The Importance of Probe Location for the Interpretation of Cerebral Microdialysis Data in Subarachnoid Hemorrhage Patients.

BACKGROUND: There is no uniform definition for cerebral microdialysis (CMD) probe location with respect to focal brain lesions, and the impact of CMD-probe location on measured molecule concentrations is unclear. METHODS: We retrospectively analyzed data of 51 consecutive subarachnoid hemorrhage patients with CMD-monitoring between 2010 and 2016 included in a prospective observational cohort study. Microdialysis probe location was assessed on all brain computed tomography (CT) scans performed during CMD-monitoring and defined as perilesional in the presence of a focal hypodense or hyperdense lesion within a 1-cm radius of the gold tip of the CMD-probe, or otherwise as normal-appearing brain tissue. RESULTS: Probe location was detected in normal-appearing brain tissue on 53/143 (37%) and in perilesional location on 90/143 (63%) CT scans. In the perilesional area, CMD-glucose levels were lower (p = 0.003), whereas CMD-lactate (p = 0.002), CMD-lactate-to-pyruvate-ratio (LPR; p < 0.001), CMD-glutamate (p = 0.002), and CMD-glycerol levels (p < 0.001) were higher. Neuroglucopenia (CMD-glucose < 0.7 mmol/l, p = 0.002), metabolic distress (p = 0.002), and mitochondrial dysfunction (p = 0.005) were more common in perilesional compared to normal-appearing brain tissue. Development of new lesions in the proximity of the CMD-probe (n = 13) was associated with a decrease in CMD-glucose levels, evidence of neuroglucopenia, metabolic distress, as well as increasing CMD-glutamate and CMD-glycerol levels. Neuroglucopenia was associated with poor outcome independent of probe location, whereas elevated CMD-lactate, CMD-LPR, CMD-glutamate, and CMD-glycerol levels were only predictive of poor outcome in normal-appearing brain tissue. CONCLUSIONS: Focal brain lesions significantly impact on concentrations of brain metabolites assessed by CMD. With the exception of CMD-glucose, the prognostic value of CMD-derived parameters seems to be higher when assessed in normal-appearing brain tissue. CMD was sensitive to detect the development of new focal lesions in vicinity to the neuromonitoring probe. Probe location should be described in the research reporting brain metabolic changes measured by CMD and integrated in statistical models.

In vivo monitoring of cerebral glucose with an updated on-line electroanalytical system.

Because cerebral species involve rapid events, increasing the temporal resolution to realize in vivo near-real-time measurements is desirable. Here, we aimed to improve the low resolution of our previous on-line electroanalytical system by decreasing the dead volume and reducing molecular dispersion. This updated system has advantages of elevated time resolution and accelerated analysis for on-line monitoring of glucose versus the previous system. Finally, this new system was successfully applied to continuous measurement of cerebral glucose in vivo during global ischemia/reperfusion events. This study is expected to offer a reliable on-line analytical platform for continuous monitoring of important species associated with fast physiological and pathological events in vivo. Graphical abstract.

Development of a highly sensitive gas chromatography-mass spectrometry method preceded by solid-phase microextraction for the analysis of propofol in low-volume cerebral microdialysate samples.

To date, the commonly used intravenous anesthetic propofol has been widely studied, and fundamental pharmacodynamic and pharmacokinetic characteristics of the drug are known. However, propofol has not yet been quantified in vivo in the target organ, the human brain. Here, cerebral microdialysis offers the unique opportunity to sample propofol in the living human organism. Therefore, a highly sensitive analytical method for propofol quantitation in small sample volumes of 30 µL, based on direct immersion solid-phase microextraction was developed. Preconcentration was followed by gas chromatographic separation and mass spectrometric detection of the compound. This optimized method provided a linear range between the lower limit of detection (50 ng/L) and 200 µg/L. Matrix-matched calibration was used to compensate recovery issues. A precision of 2.7% relative standard deviation between five consecutive measurements and an interday precision of 6.4% relative standard deviation could be achieved. Furthermore, the permeability of propofol through a cerebral microdialysate system was tested. In summary, the developed method to analyze cerebral microdialysate samples, allows the in vivo quantitation of propofol in the living human brain. Additionally the calculation of extracellular fluid levels is enabled since the recovery of the cerebral microdialysis regarding propofol was determined.

PDMS/glass hybrid device with a reusable carbon electrode for on-line monitoring of catecholamines using microdialysis sampling coupled to microchip electrophoresis with electrochemical detection.

