Jeffery A. Hall

Interictal high‐frequency oscillations (80–500 Hz) are an indicator of seizure onset areas independent of spikes in the human epileptic brain

Purpose:  High‐frequency oscillations (HFOs) known as ripples (80–250 Hz) and fast ripples (250–500 Hz) can be recorded from macroelectrodes inserted in patients with intractable focal epilepsy. They are most likely linked to epileptogenesis and have been found in the seizure onset zone (SOZ) of human ictal and interictal recordings. HFOs occur frequently at the time of interictal spikes, but were also found independently. This study analyses the relationship between spikes and HFOs and the occurrence of HFOs in nonspiking channels.

High-frequency intracerebral EEG activity (100-500 Hz) following interictal spikes

Summary:  Purpose: High‐frequency activity has been recorded with intracerebral microelectrodes in epileptic patients and related to seizure genesis. Our goal was to analyze high‐frequency activity recorded with electroencephalograph (EEG) macroelectrodes during the slow wave immediately following interictal spikes, given the potential importance of this presumed hyperpolarization in transforming spikes into seizures.

Cyclical and Dose-Dependent Responses of Adult Human Mature Oligodendrocytes to Fingolimod

Fingolimod is a sphingosine-1-phosphate (S1P) analogue that has been used in clinical trials as a systemic immunomodulatory therapy for multiple sclerosis. Fingolimod readily accesses the central nervous system, raising the issue of its direct effects on neural cells. We assessed the effects of active fingolimod on dissociated cultures of mature, myelin-producing oligodendrocytes (OLGs) derived from adult human brain. Human OLGs express S1P receptor transcripts in relative abundance of S1P5>S1P3>S1P1, with undetectable levels of S1P4. Low doses of fingolimod (100 pmol/L to 1 nmol/L) induced initial membrane elaboration (2 days), subsequent retraction (4 days), and recurrence of extension with prolonged treatment (8 days). Higher doses (10 nmol/L to 1 mumol/L) caused the opposite modulation of membrane dynamics. Retraction was rescued by co-treatment with the S1P3/S1P5 pathway antagonist, suramin, and was associated with RhoA-mediated cytoskeletal signaling. Membrane elaboration was mimicked using the S1P1 agonist SEW2871. Fingolimod rescued human OLGs from serum and glucose deprivation-induced apoptosis, which was reversed with suramin co-treatment and mimicked using an S1P5 agonist. High doses of fingolimod induced an initial down-regulation of S1P5 mRNA levels relative to control (4 hours), subsequent up-regulation (2 days), and recurrent down-regulation (8 days). S1P1 mRNA levels were inversely regulated compared with S1P5. These results indicate that fingolimod modulates maturity- and species-specific OLG membrane dynamics and survival responses that are directly relevant for myelin integrity.

NKG2D-Mediated Cytotoxicity toward Oligodendrocytes Suggests a Mechanism for Tissue Injury in Multiple Sclerosis

NKG2D is an activating or coactivating receptor expressed on human natural killer (NK) cells, CD8+ T cells, and γ/δ T cells. NKG2D ligands have been detected on many tumor cell types and can be induced on nontransformed cells by environmental signals including DNA damage and inflammation. We investigated the contribution of NKG2D–NKG2D ligand interaction on CNS-directed immune responses. We observed that primary cultures of human adult oligodendrocytes and fetal astrocytes expressed ligands for NKG2D in vitro whereas neurons, microglia, and adult astrocytes did not. Disruption of the NKG2D–NKG2D ligand interaction using blocking antibodies significantly inhibited killing of primary human oligodendrocytes mediated by activated human NK cells, γ/δ T cells, and allo-reactive CD8+ T cells. NKG2D ligands [major histocompatibility complex class I chain-related molecules A and B (MICA/B)] were detected in groups of cells and colocalized with an oligodendrocyte marker (adenomatous polyposis coli) in white matter sections obtained from multiple sclerosis lesions but not in normal control samples. CD8+ T cells could be detected in close proximity to MICA/B+ cells within multiple sclerosis lesions, supporting an in vivo interaction between these immune effectors and stressed MICA/B-expressing oligodendrocytes. These results imply that NKG2D–NKG2D ligand interaction can potentially contribute to cytotoxic responses mediated by activated immune effector cells in the inflamed CNS, as observed in multiple sclerosis.

Electroencephalography/functional magnetic resonance imaging responses help predict surgical outcome in focal epilepsy

Simultaneous electroencephalography/functional magnetic resonance imaging (EEG/fMRI) recording can noninvasively map in the whole brain the hemodynamic response following an interictal epileptic discharge. EEG/fMRI is gaining interest as a presurgical evaluation tool. This study aims to determine how hemodynamic responses related to epileptic activity can help predict surgical outcome in patients considered for epilepsy surgery.

Dendritic Cell Differentiation Signals Induce Anti-Inflammatory Properties in Human Adult Microglia

Microglia are resident cells of the CNS that belong to the myeloid cell lineage. In experimental models of neuroinflammation, they have limited capacity to function as APCs when compared with dendritic cells (DCs). Human peripheral blood monocytes have the plasticity to differentiate into mature DCs when exposed to GM-CSF and IL-4 followed by LPS. In this study we addressed the potential of human microglia to acquire phenotypic and functional properties of mature DCs under similar inducing conditions. Treated adult and fetal microglia became CD14low and acquired limited expression of CD209 (DC-SIGN); they remained CD1a− and CD83−, and decreased MHCII expression, suggesting that they had not achieved a complete DC phenotype. The monocyte-derived DCs efficiently promoted CD4 T cell proliferation in an allogeneic MLR, whereas differentiated adult microglia had a decreased ability to stimulate CD4 T cell proliferation compared with their untreated counterparts. Differentiated fetal microglia did support CD4 T cell proliferation, whereas untreated cells could not. Fetal and adult microglia produced significant amounts of IL-10 following differentiation but no detectable IL-12 p70, in contrast to differentiated monocytes that produced IL-12 p70. Our data indicate that neither adult nor fetal microglia acquired the full characteristic phenotype of mature stimulatory DCs when treated with DC-inducing cytokines in vitro. Moreover, such treatment, especially of adult microglia, induces functional responses that could promote an antiinflammatory environment in the CNS.

