Synaptic alterations and neuronal firing in human epileptic neocortical excitatory networks.

Epilepsy is a prevalent neurological condition, with underlying neuronal mechanisms involving hyperexcitability and hypersynchrony. Imbalance between excitatory and inhibitory circuits, as well as histological reorganization are relatively well-documented in animal models or even in the human hippocampus, but less is known about human neocortical epileptic activity. Our knowledge about changes in the excitatory signaling is especially scarce, compared to that about the inhibitory cell population. This study investigated the firing properties of single neurons in the human neocortex in vitro, during pharmacological blockade of glutamate receptors, and additionally evaluated anatomical changes in the excitatory circuit in tissue samples from epileptic and non-epileptic patients. Both epileptic and non-epileptic tissues exhibited spontaneous population activity (SPA), NMDA receptor antagonization reduced SPA recurrence only in epileptic tissue, whereas further blockade of AMPA/kainate receptors reversibly abolished SPA emergence regardless of epilepsy. Firing rates did not significantly change in excitatory principal cells and inhibitory interneurons during pharmacological experiments. Granular layer (L4) neurons showed an increased firing rate in epileptic compared to non-epileptic tissue. The burstiness of neurons remained unchanged, except for that of inhibitory cells in epileptic recordings, which decreased during blockade of glutamate receptors. Crosscorrelograms computed from single neuron discharge revealed both mono- and polysynaptic connections, particularly involving intrinsically bursting principal cells. Histological investigations found similar densities of SMI-32-immunopositive long-range projecting pyramidal cells in both groups, and shorter excitatory synaptic active zones with a higher proportion of perforated synapses in the epileptic group. These findings provide insights into epileptic modifications from the perspective of the excitatory system and highlight discrete alterations in firing patterns and synaptic structure. Our data suggest that NMDA-dependent glutamatergic signaling, as well as the excitatory synaptic machinery are perturbed in epilepsy, which might contribute to epileptic activity in the human neocortex.

Bursting of excitatory cells is linked to interictal epileptic discharge generation in humans.

Knowledge about the activity of single neurons is essential in understanding the mechanisms of synchrony generation, and particularly interesting if related to pathological conditions. The generation of interictal spikes-the hypersynchronous events between seizures-is linked to hyperexcitability and to bursting behaviour of neurons in animal models. To explore its cellular mechanisms in humans we investigated the activity of clustered single neurons in a human in vitro model generating both physiological and epileptiform synchronous events. We show that non-epileptic synchronous events resulted from the finely balanced firing of excitatory and inhibitory cells, which was shifted towards an enhanced excitability in epileptic tissue. In contrast, interictal-like spikes were characterised by an asymmetric overall neuronal discharge initiated by excitatory neurons with the presumptive leading role of bursting pyramidal cells, and possibly terminated by inhibitory interneurons. We found that the overall burstiness of human neocortical neurons is not necessarily related to epilepsy, but the bursting behaviour of excitatory cells comprising both intrinsic and synaptically driven bursting is clearly linked to the generation of epileptiform synchrony.

Distinct miRNA Expression Signatures of Primary and Secondary Central Nervous System Lymphomas.

Central nervous system (CNS) lymphoma is a rare and aggressive non-Hodgkin lymphoma that might arise in the CNS (primary CNS lymphoma) or disseminates from a systemic lymphoma to the CNS (secondary CNS lymphoma). Dysregulated expression of miRNAs is associated with various pathologic processes, and miRNA expression patterns may have diagnostic, prognostic, and therapeutic implications. However, miRNA expression is understudied in CNS lymphomas. We performed expression analysis of 798 miRNAs in 73 CNS lymphoma samples using the NanoString platform, followed by an analysis to identify potential diagnostic biomarkers characterizing subgroups and to examine differences based on their primary and secondary nature, molecular subtype, mutational patterns, and survival. Thirty-one differentially expressed miRNAs were identified between primary and secondary groups. In addition, 7 more miRNAs were identified associated with a molecular subtype and 25 associated with mutation status. Using unsupervised clustering methods, a small but distinct primary CNS lymphoma subgroup, with characteristically different expression patterns compared with the rest of the cases was defined. Finally, differentially regulated pathways were identified in the above comparisons and the utility of miRNA expression patterns in predicting survival was assessed. Our study identifies a novel CNS lymphoma subgroup defined by distinct miRNAs, proves the importance of specific miRNAs and pathways in the pathogenesis of CNS lymphomas, and provides the basis for future research in defining potential biomarkers.

