: It is extremely important to understand the local anatomy prior to performing appropriate and efficient robot-assisted partial nephrectomies (RAPNs). METHODS: We developed a personalized three-dimensional printed kidney model of square-block type to enhance our knowledge and understanding on the underlying anatomy during RAPN, and we consequently applied this model to six initial cases of RAPN. RESULTS: The mean warm ischemic time was 18 minutes and the mean estimated blood loss was 59 mL. Only one patient presented with a minor complication, whereas all six patients included in this study were surgical margin negative. CONCLUSIONS: We believe that this cost-effective model helped us in understanding the underlying local anatomy and facilitating an increased efficiency in the related surgery. Further studies are required to validate our preliminary results.

Training of Intra-Axial Brain Tumor Resection Using a Self-Made Simple Device with Agar and Gelatin.

INTRODUCTION: Self-made devices composed of agar and gelatin gel were used for resident training in intra-axial brain tumor resection. The mixture gel of agar and gelatin is retractable and can be suctioned. Hardness of the gel depends on the concentration of the solution. Therefore, by changing the concentration, it is easy to make gels of various hardness. METHODS: In this study, a mass of gel that looked like a tumor was placed into another gel that looked like the brain. A part of the "brain" was regarded as the eloquent area. Three types of "tumor" were prepared: hard, moderately hard, and soft tumors. Residents tried to remove the tumor entirely with minimal brain invasion. The training was repeated with 3 types of gel. After resection, the weight of the residual tumor, resected normal brain, and resected eloquent area were measured, and the time taken for removal was recorded. RESULTS: These data were compared between residents and neurosurgeons. We also analyzed how these data improved with repeated practice. In most cases, residual tumor, resected normal brain, resected eloquent area, and time taken for removal were less in neurosurgeons than in residents. Repeated training made residents more skillful. The responses of the trainees were almost all favorable. CONCLUSIONS: Our devices with "tumors" of various hardness appear to be suitable for resident training in each surgical skill. For the next step of this study, we will attempt to fabricate more practical 3-dimensional gel models for presurgical simulation.

A patient-specific intracranial aneurysm model with endothelial lining: a novel in vitro approach to bridge the gap between biology and flow dynamics.

OBJECTIVES: To develop an in vitro model for studying the biological effect of complex-flow stress on endothelial cells in three-dimensional (3D) patient-specific vascular geometry. MATERIALS AND METHODS: A vessel replica was fabricated with polydimethylsiloxanes using 3D printing technology from vascular image data acquired by rotational angiography. The vascular model was coated with fibronectin and immersed in a tube filled with a cell suspension of endothelium, and then cultured while being slowly rotated in three dimensions. Culture medium with viscosity was perfused in the circulation with the endothelialized vascular model. A computational fluid dynamics (CFD) study was conducted using perfusion conditions used in the flow experiment. The morphology of endothelial cells was observed under a confocal microscope. RESULTS: The CFD study showed low wall shear stress and circulating flow in the apex of the basilar tip aneurysm, with linear flow in the parent artery. Confocal imaging demonstrated that the inner surface of the vascular model was evenly covered with monolayer endothelial cells. After 24 h of flow circulation, endothelial cells in the parent artery exhibited a spindle shape and aligned with the flow direction. In contrast, endothelial cells in the aneurysmal apex were irregular in shape and size. CONCLUSIONS: A geometrically realistic intracranial aneurysm model with live endothelial lining was successfully developed. This in vitro model enables a new research approach combining study of the biological impact of complex flow on endothelial cells with CFD analysis and patient information, including the presence of aneurysmal growth or rupture.

Training in Cerebral Aneurysm Clipping Using Self-Made 3-Dimensional Models.

