Iver A. Langmoen

Preoperative blood oxygen level-dependent functional magnetic resonance imaging in patients with primary brain tumors: clinical application and outcome.

OBJECTIVEThis study sought to evaluate the ability of blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to successfully identify functional cortical areas in patients with primary brain tumors, to evaluate the use of the fMRI results in presurgical planning, and to assess the functional outcome of the patients with respect to the functional maps obtained with fMRI. METHODSThe study included 25 consecutive preoperative fMRI sessions in patients with primary brain tumors in or near sensorimotor and/or language cortices. All fMRI paradigms were analyzed and rated according to the degree of success. Several distances between tumor and functional cortex as delineated with BOLD fMRI were measured to assess the topographic relationship between these two structures. Pre- and postoperative neurological statuses were obtained from the patients’ journals. RESULTSAcquisition of BOLD fMRI images was successful in 80% of the cases. The primary cause of unsuccessful fMRI was echo-planar imaging signal voids that were the result of previous craniotomy; the secondary cause was excessive motion. The neurosurgeons used the fMRI results for preoperative planning in 75% of the cases in which fMRI was successful. The risk of postoperative loss of function tested with fMRI was significantly lower when the distance between tumor periphery and BOLD activity was 10 mm or more. CONCLUSIONThe majority of patients with primary brain tumors were capable of satisfactorily performing the fMRI paradigms, and the information obtained was used in the preoperative planning. A distance of 10 mm or more between the functional cortex, as delineated with fMRI, and the tumor significantly reduced the risk of postoperative loss of function.

Conductance changes and inhibitory actions of hippocampal recurrent IPSPs

Intracellular recordings were obtained from CA1 pyramidal neurons in obliquely cut in vitro hippocampal slices. Recurrent IPSPs were elicited by antidromic stimulation of alvear fibers. The mechanisms by which IPSPs depress pyramidal cell excitability were investigated. Recurrent IPSPs could be reversed in sign by small hyperpolarizing currents applied through the recording electrode, indicating an increased membrane conductance. By using an AC bridge circuit it was found that the maximum impedance decrease usually occurred slightly before the peak of the IPSP. Otherwise the time course of the impedance change matched that of the IPSP itself. Inhibitory actions of the conductance increase were studied by adjusting the membrane potential to the IPSP equilibrium potential, thus allowing only the IPSP conductance to play an inhibitory role. Under these conditions non-linear summation of recurrent IPSPs with EPSPs originating in the apical dendrites could be demonstrated only during the initial 15--25 msec ofthe IPSP, which is the period of maximum conductance increase. The inhibition afforded by the hyperpolarization of the recurrent IPSP far outlasts the period of effective EPSP shunting by the inhibitory synaptic currents. The mechanisms of recurrent inhibition in the hippocampus thus appear similar to those operating in spinal motoneuron IPSPs.

Mechanisms of norepinephrine actions on hippocampal pyramidal cells in vitro

Responses of pyramidal cells to topical application of norepinephrine (NE) were studied by intracellular recording in hippocampal slices in vitro. Norepinephrine hyperpolarized CA1 cells. Simultaneously, there was a decreased response to constant hyperpolarizing and depolarizing current pulses. The number of spikes evoked by constant depolarizing pulses was reduced. Spontaneous activity, when present, was reduced or abolished. The response to depolarizing current pulses was reduced more than the response to hyperpolarizing current pulses. The reduction of the depolarizing response was minimal for the first 6-8 msec of the pulse, whereafter it increased. The effects persisted after blocking synaptic transmission with low calcium-high magnesium concentrations in the incubation fluid. We conclude that the hyperpolarization is most likely due to a conductance increase. The mechanism behind the reduced response to depolarizing current pulses is discussed.

Surgical Mortality at 30 Days and Complications Leading to Recraniotomy in 2630 Consecutive Craniotomies for Intracranial Tumors