Perisomatic Inhibition and Its Relation to Epilepsy and to Synchrony Generation in the Human Neocortex.

Inhibitory neurons innervating the perisomatic region of cortical excitatory principal cells are known to control the emergence of several physiological and pathological synchronous events, including epileptic interictal spikes. In humans, little is known about their role in synchrony generation, although their changes in epilepsy have been thoroughly investigated. This paper demonstraits how parvalbumin (PV)- and type 1 cannabinoid receptor (CB1R)-positive perisomatic interneurons innervate pyramidal cell bodies, and their role in synchronous population events spontaneously emerging in the human epileptic and non-epileptic neocortex, in vitro. Quantitative electron microscopy showed that the overall, PV+ and CB1R+ somatic inhibitory inputs remained unchanged in focal cortical epilepsy. On the contrary, the size of PV-stained synapses increased, and their number decreased in epileptic samples, in synchrony generating regions. Pharmacology demonstrated-in conjunction with the electron microscopy-that although both perisomatic cell types participate, PV+ cells have stronger influence on the generation of population activity in epileptic samples. The somatic inhibitory input of neocortical pyramidal cells remained almost intact in epilepsy, but the larger and consequently more efficient somatic synapses might account for a higher synchrony in this neuron population. This, together with epileptic hyperexcitability, might make a cortical region predisposed to generate or participate in hypersynchronous events.

Molecular Subtypes and Genomic Profile of Primary Central Nervous System Lymphoma.

Primary central nervous system lymphomas (PCNSL) are aggressive non-Hodgkin lymphomas affecting the central nervous system (CNS). Although immunophenotyping studies suggested an uniform activated B-cell (ABC) origin, more recently a spectrum of ABC and germinal center B-cell (GC) cases has been proposed, with the molecular subtypes of PCNSL still being a matter of debate. With the emergence of novel therapies demonstrating different efficacy between the ABC and GC patient groups, precise assignment of molecular subtype is becoming indispensable. To determine the molecular subtype of 77 PCNSL and 17 secondary CNS lymphoma patients, we used the NanoString Lymphoma Subtyping Test (LST), a gene expression-based assay representing a more accurate technique of subtyping compared with standard immunohistochemical (IHC) algorithms. Mutational landscapes of 14 target genes were determined using ultra-deep next-generation sequencing. Using the LST-assay, a significantly lower proportion (80% vs 95%) of PCNSL cases displayed ABC phenotype compared with the IHC-based characterization. The most frequently mutated genes included MYD88, PIM1, and KMT2D. In summary, we successfully applied the LST-assay for molecular classification of PCNSL, reporting higher proportion of cases with GC phenotype compared with IHC analyses, leading to a more precise patient stratification potentially applicable in the diagnostic algorithm of PCNSL.

Presence of synchrony-generating hubs in the human epileptic neocortex.