INTRODUCTION: Recently, there have been increasingly fewer opportunities for junior surgeons to receive on-the-job training. Therefore, we created custom-built three-dimensional (3D) surgical simulators for training in connection with cerebral aneurysm clipping. METHODS: Three patient-specific models were composed of a trimmed skull, retractable brain, and a hollow elastic aneurysm with its parent artery. The brain models were created using 3D printers via a casting technique. The artery models were made by 3D printing and a lost-wax technique. Four residents and 2 junior neurosurgeons attended the training courses. The trainees retracted the brain, observed the parent arteries and aneurysmal neck, selected the clip(s), and clipped the neck of an aneurysm. The duration of simulation was recorded. A senior neurosurgeon then assessed the trainee's technical skill and explained how to improve his/her performance for the procedure using a video of the actual surgery. Subsequently, the trainee attempted the clipping simulation again, using the same model. After the course, the senior neurosurgeon assessed each trainee's technical skill. The trainee critiqued the usefulness of the model and the effectiveness of the training course. RESULTS: Trainees succeeded in performing the simulation in line with an actual surgery. Their skills tended to improve upon completion of the training. CONCLUSION: These simulation models are easy to create, and we believe that they are very useful for training junior neurosurgeons in the surgical techniques needed for cerebral aneurysm clipping.

Manufacture of patient-specific vascular replicas for endovascular simulation using fast, low-cost method.

Patient-specific vascular replicas are essential to the simulation of endovascular treatment or for vascular research. The inside of silicone replica is required to be smooth for manipulating interventional devices without resistance. In this report, we demonstrate the fabrication of patient-specific silicone vessels with a low-cost desktop 3D printer. We show that the surface of an acrylonitrile butadiene styrene (ABS) model printed by the 3D printer can be smoothed by a single dipping in ABS solvent in a time-dependent manner, where a short dip has less effect on the shape of the model. The vascular mold is coated with transparent silicone and then the ABS mold is dissolved after the silicone is cured. Interventional devices can pass through the inside of the smoothed silicone vessel with lower pushing force compared to the vessel without smoothing. The material cost and time required to fabricate the silicone vessel is about USD $2 and 24 h, which is much lower than the current fabrication methods. This fast and low-cost method offers the possibility of testing strategies before attempting particularly difficult cases, while improving the training of endovascular therapy, enabling the trialing of new devices, and broadening the scope of vascular research.

[Rapid 3-Dimensional Models of Cerebral Aneurysm for Emergency Surgical Clipping].

We developed a method for manufacturing solid models of cerebral aneurysms, with a shorter printing time than that involved in conventional methods, using a compact 3D printer with acrylonitrile-butadiene-styrene(ABS)resin. We further investigated the application and utility of this printing system in emergency clipping surgery. A total of 16 patients diagnosed with acute subarachnoid hemorrhage resulting from cerebral aneurysm rupture were enrolled in the present study. Emergency clipping was performed on the day of hospitalization. Digital Imaging and Communication in Medicine(DICOM)data obtained from computed tomography angiography(CTA)scans were edited and converted to stereolithography(STL)file formats, followed by the production of 3D models of the cerebral aneurysm by using the 3D printer. The mean time from hospitalization to the commencement of surgery was 242 min, whereas the mean time required for manufacturing the 3D model was 67 min. The average cost of each 3D model was 194 Japanese Yen. The time required for manufacturing the 3D models shortened to approximately 1 hour with increasing experience of producing 3D models. Favorable impressions for the use of the 3D models in clipping were reported by almost all neurosurgeons included in this study. Although 3D printing is often considered to involve huge costs and long manufacturing time, the method used in the present study requires shorter time and lower costs than conventional methods for manufacturing 3D cerebral aneurysm models, thus making it suitable for use in emergency clipping.

Preoperative Three-Dimensional Diagnosis of Neurovascular Relationships at the Root Exit Zones During Microvascular Decompression for Hemifacial Spasm.

OBJECTIVE: Hemifacial spasm occurs when a blood vessel compresses against an area near the root exit zone of the facial nerve. Developments in diagnostic neuroimaging have allowed three-dimensional (3D) observation of artery and nerve locations, an effective aid for treatment selection. However, an accurate interpretation of the 3D data remains challenging because imaging representations of complex small vessels are drowned out by noise. We used a noise elimination method to analyze artery and nerve locations and to determine their 3D relationship. METHODS: Fifteen patients treated for hemifacial spasm were included. Images fused from 3 modalities of magnetic resonance imaging, 3D computed tomography, and angiography were used as source images. Using the images, models of the nerve and candidate vessels were created and shown in 3D to observe how the arteries were compressing the nerve and to identify the portions of the offending vessels that were closest to the nerve. These preoperative results were then compared with operative field observations during surgery. 3D models of the unaffected side were created and evaluated as controls. RESULTS: We confirmed that these models were accurate reconstructions of the source images as the tubular nerve and artery cross-sections showed good alignment onto magnetic resonance imaging axial slice images. The preoperative diagnoses of the compression sites and offending arteries all matched intraoperative findings. CONCLUSIONS: An accurate identification of the offending arteries and compression sites was possible, and this method is anticipated to offer effective means of preoperative simulation.

