Spatiotemporal analysis of multichannel EEG: CARTOOL.

This paper describes methods to analyze the brain's electric fields recorded with multichannel Electroencephalogram (EEG) and demonstrates their implementation in the software CARTOOL. It focuses on the analysis of the spatial properties of these fields and on quantitative assessment of changes of field topographies across time, experimental conditions, or populations. Topographic analyses are advantageous because they are reference independents and thus render statistically unambiguous results. Neurophysiologically, differences in topography directly indicate changes in the configuration of the active neuronal sources in the brain. We describe global measures of field strength and field similarities, temporal segmentation based on topographic variations, topographic analysis in the frequency domain, topographic statistical analysis, and source imaging based on distributed inverse solutions. All analysis methods are implemented in a freely available academic software package called CARTOOL. Besides providing these analysis tools, CARTOOL is particularly designed to visualize the data and the analysis results using 3-dimensional display routines that allow rapid manipulation and animation of 3D images. CARTOOL therefore is a helpful tool for researchers as well as for clinicians to interpret multichannel EEG and evoked potentials in a global, comprehensive, and unambiguous way.

Radiosurgery for brain metastases: specific indications for Gamma Knife in lieu of Linac in a single center using both methods

INTRODUCTION: Radiosurgery (RS) is gaining increasing acceptance in the upfront management of brain metastases (BM). It was initially used in so-called radioresistant metastases (melanoma, renal cell, sarcoma) because it allowed delivering higher dose to the tumor. Now, RS is also used for BM of other cancers. The risk of high incidence of new BM questions the need for associated whole-brain radiotherapy (WBRT). Recent evidence suggests that RS alone allows avoiding cognitive impairment related to WBRT, and the latter should be upheld for salvage therapy. Thus the increase use of RS for single and multiple BM raises new technical challenges for treatment delivery and dosimetry. We present our single institution experience focusing on the criteria that led to patients' selection for RS treatment with Gamma Knife (GK) in lieu of Linac. METHODS: Leksell Gamma Knife Perfexion (Elekta, Sweden) was installed in July 2010. Currently, the Swiss federal health care supports the costs of RS for BM with Linac but not with GK. Therefore, in our center, we always consider first the possibility to use Linac for this indication, and only select patients for GK in specific situations. All cases of BM treated with GK were retrospectively reviewed for criteria yielding to GK indication, clinical information, and treatment data. Further work in progress includes a posteriori dosimetry comparison with our Linac planning system (Brainscan V.5.3, Brainlab, Germany). RESULTS: From July 2010 to March 2012, 20 patients had RS for BM with GK (7 patients with single BM, and 13 with multiple BM). During the same period, 31 had Linac-based RS. Primary tumor was melanoma in 9, lung in 7, renal in 2, and gastrointestinal tract in 2 patients. In single BM, the reason for choosing of GK was the anatomical location close to, or in highly functional areas (1 motor cortex, 1 thalamic, 1 ventricular, 1 mesio-temporal, 3 deep cerebellar close to the brainstem), especially since most of these tumors were intended to be treated with high-dose RS (24 Gy at margin) because of their histology (3 melanomas, 1 renal cell). In multiple BM, the reason for choosing GK in relation with the anatomical location of the lesions was either technical (limitations of Linac movements, especially in lower posterior fossa locations) or closeness of multiple lesions to highly functional areas (typically, multiple posterior fossa BM close to the brainstem), precluding optimal dosimetry with Linac. Again, this was made more critical for multiple BM needing high-dose RS (6 melanoma, 2 hypernephroma). CONCLUSION: Radiosurgery for BM may represent some technical challenge in relation with the anatomical location and multiplicity of the lesions. These considerations may be accentuated for so-called radioresistant BM, when higher dose RS in needed. In our experience, Leksell Gamma Knife Perfexion proves to be useful in addressing these challenges for the treatment of BM.

Role of brain alpha 1B-adrenoceptors in modafinil-induced behavioral activity.

These studies show that either central pharmacological blockade or genetic ablation of alpha(1B)-adrenoceptors markedly attenuates the behavioral activation caused by modafinil, implicating these receptors in the drug's action.

Biochemical characterization of a myelin fraction isolated from rat brain aggregating cell cultures.