KEY POINTS: •Initiation of pathological synchronous events such as epileptic spikes and seizures is linked to the hyperexcitability of the neuronal network in both humans and animals. •In the present study, we show that epileptiform interictal-like spikes and seizures emerged in human neocortical slices by blocking GABAA receptors, following the disappearance of the spontaneously occurring synchronous population activity. •Large variability of temporally and spatially simple and complex spikes was generated by tissue from epileptic patients, whereas only simple events appeared in samples from non-epileptic patients. •Physiological population activity was associated with a moderate level of principal cell and interneuron firing, with a slight dominance of excitatory neuronal activity, whereas epileptiform events were mainly initiated by the synchronous and intense discharge of inhibitory cells. •These results help us to understand the role of excitatory and inhibitory neurons in synchrony-generating mechanisms, in both epileptic and non-epileptic conditions. ABSTRACT: Understanding the role of different neuron types in synchrony generation is crucial for developing new therapies aiming to prevent hypersynchronous events such as epileptic seizures. Paroxysmal activity was linked to hyperexcitability and to bursting behaviour of pyramidal cells in animals. Human data suggested a leading role of either principal cells or interneurons, depending on the seizure morphology. In the present study, we aimed to uncover the role of excitatory and inhibitory processes in synchrony generation by analysing the activity of clustered single neurons during physiological and epileptiform synchronies in human neocortical slices. Spontaneous population activity was detected with a 24-channel laminar microelectrode in tissue derived from patients with or without preoperative clinical manifestations of epilepsy. This population activity disappeared by blocking GABAA receptors, and several variations of spatially and temporally simple or complex interictal-like spikes emerged in epileptic tissue, whereas peritumoural slices generated only simple spikes. Around one-half of the clustered neurons participated with an elevated firing rate in physiological synchronies with a slight dominance of excitatory cells. By contrast, more than 90% of the neurons contributed to interictal-like spikes and seizures, and an intense and synchronous discharge of inhibitory neurons was associated with the start of these events. Intrinsically bursting principal cells fired later than other neurons. Our data suggest that a balanced excitation and inhibition characterized physiological synchronies, whereas disinhibition-induced epileptiform events were initiated mainly by non-synaptically synchronized inhibitory neurons. Our results further highlight the differences between humans and animal models, and between in vivo and (pharmacologically manipulated) in vitro conditions.

PD-L1 Expression of Lung Cancer Cells, Unlike Infiltrating Immune Cells, Is Stable and Unaffected by Therapy During Brain Metastasis.

BACKGROUND: Approximately 50% of brain metastases originate from non-small-cell lung cancer. The median survival of patients with brain metastases is 1 month without treatment. Novel immunotherapeutic strategies, such as those targeting the programmed death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) axis, are promising in patients with advanced systemic disease but are often preferentially administered to patients with tumors showing PD-L1 positivity. PATIENTS AND METHODS: Surgically resected paired primary lung adenocarcinoma and brain metastasis samples of 61 patients were analyzed. We compared the paired samples regarding the amount of peritumoral and stromal mononuclear infiltration, PD-L1 expression of tumor and immune cells, and PD-1 expression of immune cells. We investigated the effect of radiotherapy, chemotherapy, and steroid therapy on PD-L1 expression in brain metastases. RESULTS: There was significant positive correlation regarding the PD-L1 expression of tumor cells between the paired primary lung adenocarcinoma and brain metastatic samples with the use of different cutoff levels (1%, 5%, 50%). We found no impact of chemotherapy or steroid therapy on the changes of PD-L1 expression of tumor cells between the 2 sites. There is no or only limited concordance of the proportion of PD-1- or PD-L1-positive tumor-associated immune cells between the paired tumor samples, which suggests that brain metastases develop their own immune environment. CONCLUSION: We observed a strong correlation of PD-L1 positive tumor cells between primary lung adenocarcinoma cases and their corresponding brain metastases, which is not significantly influenced by chemotherapy or steroid therapy.

Discrepancy Between Low Levels of mTOR Activity and High Levels of P-S6 in Primary Central Nervous System Lymphoma May Be Explained by PAS Domain-Containing Serine/Threonine-Protein Kinase-Mediated Phosphorylation.

The primary aim of this study was to determine mTOR-pathway activity in primary central nervous system lymphoma (PCNSL), which could be a potential target for therapy. After demonstrating that p-S6 positivity largely exceeded mTOR activity, we aimed to identify other pathways that may lead to S6 phosphorylation. We measured mTOR activity with immunohistochemistry for p-mTOR and its downstream effectors p(T389)-p70S6K1, p-S6, and p-4E-BP1 in 31 cases of PCNSL and 51 cases of systemic diffuse large B-cell lymphoma (DLBCL) and evaluated alternative S6 phosphorylation pathways with p-RSK, p(T229)-p70S6K1, and PASK antibodies. Finally, we examined the impact of PASK inhibition on S6 phosphorylation on BHD1 cell line. mTOR-pathway activity was significantly less frequent in PCNSL compared with DLBCL. p-S6 positivity was related to mTOR-pathway in DLBCL, but not in PCNSL. Among the other kinases potentially responsible for S6 phosphorylation, PASK proved to be positive in all cases of PCNSL and DLBCL. Inhibition of PASK resulted in reduced expression of p-S6 in BHD1-cells. This is the first study demonstrating an mTOR independent p-S6 activity in PCNSL and that PASK may contribute to the phosphorylation of S6. Our findings also suggest a potential role of PASK in the pathomechanism of PCNSL and in DLBCL.