A Case of Dural Arteriovenous Fistula in the Falx Cerebri: Case Report and Review of the Literature.

A 67-year-old man presented with consciousness disturbance and right hemiparesis. Computed tomography (CT) scan showed an intracerebral hematoma with two enhanced vascular lesions. Digital subtraction angiography revealed the dural arteriovenous fistula (dAVF) in the falx cerebri which was supplied by both bilateral middle meningeal arteries and left pericallosal artery and drained into both the superior sagittal sinus and the vein of Galen via the posterior callosal vein accompanied by two venous pouches. The dAVF was obliterated by a combination of the endovascular and the direct surgeries. A dAVF in a falx cerebri is very rare and only five cases were reported. Clinical characteristics of the dAVFs are uncertain. Before deciding the strategy of treatment, it is important to consider the pathological condition including embryology of the falx, the falcine sinus, and the falcine venous plexus.

Training in Brain Retraction Using a Self-Made Three-Dimensional Model.

A hollow brain model was created using soft urethane. A tube passing through the hollow was attached for use as a water inlet and manometer. Water sufficient in quantity to realize the intended initial pressure was infused through the tube. The brain model was retracted with a brain spatula and the surgical corridor was opened. By measuring local force with a sensor set on the brain spatula, the model could be used for training in brain retraction. At the same time, the water column of the manometer was measured and the relationship with the force of the brain spatula was investigated. A positive correlation between the water column and local force was confirmed. This indicated that it was possible to use this model without a force sensor for the same training using water column measurements.

[Shunt passer clamp: a new device to prevent rotation of CSF-shunt passer].

Cerebrospinal fluid shunting is a surgical treatment alternative for hydrocephalus. In general, ventriculoperitoneal (VP) and lumboperitoneal (LP) shunts have been widely practiced as standard procedures. However, these procedures are difficult because the shunt passer often rotates unintentionally. Therefore, we developed a simple device that prevents shunt passer rotation and termed it a "shunt passer-clamp"(SP-C). This device consists of two parts: the first part is the body with a hole through which the passer goes and a "female" screw perpendicular to the hole. The second part is a "male" screw set to the body. The surgeon can attach the SP-C to the shunt passer without the requirement for remodeling. We employed a SP-C for 14 consecutive shunt surgeries and received favorable feedback from the surgeons. Handling was considered "easy" in all cases. The surgical duration was significantly shorter than that if the SP-C was not employed. We conclude that our specially designed SP-C is relatively effective.

Microcatheter Shaping for Intracranial Aneurysm Coiling Using the 3-Dimensional Printing Rapid Prototyping Technology: Preliminary Result in the First 10 Consecutive Cases.

OBJECTIVE: An optimal microcatheter is necessary for successful coiling of an intracranial aneurysm. The optimal shape may be predetermined before the endovascular surgery via the use of a 3-dimensional (3D) printing rapid prototyping technology. We report a preliminary series of intracranial aneurysms treated with a microcatheter shape determined by the patient's anatomy and configuration of the aneurysm, which was fabricated with a 3D printer aneurysm model. METHODS: A solid aneurysm model was fabricated with a 3D printer based on the data acquired from the 3D rotational angiogram. A hollow aneurysm model with an identical vessel and aneurysm lumen to the actual anatomy was constructed with use of the solid model as a mold. With use of the solid model, a microcatheter shaping mandrel was formed to identically line the 3D curvature of the parent vessel and the long axis of the aneurysm. With use of the mandrel, a test microcatheter was shaped and validated for the accuracy with the hollow model. All the planning processes were undertaken at least 1 day before treatment. The preshaped mandrel was then applied in the endovascular procedure. Ten consecutive intracranial aneurysms were coiled with the pre-planned shape of the microcatheter and evaluated for the clinical and anatomical outcomes and microcatheter accuracy and stability. RESULTS: All of pre-planned microcatheters matched the vessel and aneurysm anatomy. Seven required no microguidewire assistance in catheterizing the aneurysm whereas 3 required guiding of a microguidewire. All of the microcatheters accurately aligned the long axis of the aneurysm. The pre-planned microcatheter shapes demonstrated stability in all except in 1 large aneurysm case. CONCLUSION: When a 3D printing rapid type prototyping technology is used, a patient-specific and optimal microcatheter shape may be determined preoperatively.