On-line separations-based sensors employing microdialysis (MD) coupled to microchip electrophoresis (ME) enable the continuous monitoring of multiple analytes simultaneously. Electrochemical detection (EC) is especially amenable to on-animal systems employing MD-ME due to its ease of miniaturization. However, one of the difficulties in fabricating MD-ME-EC systems is incorporating carbon working electrodes into the device. In this paper, a novel fabrication procedure is described for the production of a PDMS/glass hybrid device that is capable of integrating hydrodynamic MD flow with ME-EC using a flow-gated interface and a pyrolyzed photoresist film carbon electrode. This fabrication method enables the reuse of carbon electrodes on a glass substrate, while still maintaining a good seal between the PDMS and glass to allow for pressure-driven MD flow. The on-line MD-ME-EC device was characterized in vitro and in vivo for monitoring analytes in the dopamine metabolic pathway. The ultimate goal is to use this device and associated instrumentation to perform on-animal, near-real time in vivo monitoring of catecholamines.

Assessment of changes in blood glucose concentration with intravascular microdialysis.

Blood glucose and its variability of is a major prognostic factor associated with morbidity. We hypothesized that intravenous microdialysis incorporated in a central venous catheter (CVC) would be interchangeable with changes in blood glucose measured by the reference method using a blood gas analyzer. Microdialysis and central venous blood glucose measurements were simultaneously recorded in high-risk cardiac surgical patients. The correlation between absolute values was determined by linear regression and the Bland-Altman test for repeated measurements was used to compare bias, precision, and limits of agreement. Changes in blood glucose measurement were evaluated by four-quadrant plot and trend interchangeability methods (TIM). In the 23 patients analyzed, the CVC was used as part of standard care with no complications. The correlation coefficient for absolute values (N = 99) was R = 0.91 (P < 0.001). The bias, precision and limits of agreement were - 9.1, 17.4 and - 43.2 to 24.9 mg/dL, respectively. The concordance rate for changes in blood glucose measurements (N = 77) was 85% with the four-quadrant plot. The TIM showed that 14 (18%) changes of blood glucose measurements were uninterpretable. Among the remaining 63 (82%) interpretable changes, 23 (37%) were interchangeable, 13 (20%) were in the gray zone, and 27 (43%) were not interchangeable. Microdialysis using a CVC appears to provide imprecise absolute blood glucose values with risk of insulin misuse. Moreover, only one third of changes in blood glucose measurements were interchangeable with the reference method using the TIM.

Highly Selective Cerebral ATP Assay Based on Micrometer Scale Ion Current Rectification at Polyimidazolium-Modified Micropipettes.

Development of new principles and methods for cerebral ATP assay is highly imperative not only for determining ATP dynamics in brain but also for understanding physiological and pathological processes related to ATP. Herein, we for the first time demonstrate that micrometer scale ion current rectification (MICR) at a polyimidazolium brush-modified micropipette can be used as the signal transduction output for the cerebral ATP assay with a high selectivity. The rationale for ATP assay is essentially based on the competitive binding ability between positively charged polyimidazolium and ATP toward negatively charged ATP aptamer. The method is well responsive to ATP with a good linearity within a concentration range from 5 nM to 100 nM, and high selectivity toward ATP. These properties essentially enable the method to determine the cerebral ATP by combining in vivo microdialysis. The basal dialysate level of ATP in rat brain cortex is determined to be 11.32 ± 2.36 nM (n = 3). This study demonstrates that the MICR-based sensors could be potentially used for monitoring neurochemicals in cerebral systems.

Assessment of changes in lactate concentration with intravascular microdialysis during high-risk cardiac surgery using the trend interchangeability method.

Background: Blood lactate is a strong predictor of mortality, and repeated blood lactate assays are recommended during surgery in high-risk patients. We hypothesized that the use of intravascular microdialysis incorporated in a central venous catheter would be interchangeable with the reference blood gas technique to monitor changes in blood lactate. Methods: Microdialysis and central venous blood lactate measurements were recorded simultaneously in high-risk cardiac surgical patients. The correlation between absolute values was determined by linear regression, and the Bland-Altman test for repeated measurements was used to compare bias, precision, and limits of agreement. Changes in lactate measurements were evaluated with a four-quadrant plot and trend interchangeability method (TIM). Results: In the 23 patients analysed, the central venous catheter was used as part of standard care, with no complications. The correlation coefficient for absolute values ( n =104) was 0.96 ( P <0.0001). The bias, precision, and limits of agreement were -0.19, 0.51, and -1.20 to 0.82 mmol litre -1 , respectively. The concordance rate for changes in blood lactate measurements ( n =80) was 94% with the four-quadrant plot. In contrast, the TIM showed that 23 (29) changes in lactate measurements were not interpretable, and among the remaining 57 (71) interpretable changes, 18 (32) were interchangeable, 8 (14) were in the grey zone, and 31 (54) were not interchangeable. Conclusions: Microdialysis with a central venous catheter appears to provide reliable absolute blood lactate values. Although changes in blood lactate measurements showed an excellent concordance rate, changes between the two methods were poorly interchangeable with the TIM. Clinical trial registration: NCT02296593.

Microfabrication and in Vivo Performance of a Microdialysis Probe with Embedded Membrane.