BACKGROUND:In order to weigh the risks of surgery against the presumed advantages, it is important to have specific knowledge about complication rates. OBJECTIVE:To study the surgical mortality and rate of reoperations for hematomas and infections after intracranial surgery for brain tumors in a large, contemporary, single-institution consecutive series. METHODS:All adult patients from a well-defined population of 2.7 million inhabitants who underwent craniotomies for intracranial tumors at Oslo University Hospital from 2003 to 2008 were included (n = 2630). The patients were identified from our prospectively collected database and their charts studied retrospectively. Follow-up was 100%. RESULTS:The overall surgical mortality, defined as death within 30 days of surgery, was 2.3% (n = 60). The mortality rates for high- and low-grade gliomas, meningiomas, and metastases were 2.9%, 1.0%, 0.9%, and 4.5%, respectively. Age >60 (odds ratio 1.84, P < 0.05) and biopsy compared with resection (odds ratio 4.67, P < 0.01) were significantly positively associated with increased surgical mortality. Hematomas accounted for 35% of the surgical mortality. Postoperative hematomas needing evacuation occurred in 2.1% (n = 54). Age >60 was significantly correlated to increased risk of postoperative hematomas (odds ratio 2.43, P < 0.001). A total of 39 patients (1.5%) were reoperated for postoperative infection. Meningiomas had an increased risk of infections compared with high-grade gliomas (odds ratio 4.61, P < 0.001). CONCLUSION:The surgical mortality within 30 days of surgery was 2.3%, with age >60 and biopsy vs resection being the 2 factors significantly associated with increased mortality. Postoperative hematomas caused about one third of the surgical mortality.

Mechanisms concerned in the direct effect of isoflurane on rat hippocampal and human neocortical neurons

The effect of isoflurane on postsynaptic neurons was studied by intracellular recordings from rat hippocampus and human neocortex in vitro. Isoflurane caused a hyperpolarization of the cell membrane. The hyperpolarization was reversed (although incompletely in some neurons) by increasing the membrane potential. The reversal potential was -80 +/- 12 mV (mean +/- S.D.) or 12 +/- 6 mV negative to the resting membrane potential. Potassium channel blockers reduced the isoflurane-induced hyperpolarization, while chloride loading was without effect. The transient depolarization preceding the hyperpolarization in some of the neurons was not reversed by hyperpolarization. The action potential was prolonged by 19 +/- 3% due to a slower rate of rise. The rise time was almost doubled. Firing threshold was increased by 4 +/- 3 mV (relative to the reference electrode). Subthreshold inward rectification was reduced or abolished. Some cells showed subthreshold outward rectification during isoflurane administration. These results suggest that isoflurane depressed neuronal excitability by (1) hyperpolarizing the cell membrane, at least partly by an increase in potassium conductance, (2) slowing the rate of rise of the action potential, presumably due to interference with the fast sodium channel, (3) decreasing subthreshold inward rectification and (4) increasing firing threshold.

Comparison of glioma stem cells to neural stem cells from the adult human brain identifies dysregulated Wnt- signaling and a fingerprint associated with clinical outcome

Glioblastoma is the most common brain tumor. Median survival in unselected patients is <10 months. The tumor harbors stem-like cells that self-renew and propagate upon serial transplantation in mice, although the clinical relevance of these cells has not been well documented. We have performed the first genome-wide analysis that directly relates the gene expression profile of nine enriched populations of glioblastoma stem cells (GSCs) to five identically isolated and cultivated populations of stem cells from the normal adult human brain. Although the two cell types share common stem- and lineage-related markers, GSCs show a more heterogeneous gene expression. We identified a number of pathways that are dysregulated in GSCs. A subset of these pathways has previously been identified in leukemic stem cells, suggesting that cancer stem cells of different origin may have common features. Genes upregulated in GSCs were also highly expressed in embryonic and induced pluripotent stem cells. We found that canonical Wnt-signaling plays an important role in GSCs, but not in adult human neural stem cells. As well we identified a 30-gene signature highly overexpressed in GSCs. The expression of these signature genes correlates with clinical outcome and demonstrates the clinical relevance of GSCs.

A comparison between stem cells from the adult human brain and from brain tumors.

OBJECTIVE To directly compare stem cells from the normal adult human brain (adult human neural stem cells [AHNSC]), Grade II astrocytomas (AC II), and glioblastoma multiforme (GBM), with respect to proliferative and tumor-forming capacity and differentiation potential. METHODS Cells were isolated from tissue obtained during epilepsy surgery (AHNSCs) or tumor surgery (glioma stem cells [GSC]). They were cultured and investigated in vitro or after transplantation in immunodeficient mice. RESULTS Under identical experimental conditions, the following were found: 1) GBM stem cells formed tumors after orthotopic transplantation; AHNSCs showed no sign of tumor formation; 2) GSCs showed a significantly higher growth rate and self-renewal capacity; 3) both the growth rate and telomerase expression were high in GSCs and correlated with malignancy grade (GBM higher than AC II); AHNSCs had low telomerase expression; 4) GSCs invaded normal neurospheres, not vice versa; 5) both AHNSCs and stem cells from AC II and GBM responded to differentiation cues with a dramatic decrease in the proliferation index (Ki-67); 6) GSCs differentiated faster than AHNSCs; 7) upon differentiation, AHNSCs produced normal glia and neurons; GSCs produced morphologically aberrant cells often expressing both glial and neuronal antigens; and 8) differentiation of AHNSCs resulted in 2 typical functional phenotypes: neurons (high electrical membrane resistance, ability to generate action potentials) and glial cells (low membrane resistance, no action potentials). In contrast, GSCs resulted in only 1 functional phenotype: cells with high electrical resistance and active membrane properties capable of generating action potentials. CONCLUSION AHNSCs and stem cells from AC II and GBM differ with respect to proliferation, tumor-forming capacity, and rate and pattern of differentiation.