[Pre-surgical simulation of microvascular decompression for hemifacial spasm using 3D-models].

We have been performing pre-surgical simulations using custom-built patient-specific 3D-models. Here we report the advantageous use of 3D-models for simulating microvascular decompression(MVD)for hemifacial spasms. Seven cases of MVD surgery were performed. Two types of 3D-printers were used to fabricate the 3D-models:one using plaster as the modeling material(Z Printer®450, 3D systems, Rock Hill, SC, USA)and the other using acrylonitrile butadiene styrene(ABS)(UP! Plus 3D printer®, Beijing Tiertime Technology, Beijing). We tested three types of models. Type 1 was a plaster model of the brainstem, cerebellum, facial nerve, and the artery compressing the root exit zone of the facial nerve. Part of the cerebellum was digitally trimmed off to observe "the compressing point" from the same angle as that used during actual surgery. Type 2 was a modified Type 1 in which part of the skull was opened digitally to mimic a craniectomy. Type 3 was a combined model in which the cerebellum and the artery of the Type 2 model were replaced by a soft retractable cerebellum and an elastic artery. The cerebellum was made from polyurethane and cast from a plaster prototype. To fabricate elastic arteries, liquid silicone was painted onto the surface of an ABS artery and the inner ABS model was dissolved away using solvent. In all cases, the 3D-models were very useful. Although each type has advantages, the Type-3 model was judged extremely useful for training junior surgeons in microsurgical approaches.

Early diagnosis of cerebral ischemia in cerebral vasospasm by oxygen-pulse near-infrared optical topography.

PURPOSE: Early diagnosis of vasospasm is a key factor in the choice of treatment after subarachnoid hemorrhage (SAH). However, a noninvasive method of diagnosing delayed ischemic neurological deficit (DIND) has not been established. We therefore propose a new method of diagnosing cerebral ischemia using near-infrared optical topography (OT) with oxygen inhalation. MATERIALS AND METHODS: We used a 44-channel OT system that covers the bilateral front otemporoparietal areas to assess 29 patients who underwent surgery within 72 h of the onset of SAH. The patients inhaled room air followed by oxygen for 2 min, and then peripheral oxygen saturation (SpO2) was continuously monitored at the index fingertip. The patients were assessed by N-isopropyl-p-[¹²³I]iodoamphetamine (IMP)-SPECT and OT on the same day. Ischemic findings were confirmed using principal component analysis with reference to the systemic SpO2value. RESULTS: Seven of 29 patients developed DIND. Evidence of ischemia was identified by OT in all seven of these patients before the onset of DIND. The OT and SPECT findings agreed in 27 (93 %) of the 29 patients. DISCUSSION AND CONCLUSIONS: Our method might detect cerebral ischemia before the onset of DIND and thus be clinically useful for assessing cerebral ischemia with vasospasm.

Development of three-dimensional hollow elastic model for cerebral aneurysm clipping simulation enabling rapid and low cost prototyping.

OBJECTIVE: We developed a method for fabricating a three-dimensional hollow and elastic aneurysm model useful for surgical simulation and surgical training. In this article, we explain the hollow elastic model prototyping method and report on the effects of applying it to presurgical simulation and surgical training. METHODS: A three-dimensional printer using acrylonitrile-butadiene-styrene as a modeling material was used to produce a vessel model. The prototype was then coated with liquid silicone. After the silicone had hardened, the acrylonitrile-butadiene-styrene was melted with xylene and removed, leaving an outer layer as a hollow elastic model. RESULTS: Simulations using the hollow elastic model were performed in 12 patients. In all patients, the clipping proceeded as scheduled. The surgeon's postoperative assessment was favorable in all cases. This method enables easy fabrication at low cost. CONCLUSION: Simulation using the hollow elastic model is thought to be useful for understanding of three-dimensional aneurysm structure.