Evaluating the significance of density, localization, and PD-1/PD-L1 immunopositivity of mononuclear cells in the clinical course of lung adenocarcinoma patients with brain metastasis.

BACKGROUND: Management of lung cancer patients who suffer from brain metastases represents a major challenge. Considering the promising results with immune checkpoint inhibitor treatment, evaluating the status of immune cell (IC) infiltrates in the prognosis of brain metastasis may lead to better therapeutic strategies with these agents. The aim of this study was to characterize the distribution of ICs and determine the expression of the checkpoint molecules programmed death protein 1 (PD-1) and its ligand, PD-L1, in brain metastasis of lung adenocarcinoma (LUAD) patients and to analyze their clinicopathological correlations. METHODS: We determined the presence of peritumoral mononuclear cells (mononuclear ring) and the density of intratumoral stromal mononuclear cells on brain metastasis tissue sections of 208 LUAD patients. PD-L1/PD-1 expressions were analyzed by immunohistochemistry. RESULTS: Mononuclear rings were significantly associated with better survival after brain metastasis surgery. Cases with massive stromal IC infiltration also showed a tendency for better overall survival. Lower expression of PD-1 and PD-L1 was associated with better survival in patients who underwent surgery for the primary tumor and had multiple brain metastases. Steroid administration and chemotherapy appear not to influence the density of IC in brain metastasis. CONCLUSION: This is the first study demonstrating the independent prognostic value of mononuclear rings in LUAD cases with brain metastasis. Our results also suggest that the density of tumor-associated ICs in addition to PD-L1 expression of tumor cells and ICs as well as PD-1 expression of ICs may hold relevant information for the appropriate selection of patients who might benefit from anti-PD-L1 or anti-PD-1 therapy.

Localization of SUCLA2 and SUCLG2 subunits of succinyl CoA ligase within the cerebral cortex suggests the absence of matrix substrate-level phosphorylation in glial cells of the human brain.

We have recently shown that the ATP-forming SUCLA2 subunit of succinyl-CoA ligase, an enzyme of the citric acid cycle, is exclusively expressed in neurons of the human cerebral cortex; GFAP- and S100-positive astroglial cells did not exhibit immunohistoreactivity or in situ hybridization reactivity for either SUCLA2 or the GTP-forming SUCLG2. However, Western blotting of post mortem samples revealed a minor SUCLG2 immunoreactivity. In the present work we sought to identify the cell type(s) harboring SUCLG2 in paraformaldehyde-fixed, free-floating surgical human cortical tissue samples. Specificity of SUCLG2 antiserum was supported by co-localization with mitotracker orange staining of paraformaldehyde-fixed human fibroblast cultures, delineating the mitochondrial network. In human cortical tissue samples, microglia and oligodendroglia were identified by antibodies directed against Iba1 and myelin basic protein, respectively. Double immunofluorescence for SUCLG2 and Iba1 or myelin basic protein exhibited no co-staining; instead, SUCLG2 appeared to outline the cerebral microvasculature. In accordance to our previous work there was no co-localization of SUCLA2 immunoreactivity with either Iba1 or myelin basic protein. We conclude that SUCLG2 exist only in cells forming the vasculature or its contents in the human brain. The absence of SUCLA2 and SUCLG2 in human glia is in compliance with the presence of alternative pathways occurring in these cells, namely the GABA shunt and ketone body metabolism which do not require succinyl CoA ligase activity, and glutamate dehydrogenase 1, an enzyme exhibiting exquisite sensitivity to inhibition by GTP.

Exclusive neuronal expression of SUCLA2 in the human brain.