Subcellular fractions isolated from rat brain aggregating cell cultures were studied by electron microscopy and showed the presence of typical myelin membranes. The chemical composition of purified culture myelin was similar to the fraction isolated from rat brain in terms of CNP specific activity, protein and lipid composition. The ratio of small to large components of myelin basic protein was comparable in culture and in vivo. These two proteins incorporated radioactive phosphorus. The major myelin glycoprotein was present and during development in culture its apparent molecular weight decreased although it never reached the position observed in myelin isolated from adult rats. In culture, the yield of myelin did not increase substantially between 33 and 50 days and was comparable to that of 15-day-old rat brain. The ratio basic protein to proteolipid protein resembled immature myelin and the cerebroside content was very low. A 'floating fraction' was isolated from the cultures and contained some myelin but mostly single membranes. Although these results indicate that myelin maturation is delayed in vitro this culture system provides substantial amounts of purified myelin to allow a complete biochemical analysis and metabolic studies during development.

Impact of tight glycemic control on cerebral glucose metabolism after severe brain injury: a microdialysis study.

OBJECTIVES: To analyze the effect of tight glycemic control with the use of intensive insulin therapy on cerebral glucose metabolism in patients with severe brain injury. DESIGN: Retrospective analysis of a prospective observational cohort. SETTING: University hospital neurologic intensive care unit. PATIENTS: Twenty patients (median age 59 yrs) monitored with cerebral microdialysis as part of their clinical care. INTERVENTIONS: Intensive insulin therapy (systemic glucose target: 4.4-6.7 mmol/L [80-120 mg/dL]). MEASUREMENTS AND MAIN RESULTS: Brain tissue markers of glucose metabolism (cerebral microdialysis glucose and lactate/pyruvate ratio) and systemic glucose were collected hourly. Systemic glucose levels were categorized as within the target "tight" (4.4-6.7 mmol/L [80-120 mg/dL]) vs. "intermediate" (6.8-10.0 mmol/L [121-180 mg/dL]) range. Brain energy crisis was defined as a cerebral microdialysis glucose <0.7 mmol/L with a lactate/pyruvate ratio >40. We analyzed 2131 cerebral microdialysis samples: tight systemic glucose levels were associated with a greater prevalence of low cerebral microdialysis glucose (65% vs. 36%, p < 0.01) and brain energy crisis (25% vs.17%, p < 0.01) than intermediate levels. Using multivariable analysis, and adjusting for intracranial pressure and cerebral perfusion pressure, systemic glucose concentration (adjusted odds ratio 1.23, 95% confidence interval [CI] 1.10-1.37, for each 1 mmol/L decrease, p < 0.001) and insulin dose (adjusted odds ratio 1.10, 95% CI 1.04-1.17, for each 1 U/hr increase, p = 0.02) independently predicted brain energy crisis. Cerebral microdialysis glucose was lower in nonsurvivors than in survivors (0.46 +/- 0.23 vs. 1.04 +/- 0.56 mmol/L, p < 0.05). Brain energy crisis was associated with increased mortality at hospital discharge (adjusted odds ratio 7.36, 95% CI 1.37-39.51, p = 0.02). CONCLUSIONS: In patients with severe brain injury, tight systemic glucose control is associated with reduced cerebral extracellular glucose availability and increased prevalence of brain energy crisis, which in turn correlates with increased mortality. Intensive insulin therapy may impair cerebral glucose metabolism after severe brain injury.

Minocycline promotes remyelination in aggregating rat brain cell cultures after interferon-γ plus lipopolysaccharide-induced demyelination.

Minocycline has been shown to inhibit microglia reactivity, and to decrease the severity and progression of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. It remained to be examined whether minocycline was also able to promote remyelination. In the present study, myelinating aggregating brain cell cultures were used as a model to study the effects of minocycline on microglial reactivity, demyelination, and remyelination. Cultures were treated simultaneously with two inflammatory agents, interferon-γ (IFN-γ) and lipopolysaccharide (LPS), which caused an inflammatory response accompanied by demyelination. The inflammatory response was characterized by microglial reactivity, upregulation of inflammatory cytokines and iNOS, and increased phophorylation of P38 and P44/42 mitogen activated protein (MAP) kinases. Minocycline inhibited microglial reactivity, and attenuated the increased phophorylation of P38 and P44/42 MAP kinases. Demyelination, determined by a decrease in myelin basic protein (MBP) content and immunoreactivity 48 h after the treatment with the inflammatory agents, was not prevented by minocycline. However, 1 week after demyelination was assessed, the MBP content was restored in presence of minocycline, indicating that remyelination was promoted. Concomitantly, in cultures treated with minocycline, the markers of oligodendrocyte precursors cells (OPCs) and immature oligodendrocytes NG2 and O4, respectively, were decreased compared to cultures treated with the inflammatory agents only. These results suggest that minocycline attenuates microglial reactivity and favors remyelination by enhancing the differentiation of OPCs and immature oligodendrocytes.

Serial brain (18)FDG-PET in anti-AMPA receptor limbic encephalitis.