Ischemic preconditioning blocks BAD translocation, Bcl-xL cleavage, and large channel activity in mitochondria of postischemic hippocampal neurons.

Transient forebrain or global ischemia induces delayed neuronal death in vulnerable CA1 pyramidal cells with many features of apoptosis. A brief period of ischemia, i.e., ischemic preconditioning, affords robust protection of CA1 neurons against a subsequent more prolonged ischemic challenge. Here we show that preconditioning acts via PI3K/Akt signaling to block the ischemia-induced cascade involving mitochondrial translocation of Bad, assembly of Bad with Bcl-x(L), cleavage of Bcl-x(L) to form its prodeath fragment, DeltaN-Bcl-x(L), activation of large-conductance channels in the mitochondrial outer membrane, mitochondrial release of cytochrome c and Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), caspase activation, and neuronal death. These findings show how preconditioning acts to prevent the release of cytochrome c and Smac/DIABLO from mitochondria and to preserve the integrity of the mitochondrial membrane. The specific PI3K inhibitor LY294002 administered in vivo 1 h before or immediately after ischemia or up to 120 h later significantly reverses preconditioning-induced protection, indicating a requirement for sustained PI3K signaling in ischemic tolerance. These findings implicate PI3K/Akt signaling in maintenance of the integrity of the mitochondrial outer membrane.

Ischemic insults promote epigenetic reprogramming of mu opioid receptor expression in hippocampal neurons.

Transient global ischemia is a neuronal insult that induces delayed, selective death of hippocampal CA1 pyramidal neurons. A mechanism underlying ischemia-induced cell death is activation of the gene silencing transcription factor REST (repressor element-1 silencing transcription factor)/NRSF (neuron-restrictive silencing factor) and REST-dependent suppression of the AMPA receptor subunit GluR2 in CA1 neurons destined to die. Here we show that REST regulates an additional gene target, OPRM1 (mu opioid receptor 1 or MOR-1). MORs are abundantly expressed by basket cells and other inhibitory interneurons of CA1. Global ischemia induces a marked decrease in MOR-1 mRNA and protein expression that is specific to the selectively vulnerable area CA1, as assessed by quantitative real-time RT-PCR, Western blotting, and ChIP. We further show that OPRM1 gene silencing is REST-dependent and occurs via epigenetic modifications. Ischemia promotes deacetylation of core histone proteins H3 and H4 and dimethylation of histone H3 at lysine-9 (H3-K9) over the MOR-1 promoter, an signature of epigenetic gene silencing. Acute knockdown of MOR-1 gene expression by administration of antisense oligodeoxynucleotides to hippocampal slices in vitro or injection of the MOR antagonist naloxone to rats in vivo affords protection against ischemia-induced death of CA1 pyramidal neurons. These findings implicate MORs in ischemia-induced death of CA1 pyramidal neurons and document epigenetic remodeling of expression of OPRM1 in CA1 inhibitory interneurons.

Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death.

Transient global or forebrain ischemia induced experimentally in animals can cause selective, delayed neuronal death of hippocampal CA1 pyramidal neurons. A striking feature is a delayed rise in intracellular free Zn(2+) in CA1 neurons just before the onset of histologically detectable cell death. Here we show that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) at Schaffer collateral to CA1 synapses in postischemic hippocampus exhibit properties of Ca(2+)/Zn(2+)-permeable, Glu receptor 2 (GluR2)-lacking AMPARs before the rise in Zn(2+) and cell death. At 42 h after ischemia, AMPA excitatory postsynaptic currents exhibited pronounced inward rectification and marked sensitivity to 1-naphthyl acetyl spermine (Naspm), a selective channel blocker of GluR2-lacking AMPARs. In control hippocampus, AMPA excitatory postsynaptic currents were electrically linear and relatively insensitive to Naspm. Naspm injected intrahippocampally at 9-40 h after insult greatly reduced the late rise in intracellular free Zn(2+) in postischemic CA1 neurons and afforded partial protection against ischemia-induced cell death. These results implicate GluR2-lacking AMPA receptors in the ischemia-induced rise in free Zn(2+) and death of CA1 neurons, although a direct action at the time of the rise in Zn(2+) is unproven. This receptor subtype appears to be an important therapeutic target for intervention in ischemia-induced neuronal death in humans.