Methylprednisolone Treatment Does Not Influence Axonal Regeneration or Degeneration Following Optic Nerve Injury in the Adult Rat

Background: Methylprednisolone (MP) is often used to treat optic nerve injury. However, its effects in experimental crush injury have not been extensively evaluated. Methods: Adult Sprague-Dawley rats were subjected to a standardized optic nerve crush injury. Animals were treated either with 30 mg/kg MP intravenous bolus followed by subcutaneous injections every 6 hours for 48 hours, or with a drug vehicle alone. Results: The injury resulted in a partial loss of neuronal nuclei-labeled retinal neurons and a corresponding degeneration of axons distal to the injury. ED1-labeled macrophages accumulated at the site of lesion, phagocyting FJ-labeled axonal debris. Regenerative fibers expressing growth associated protein-43 were seen proximal to the lesion, but did not traverse the glial scar. Analysis of optic nerve function using visual evoked potentials showed typical signals in intact animals, which were abolished after injury in MP-treated and untreated animals. Conclusions: We did not detect any effects of MP on retinal cell survival, macrophage activity at the site of injury, axonal degeneration/regeneration, or visual function. These experimental results provide a physiologic underpinning for the lack of efficacy demonstrated in a large trial of MP treatment of clinical optic nerve injury.

The effect of the volatile anesthetic isoflurane on Ca2+-dependent glutamate release from rat cerebral cortex☆

A major effect of volatile anesthetics is to reduce excitatory synaptic transmission. In the present study the stimulated release of glutamate under the influence of increasing concentrations of isoflurane was studied in vitro by utilizing hippocampal slices from Wistar rats. Ca(2+)-dependent release was calculated by subtracting stimulated release with blocked synaptic transmission (50 mM K+, 0 mM Ca2+ and 4 mM Mg2+) from total evoked release (50 mM K+, 2 mM Ca2+ and 1 mM Mg2+). Isoflurane 0.5, 1.5 and 3% reduced Ca(2+)-dependent release of glutamate to 69, 58 and 49%, respectively (P < 0.05 for all related to control). These results are in agreement with the possibility of reduced release of transmitter as a mechanism of action of volatile anesthetics.

Transplantation of stem cells from the adult human brain to the adult rat brain.

OBJECTIVETo investigate the migration, proliferation, and differentiation of stem cells and neural progenitor cells (NPCs) from the adult human brain after transplantation into adult rodent brains. METHODSAdult human NPCs were obtained from temporal lobe specimens removed because of medical intractable epilepsy. The cells were transplanted into the posterior periventricular region above the hippocampus in the brains of either healthy adult rats (control) or rats with selective injury of the hippocampal CA1 region (global ischemia). RESULTSIn the control animals, grafted cells were mainly distributed from the site of transplantation toward the midline along white matter tracts. The density of transplanted cells elsewhere, including the hippocampus, was low and apparently random. In animals with CA1 damage, NPCs showed targeted migration into the injured area. Cell survival at 10 weeks was 4.7 ± 0.3% (control, n = 3) and 3.7 ± 1.1% (ischemia, n = 3); at 16 weeks, cell survival was 3.4 ± 0.6% (control, n = 2) and 7.2 ± 1.5% (ischemia, n = 2), i.e., comparable to what has been observed earlier when transplanting embryonic tissue into the human brain or progenitor cells between inbred rats. The number of dividing cells decreased with time. Sixteen weeks after transplantation, 4 ± 1% (n = 4) of the cells showed proliferative activity. We did not observe signs of tumor formation or aberrant cell morphology. Neuronal differentiation was much slower than what has been observed earlier in vitro or after transplantation to the developing nervous system, and 16 weeks after transplantation many surviving cells were still in maturation. CONCLUSIONThe present study shows that adult human NPCs survive, show targeted migration, proliferate, and differentiate after grafting into the adult rat brain.