Pathologic substrates of focal epilepsy influence the generation of high-frequency oscillations.

Although a clear correlation has been observed between high‐frequency oscillations (HFOs) and the seizure‐onset zone in distinct lesions, the role of the underlying pathologic substrates in the generation of HFOs is not well established. We aimed to investigate HFO correlates of different pathologic substrates in patients with drug‐resistant epilepsy, and to examine the relation of HFOs with the anatomic location of the dysplastic lesion and surrounding tissue in patients with focal cortical dysplasia (FCD).

Brain shift in neuronavigation of brain tumors: A review

Purpose: Neuronavigation based on preoperative imaging data is a ubiquitous tool for image guidance in neurosurgery. However, it is rendered unreliable when brain shift invalidates the patient‐to‐image registration. Many investigators have tried to explain, quantify, and compensate for this phenomenon to allow extended use of neuronavigation systems for the duration of surgery. The purpose of this paper is to present an overview of the work that has been done investigating brain shift. Methods: A review of the literature dealing with the explanation, quantification and compensation of brain shift is presented. The review is based on a systematic search using relevant keywords and phrases in PubMed. The review is organized based on a developed taxonomy that classifies brain shift as occurring due to physical, surgical or biological factors. Results: This paper gives an overview of the work investigating, quantifying, and compensating for brain shift in neuronavigation while describing the successes, setbacks, and additional needs in the field. An analysis of the literature demonstrates a high variability in the methods used to quantify brain shift as well as a wide range in the measured magnitude of the brain shift, depending on the specifics of the intervention. The analysis indicates the need for additional research to be done in quantifying independent effects of brain shift in order for some of the state of the art compensation methods to become useful. Conclusion: This review allows for a thorough understanding of the work investigating brain shift and introduces the needs for future avenues of investigation of the phenomenon. HighlightsA comprehensive review of research on the phenomenon of brain shift.A new taxonomy separating brain shift into physical, biological and surgical factors.Contrast between brain shift corrections through intraoperative imaging methods.Recommendations for future focus of brain shift research. Graphical abstract Figure. Image, graphical abstract

Influence of contact size on the detection of HFOs in human intracerebral EEG recordings.

OBJECTIVE High frequency oscillations (HFOs) are brief electroencephalographic events associated with epileptic activity, and likely representing biological markers of the epileptogenic zone. HFOs are usually detected with intracranial EEG and detection is influenced by contact size. The size of commercially available intracerebral electrodes varies widely. This study assesses HFO detection rates from adjacent electrode contacts in human intracerebral recordings. METHODS Intracerebral recordings were collected from 11 patients undergoing stereoelectroencephalographic investigation using hybrid depth electrodes containing adjacent large (0.8 or 5 mm(2)) and small (0.2 or 0.3 mm(2)) contacts. HFOs were marked manually during 5-min tracings in 131 pairs of adjacent large and small contacts. HFO rates per minute and mean event durations were compared between adjacent contacts. RESULTS A minimal but statistically significant advantage in ripple detection was found in a subgroup of large contacts. Otherwise, HFO rates and mean event durations were not statistically different between groups. CONCLUSION The size of clinical contacts within the studied range did not influence HFO detection in a clinically relevant manner. Larger contacts provide a minimal advantage for ripple detection. SIGNIFICANCE Our findings suggest that commercially available intracerebral electrodes with contacts between 0.2 and 5 mm(2) likely possess similar HFO detection abilities.

MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells

Multifocal inflammatory lesions featuring destruction of lipid-rich myelin are pathologic hallmarks of multiple sclerosis. Lesion activity is assessed by the extent and composition of myelin uptake by myeloid cells present in such lesions. In the inflamed CNS, myeloid cells are comprised of brain-resident microglia, an endogenous cell population, and monocyte-derived macrophages, which infiltrate from the systemic compartment. Using microglia isolated from the adult human brain, we demonstrate that myelin phagocytosis is dependent on the polarization state of the cells. Myelin ingestion is significantly enhanced in cells exposed to TGF-β compared with resting basal conditions and markedly reduced in classically activated polarized cells. Transcriptional analysis indicated that TGF-β–treated microglia closely resembled M0 cells. The tyrosine kinase phagocytic receptor MerTK was one of the most upregulated among a select number of differentially expressed genes in TGF-β–treated microglia. In contrast, MerTK and its known ligands, growth arrest-specific 6 and Protein S, were downregulated in classically activated cells. MerTK expression and myelin phagocytosis were higher in CNS-derived microglia than observed in monocyte-derived macrophages, both basally and under all tested polarization conditions. Specific MerTK inhibitors reduced myelin phagocytosis and the resultant anti-inflammatory biased cytokine responses for both cell types. Defining and modulating the mechanisms that regulate myelin phagocytosis has the potential to impact lesion and disease evolution in multiple sclerosis. Relevant effects would include enhancing myelin clearance, increasing anti-inflammatory molecule production by myeloid cells, and thereby permitting subsequent tissue repair.