SUCLA2 encodes the ATP-forming ß subunit (A-SUCL-ß) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here, we show that immunoreactivity of A-SUCL-ß in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL-ß immunoreactivity co-localized >99 % with that of the d subunit of the mitochondrial F0-F1 ATP synthase. Specificity of the anti-A-SUCL-ß antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. A-SUCL-ß immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming ß subunit (G-SUCL-ß) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL-ß immunoreactivity that was, however, not upregulated in samples obtained from diabetic versus non-diabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex.

Paralemniscal TIP39 is induced in rat dams and may participate in maternal functions.

The paralemniscal area, situated between the pontine reticular formation and the lateral lemniscus in the pontomesencephalic tegmentum contains some tuberoinfundibular peptide of 39 residues (TIP39)-expressing neurons. In the present study, we measured a 4 times increase in the level of TIP39 mRNA in the paralemniscal area of lactating mothers as opposed to nulliparous females and mothers deprived of pups using real-time RT-PCR. In situ hybridization histochemistry and immunolabeling demonstrated that the induction of TIP39 in mothers takes place within the medial paralemniscal nucleus, a cytoarchitectonically distinct part of the paralemniscal area, and that the increase in TIP39 mRNA levels translates into elevated peptide levels in dams. The paralemniscal area has been implicated in maternal control as well as in pain perception. To establish the function of induced TIP39, we investigated the activation of TIP39 neurons in response to pup exposure as maternal, and formalin injection as noxious stimulus. Both stimuli elicited c-fos expression in the paralemniscal area. Subsequent double labeling demonstrated that 95% of neurons expressing Fos in response to pup exposure also contained TIP39 immunoreactivity and 91% of TIP39 neurons showed c-fos activation by pup exposure. In contrast, formalin-induced Fos does not co-localize with TIP39. Instead, most formalin-activated neurons are situated medial to the TIP39 cell group. Our data indicate that paralemniscal neurons may be involved in the processing of maternal and nociceptive information. However, two different groups of paralemniscal neurons participate in the two functions. In particular, TIP39 neurons may participate in the control of maternal functions.

Neuronavigation and fluoroscopy-assisted subdural strip electrode positioning: a simple method to increase intraoperative accuracy of strip localization in epilepsy surgery.

For localization of the epileptogenic zone in cases of focal epilepsy, detailed clinical investigations, imaging studies, and electrophysiological methods are used. If the noninvasive presurgical evaluation provides insufficient data, intracranial electrodes are necessary. Computed tomography and MR imaging techniques are the gold standard for localization of the postoperative position of the implanted intracranial electrode contacts. If the electrode strips are inserted through a bur hole, however, the exact localization of the electrode contacts on the patient's brain remains uncertain for the surgeon during insertion. Therefore, the authors developed a simple method to visualize the electrodes during the procedure. In this method they combine neuronavigation and intraoperative fluoroscopy for parallel visualization of the cortex, electrodes, and the navigation probe. The target region is searched with neuronavigation, a bur hole is made over the optimal entry point, and using real-time fluoroscopy the strip electrode is slid to the tip of the navigation probe, which was kept over the area of interest. At the authors' institution 26 strips in 8 patients have been inserted with this technique, and none of the strips had to be repositioned. There were no complications with this procedure and the prolongation of surgery time is acceptable. Compared to previously published electrode placement methods, this one enhances the accuracy of electrode placement at occipital, parietal, frontal, or interhemispheric regions as well. Intraoperative visualization of the electrodes with fluoroscopy combined with neuronavigation during positioning through a bur hole gives the neurosurgeon the ability to control the real position of the electrode over the gyri during the procedure.

Tuberoinfundibular peptide of 39 residues in the embryonic and early postnatal rat brain.

