Real-time monitoring of human blood-brain barrier disruption

Abstract

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 μV 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 blood-brain barrier disruption augmented drug delivery.

Fluctuations of the EEG‐fMRI correlation reflect intrinsic strength of functional connectivity in default mode network

“…In addition to neuronal generators for EEG ISFs (Birbaumer, Elbert, Canavan, & Rockstroh, ; Caspers, Speckmann, & Lehmenkuhler, ; He & Raichle, ), also nonneuronal sources have been proposed (Vanhatalo et al, b; Voipio, Tallgren, Heinonen, Vanhatalo, & Kaila, ). The DC‐potential in EEG is thought to arise from the 1–5 mV potential difference between blood and brain tissue, since opening of the BBB in the absence of neuronal activity induces marked DC‐EEG changes (Kiviniemi et al, ; Nita et al, ; Voipio et al, ). As the resting‐state DC‐EEG readily picks up changes in BBB potential difference, it seems likely that high‐activity RSN states would lead to changes in the BBB potential difference and would be directly detected by EEG as ISFs.…”

“…The infra‐slow vasomotor glymphatic pulsation mechanisms may cause predilection of some hemodynamic patterns in RSNs to be detected in BOLD fMRI. In addition, the changes in glymphatic CSF flow mechanisms being next to BBB (Nedergaard, ) may alter the BBB potential changes and thus directly the scalp EEG ISFs per se (Kiviniemi et al, ; Nita et al, ; Voipio et al, ).…”

“…Importantly, in order to study the direct correlations between infra‐slow sources of EEG and MREG data, recently shown to be related to integrity of the blood brain barrier (BBB) (Kiviniemi et al, ), we did not use any temporal delay or hemodynamic convolution to match the EEG versus MREG signal. In other words, we use magnetoelectrical properties of the brain cortex that reflect the current electrophysiological state over the regional neurovascular unit, i.e., EEG ISFs and BOLD contrasts (Kiviniemi et al, ; Logothetis, 2000; Nita et al, 2004; Ogawa, Lee, Kay, & Tank ). The correlation maps were thresholded with histogram mixture modeling in a way similar to MREG data.…”

Blood–brain barrier and laser technology for drug brain delivery

“…[51][52][53][54] However, no approaches for the opening of BBB, which are widely used in daily clinical practice due to their invasiveness and challenge in performing such as intra-arterial injection of mannitol, limitation of drug concentration using intranasal drug delivery or area of treatment (1-3 mm) using focused ultrasound. [55][56][57] Here, we discuss technology, which is used in clinical practice but with completely new view on this method as novel approach for the brain drug delivery. Photodynamic therapy (PDT) with using 5-aminolevulinic acid (5-ALA)-PDT is a valuable method for surgical navigation of glioblastoma.…”

Transitory Increase of Hematoencephalic Barrier Permeability by Intracarotid Introduction of Ozonized Saline Solution

“…Methods capable to entail a temporary HEB opening have been described in the literature: hyperthermia, pressure elevation in the cerebral vessels above 90 mm Hg, inhalation of gas mixture with an increased content of carbon dioxide, injection of histamine, calcium channel blockers, leukotriene C4, bradykinine, intracarotid introduction of hyperosmolar solutions of mannitol; physiological transport mechanisms are currently under study as well [4][5][6][7][8]. But the majority of them have some drawbacks, among which are serious complications and a short therapeutic window, i.e.…”