Real-time monitoring of human blood-brain barrier disruption

Chemotherapy aided by opening of the blood-brain barrier with intra-arterial infusion of hyperosmolar mannitol improves the outcome in primary central nervous system lymphoma. Proper opening of the blood-brain barrier is crucial for the treatment, yet there are no means available for its real-time monitoring. The intact blood-brain barrier maintains a mV-level electrical potential difference between blood and brain tissue, giving rise to a measurable electrical signal at the scalp. Therefore, we used direct-current electroencephalography ( DC-EEG) to characterize the spatiotemporal behavior of scalp-recorded slow electrical signals during blood-brain barrier opening. Nine anesthetized patients receiving chemotherapy were monitored continuously during 47 blood-brain barrier openings induced by carotid or vertebral artery mannitol infusion. Left or right carotid artery mannitol infusion generated a strongly lateralized DC-EEG response that began with a 2 min negative shift of up to 2000 mu V followed by a positive shift lasting up to 20 min above the infused carotid artery territory, whereas contralateral responses were of opposite polarity. Vertebral artery mannitol infusion gave rise to a minimally lateralized and more uniformly distributed slow negative response with a posterior-frontal gradient. Simultaneously performed near-infrared spectroscopy detected a multiphasic response beginning with mannitol-bolus induced dilution of blood and ending in a prolonged increase in the oxy/deoxyhemoglobin ratio. The pronounced DC-EEG shifts are readily accounted for by opening and sealing of the blood-brain barrier. These data show that DC-EEG is a promising real-time monitoring tool for bloodbrain barrier disruption augmented drug delivery.Peer reviewe

Atypical perceptual narrowing in prematurely born infants is associated with compromised language acquisition at 2 years of age

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Young male patients are at elevated risk of developing serious central nervous system complications during acute Puumala hantavirus infection

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Grand average DC-EEG and average NIRS traces illustrating characteristic responses evoked by intra-arterial mannitol infusion.

<p>Each DC-EEG trace (upper panels; shaded area indicates values within ±1 SD) was generated by first calculating the mean of five electrode signals and then calculating the grand average of each recording. Mannitol infusion starts at time = 0 and lasts 30 s. DC-EEG responses upon carotid or vertebral artery mannitol infusion are shown using the common average montage (CA), however the responses to vertebral artery infusion are shown also after re-referencing to the distant ECG reference electrode (ECG; upper panel on the right). Bottom graphs show corresponding average oxy- and deoxyhemoglobin NIRS traces in arbitrary units (a.u.; ±1 SD). The number of NIRS recordings is less than that of DC-EEG, but all NIRS recordings are paralleled by simultaneously recorded DC-EEG data included in the upper graphs. Left (n = 13) and right (n = 16) carotid artery infusions induce a negative DC-EEG shift in electrodes above the treated arterial territory, which outlasts the infusion and is followed by a slower shift of opposite polarity. Contralateral posterior electrodes record a response that is qualitatively similar but reversed in polarity. A clear fall in the NIRS signals is seen during left (n = 8) and right (n = 8) carotid artery infusions, followed by a pronounced rise in HbO and a transient partial recovery of Hb after which Hb settles down on a level below the original baseline and HbO decreases slowly but does not fully recover. Vertebral artery infusions show a fronto-occipital DC-EEG potential shift (n = 18) without a lateralized effect, as expected. Re-referencing to the distant ECG reference electrode reveals that there is a negative shift throughout the entire scalp. The early transient shifts in the NIRS signals shown for vertebral artery infusions (n = 7) are more delayed and have much smaller amplitudes because NIRS was always measured on the forehead, i.e. they show responses generated in a non-infused brain area.</p

Spatiotemporal analysis of the DC-EEG data illustrated using heat maps.

<p>(a) Thiopental given at time 0 min generates a weak response in 3 min with slightly positive values along the midline and negative values at lateral electrode locations. Re-referencing the common average (CA) referenced data to the ECG reference renders the entire response slightly more negative. Data from all recordings (47 infusions) were pooled because thiopental was applied intravenously. (b) Temporal evolvement of the spatial distribution of DC-EEG responses to mannitol infusion shown using logarithmically increasing time intervals. The signal level preceding mannitol infusion (0 min) defines the zero level for the average responses calculated for 13 left carotid artery, 16 right carotid artery and 18 vertebral artery infusions. All data are shown using the CA reference montage. In addition, the bottom row of heat plots shows vertebral artery infusion data after re-referencing to the ECG reference.</p

Typical spatial distribution of the DC-EEG responses.