Tuberoinfundibular peptide of 39 residues (TIP39) was identified as the endogenous ligand of parathyroid hormone 2 receptor. We have recently demonstrated that TIP39 expression in adult rat brain is confined to the subparafascicular area of the thalamus with a few cells extending laterally into the posterior intralaminar thalamic nucleus (PIL), and the medial paralemniscal nucleus (MPL) in the lateral pontomesencephalic tegmentum. During postnatal development, TIP39 expression increases until postnatal day 33 (PND-33), then decreases, and almost completely disappears by PND-125. Here, we report the expression of TIP39 during early brain development. TIP39-immunoreactive (TIP39-ir) neurons in the subparafascicular area first appeared at PND-1. In contrast, TIP39-ir neurons were detectable in the MPL at embryonic day 14.5 (ED-14.5), and the intensity of their labeling increased thereafter. We also identified TIP39-ir neurons between ED-16.5 and PND-5 in two additional brain areas, the PIL and the amygdalo-hippocampal transitional zone (AHi). We confirmed the specificity of TIP39 immunolabeling by demonstrating TIP39 mRNA using in situ hybridization histochemistry. In the PIL, TIP39 neurons are located medial to the CGRP group as demonstrated by double immunolabeling. All TIP39-ir neurons in the AHi and most TIP39-ir neurons in the PIL disappear during early postnatal development. The adult pattern of TIP39-ir fibers emerge during postnatal development. However, fibers emanating from PIL can be followed in the supraoptic decussations towards the hypothalamus at ED-18.5. These TIP39-ir fibers disappear by PND-1. The complex pattern of TIP39 expression during early brain development suggests the involvement of TIP39 in transient functions during ontogeny.

Evidence for the expression of parathyroid hormone 2 receptor in the human brainstem.

BACKGROUND AND PURPOSE: The parathyroid hormone 2 receptor (PTH2R) is a G protein coupled receptor. Pharmacological and anatomical evidence suggests that the recently identified tuberoinfundibular peptide of 39 residues is, and parathyroid hormone and parathyroid hormone-related peptide are not, its endogenous ligand. Initial functional studies suggest that the PTH2R is involved in the regulation of viscerosensory information processing. As a first step towards clinical applications, herein we describe the presence of the PTH2R in the human brainstem. MATERIAL AND METHODS: Total RNA was isolated from postmortem human cortical and brainstem samples for RT-PCR. Good quality RNA, as assessed on formaldehyde gel, was reverse transcribed. The combined cDNA products were used as template in PCR reactions with primer pairs specific for the human PTH2R. In addition, PTH2R immunolabelling was performed on free floating sections of the human medulla oblongata using fluorescent amplification immunochemistry. RESULTS: Specific bands in the RT-PCR experiments and sequencing of PCR products demonstrated the expression of PTH2R mRNA in the human brainstem. A high density of PTH2R-immunoreactive fibers was found in brain regions of the medulla oblongata including the nucleus of the solitary tract, the spinal trigeminal nucleus, and the dorsal reticular nucleus of the medulla. CONCLUSION: Independent demonstration of the presence of PTH2R mRNA and immunoreactivity supports the specific expression of the PTH2R in the human brainstem. The distribution of PTH2R-immunoreactive fibers in viscerosensory brain regions is similar to that reported in mouse and rat suggesting a similar role of the PTH2R in human as in rodents. This finding will have important implications when experimental data obtained on the function of the TIP39-PTH2R neuromodulator system in rodents are to be utilized in human.

Single-dose contrast agent for intraoperative MR imaging of intrinsic brain tumors by using ferumoxtran-10.

BACKGROUND AND PURPOSE: Intraoperative MR imaging (IMRI) has advantages over conventional framed and frameless techniques. IMRI, however, also has some drawbacks, especially related to interpretation of gadolinium-enhanced intraoperative imaging resulting from surgically induced blood brain barrier injury, vascular changes, and hemorrhage. Ultra-small superparamagnetic iron particles like ferumoxtran-10 have a long plasma half-life and are trapped by reactive cells within the tumor. These trapped particles provide a method to demonstrate enhancing lesions without the artifact of repeat gadolinium administration in the face of blood brain barrier and vascular injury. METHODS: We present a review of the literature and the cases of two patients who underwent surgery in which IMRI with ferumoxtran-10 was used. RESULTS: Ultra-small superparamagnetic iron particles represent a method to demonstrate enhancing intrinsic brain tumors without the drawbacks of intraoperative gadolinium enhancement. These lesions appear even on low-field strength IMRI. Ferumoxtran-10, administered preoperatively, provides a stable imaging marker, even after surgical manipulation of the brain. CONCLUSION: Fermumoxtran-10 provides a way to lessen artifactual enhancement during IMRI related to the administration of gadolinium.