Immunotherapy-responsive autoimmune CNS syndromes linked to antibodies targeting surface neuronal antigens lack reliable biomarkers of disease activity. We report serial cerebral (18)FDG PET studies in a woman with AMPA receptor (AMPA-R) autoimmune limbic encephalitis. During her follow-up, despite an aggressive immunotherapy, she displayed a persistent, predominantly left hippocampal FDG hypermetabolism, in the absence of CNS inflammatory signs. Brain metabolism abnormalities regressed after increasing antiepileptic treatment, correlating with a moderate clinical improvement. Brain (18)F-FDG PET could thus represent a useful complementary tool to orient the clinical follow-up.

Methods for Determining Frequency- and Region-Dependent Relationships Between Estimated LFPs and BOLD Responses in Humans

The relationship between electrophysiological and functional magnetic resonance imaging (fMRI) signals remains poorly understood. To date, studies have required invasive methods and have been limited to single functional regions and thus cannot account for possible variations across brain regions. Here we present a method that uses fMRI data and singe-trial electroencephalography (EEG) analyses to assess the spatial and spectral dependencies between the blood-oxygenation-level-dependent (BOLD) responses and the noninvasively estimated local field potentials (eLFPs) over a wide range of frequencies (0-256 Hz) throughout the entire brain volume. This method was applied in a study where human subjects completed separate fMRI and EEG sessions while performing a passive visual task. Intracranial LFPs were estimated from the scalp-recorded data using the ELECTRA source model. We compared statistical images from BOLD signals with statistical images of each frequency of the eLFPs. In agreement with previous studies in animals, we found a significant correspondence between LFP and BOLD statistical images in the gamma band (44-78 Hz) within primary visual cortices. In addition, significant correspondence was observed at low frequencies (<14 Hz) and also at very high frequencies (>100 Hz). Effects within extrastriate visual areas showed a different correspondence that not only included those frequency ranges observed in primary cortices but also additional frequencies. Results therefore suggest that the relationship between electrophysiological and hemodynamic signals thus might vary both as a function of frequency and anatomical region.

In vivo measurement of glycine with short echo-time 1H MRS in human brain at 7 T.

OBJECT: To determine whether glycine can be measured at 7 T in human brain with (1)H magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: The glycine singlet is overlapped by the larger signal of myo-inositol. Density matrix simulations were performed to determine the TE at which the myo-inositol signal was reduced the most, following a single spin-echo excitation. (1)H MRS was performed on an actively shielded 7 T scanner, in five healthy volunteers. RESULTS: At the TE of 30 ms, the myo-inositol signal intensity was substantially reduced. Quantification using LCModel yielded a glycine-to-creatine ratio of 0.14 +/- 0.01, with a Cramer-Rao lower bound (CRLB) of 7 +/- 1%. Furthermore, quantification of metabolites other than glycine was possible as well, with a CRLB mostly below 10%. CONCLUSION: It is possible to detect glycine at 7 T in human brain, at the short TE of 30 ms with a single spin-echo excitation scheme.

Electroconvulsive therapy-induced brain plasticity determines therapeutic outcome in mood disorders.

There remains much scientific, clinical, and ethical controversy concerning the use of electroconvulsive therapy (ECT) for psychiatric disorders stemming from a lack of information and knowledge about how such treatment might work, given its nonspecific and spatially unfocused nature. The mode of action of ECT has even been ascribed to a "barbaric" form of placebo effect. Here we show differential, highly specific, spatially distributed effects of ECT on regional brain structure in two populations: patients with unipolar or bipolar disorder. Unipolar and bipolar disorders respond differentially to ECT and the associated local brain-volume changes, which occur in areas previously associated with these diseases, correlate with symptom severity and the therapeutic effect. Our unique evidence shows that electrophysical therapeutic effects, although applied generally, take on regional significance through interactions with brain pathophysiology.

Protein kinases expressed in aggregating brain cell cultures during myelination.

Serum-free aggregating rat brain cell cultures provide sufficient cell surface and paracrine interactions between neurons and glial cells for compact myelination. We are interested in the part played in these signalling pathways by protein kinases and have used a PCR cDNA cloning approach to catalogue the protein kinase genes expressed by these cultures. 8 transmembrane protein kinases were identified: IGF1-R, trk B, bFGF-R, c-met, Tyro2, Tyro1, Tyro4 and a novel eck-related gene. The first 4 are receptors for ligands with known trophic functions. Tyro2 is a novel gene related to the EGF-R. The latter 3 belong to the eck gene family of more than 8 highly related putative receptors for, as yet, unknown ligands. 8 cDNAs for intracellular protein kinases were also isolated including 3 novel genes. Ongoing studies are investigating whether these proteins contribute to myelination and/or could be used as therapeutic targets in demyelinating diseases.