<p>Specimen traces recorded during the BBBD procedure with left (a), right (b) and vertebral (c, d) artery infusion of mannitol. On average, carotid artery infusion evoked responses of the kind shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0174072#pone.0174072.g001" target="_blank">Fig 1</a> in electrodes of the 10-10 system located anterior to vertex on the side of the infusion, whereas posterior electrodes on the opposite side showed rather similar responses with opposite polarity (common average reference montage). Therefore, the four subsets of five electrodes shown here were chosen for further characterization of the signals. When using the common average montage, responses evoked by vertebral artery mannitol infusion (c) were strikingly small in amplitude compared to those seen upon carotid artery infusion, suggesting in the former case the presence of a uniformly distributed signal component that cancels out in a differential recording against the common average reference. A reference point distant to the electrodes of the 10-10 system was provided by the ECG reference electrode, and indeed, re-referencing to the low-pass filtered ECG reference electrode signal revealed a prolonged negative shift (d).</p

Region of interest analysis of the cbCT following i.a. multi-chemotherapy.

<p>Selected major territories are described using white ellipses marked by numbers 1-5 bilaterally (a). HU-values calculated from these areas and mean of them (named as ‘all’) are illustrated by treated artery; right carotis (b), left carotis (c) and vertebralis (d). In every case right (blue) and left (red) side are separated and also SD bars are represented.</p

Characteristic EEG and NIRS responses seen during the BBBD procedure.

<p>Specimen traces illustrating simultaneous changes in raw EEG (upper graph) and NIRS signals (lower graph) during right carotid intra-arterial (i.a.) mannitol infusion. Deepening anesthesia with intravenous (i.v.) thiopental bolus (marked with an arrow) induces a baseline shift and suppresses activity at conventional EEG frequencies (insets a to d show 15 s sample traces on a 6 times expanded vertical scale) prior to mannitol infusion. Mannitol infusion (2nd arrow) then induces a multi-phasic potential response that begins with a pronounced negative shift reaching nearly -2000 μV in less than 1 min. The negative peak is followed by a slow potential descent below the pre-bolus level. Note the emerging burst-suppression (c) and subsequent faster EEG activity (d) similar to baseline state (a) as the thiopental effect slowly dissipates over 15 minutes. The simultaneously recorded NIRS graph shows first how the i.v. thiopental bolus produces a minor elevation to both NIRS HbO and Hb signals (red solid line and blue dashed line, respectively). When the 30 s i.a. mannitol infusion starts both NIRS signals plummet due to dilution of blood and they start to increase towards the original levels after the infusion. Subsequently, HbO rises above the baseline and stays there over the 15 minutes. On the other hand, Hb approaches the baseline level but soon starts to fall again obtaining a steady level clearly below the original baseline.</p

Altered physiological brain variation in drug‐resistant epilepsy

Abstract Introduction: Functional magnetic resonance imaging (fMRI) combined with simultaneous electroencephalography (EEG‐fMRI) has become a major tool in mapping epilepsy sources. In the absence of detectable epileptiform activity, the resting state fMRI may still detect changes in the blood oxygen level‐dependent signal, suggesting intrinsic alterations in the underlying brain physiology. Methods: In this study, we used coefficient of variation (CV) of critically sampled 10 Hz ultra‐fast fMRI (magnetoencephalography, MREG) signal to compare physiological variance between healthy controls (n = 10) and patients (n = 10) with drug‐resistant epilepsy (DRE). Results: We showed highly significant voxel‐level (p &lt; 0.01, TFCE‐corrected) increase in the physiological variance in DRE patients. At individual level, the elevations range over three standard deviations (σ) above the control mean (μ) CVMREG values solely in DRE patients, enabling patient‐specific mapping of elevated physiological variance. The most apparent differences in group‐level analysis are found on white matter, brainstem, and cerebellum. Respiratory (0.12–0.4 Hz) and very‐low‐frequency (VLF = 0.009–0.1 Hz) signal variances were most affected. Conclusions: The CVMREG increase was not explained by head motion or physiological cardiorespiratory activity, that is, it seems to be linked to intrinsic physiological pulsations. We suggest that intrinsic brain pulsations play a role in DRE and that critically sampled fMRI may provide a powerful tool for their identification