Microdialysis sampling is an essential tool for in vivo neurochemical monitoring. Conventional dialysis probes are over 220 µm in diameter and have limited flexibility in design because they are made by assembly using preformed membranes. The probe size constrains spatial resolution and governs the amount of tissue damaged caused by probe insertion. To overcome these limitations, we have developed a method to microfabricate probes in Si that are 45 µm thick × 180 µm wide. The probes contain a buried, U-shaped channel that is 30 µm deep × 60 µm wide and terminates in ports for external connection. A 4 mm length of the probe is covered with a 5 µm thick nanoporous membrane. The membrane was microfabricated by deep reactive ion etching through a porous aluminum oxide layer. The microfabricated probe has cross-sectional area that is 79% less than that of the smallest conventional microdialysis probes. The probes yield 2-20% relative recovery at 100 nL/min perfusion rate for a variety of small molecules. The probe was successfully tested in vivo by sampling from the striatum of live rats. Fractions were collected at 20 min intervals (2 µL) before and after an intraperitoneal injection of 5 mg/kg amphetamine. Analysis of fractions by liquid chromatography-mass spectrometry revealed reliable detection of 14 neurochemicals, including dopamine and acetylcholine, at basal conditions. Amphetamine evoked a 43-fold rise in dopamine, a result nearly identical to a conventional dialysis probe in the same animal. The microfabricated probes have potential for sampling with higher spatial resolution and less tissue disruption than conventional probes. It may also be possible to add functionality to the probes by integrating other components, such as electrodes, optics, and additional channels.

Outcome of microdialysis sampling on liver surface and parenchyma.

BACKGROUND: To investigate whether surface microdialysis (µD) sampling in probes covered by a plastic film, as compared to noncovered and to intraparenchymatous probes, would increase the technique's sensitivity for pathophysiologic events occurring in a liver ischemia-reperfusion model. Placement of µD probes in the parenchyma of an organ, as is conventionally done, may cause adverse effects, e.g., bleeding, possibly influencing outcome. METHODS: A transient ischemia-reperfusion model of the liver was used in six anesthetized normoventilated pigs. µD probes were placed in the parenchyma and on the liver surface. Surface probes were either left uncovered or were covered by plastic film. RESULTS: Lactate and glucose levels were significantly higher in plastic film covered probes than in uncovered surface probes throughout the ischemic period. Glycerol levels were significantly higher in plastic film covered probes than in uncovered surface probes at 30 and 45 min into ischemia. CONCLUSIONS: Covering the µD probe increases the sensibility of the µD-technique in monitoring an ischemic insult and reperfusion in the liver. These findings confirm that the principle of surface µD works, possibly replacing need of intraparenchymatous placement of µD probes. Surface µD seemingly allows, noninvasively from an organ's surface, via the extracellular compartment, assessment of intracellular metabolic events. The finding that covered surface µD probes allows detection of local metabolic changes earlier than do intraparenchymatous probes, merit further investigation focusing on µD probe design.

Surface microdialysis on small bowel serosa in monitoring of ischemia.

BACKGROUND: Ischemic injury of an organ causes metabolic change from aerobic to anaerobic metabolism. It has been shown in experimental studies on the heart and liver that such conversion may be detected by conventional microdialysis probes placed intra-parenchymatously, as well as on organ surfaces, by assaying lactate, pyruvate, glucose, and glycerol in dialysate. We developed a microdialysis probe (S-µD) intended for use solely on organ surfaces. The aim of this study was to assess whether the newly developed S-µD probe could be used for detection and monitoring of small bowel ischemia. METHODS: In anesthetized normoventilated pigs, a control S-µD probe was applied on the jejunal serosa 50 cm downstream from the duodenojejunal junction (DJJ). Starting 100 cm from DJJ, a 100-cm long ischemic segment was created by division of all mesenteric vessels. S-µDs were applied at 2.5, 5, 20, and 50 cm from the starting point of ischemia by serosal sutures. A standard µD probe was placed in the abdominal cavity as a further control. Dialysate was harvested before inducing ischemia and subsequently every 20 min for 4 h. Central venous blood was drawn every hour to monitor systemic lactate, C-reactive protein, and white blood cell count. RESULTS: Microdialysis lactate levels were significantly higher than baseline from 20 min on into protocol time in the ischemic segment and in the control S-µD probe. The peritoneal cavity probe showed no significant elevation. Lactate levels from the ischemic segment reached a plateau at 60 min. Courses of pyruvate, glucose, and glycerol levels were in accordance with transition from an aerobic to anaerobic metabolism in the bowel wall. No statistically significant changes in hemoglobin, white blood cell count, or lactate values in central venous blood were recorded. CONCLUSIONS: Assaying the aforementioned compounds in dialysate, harvested by the newly developed S-µD probe, allowed detection and monitoring of small bowel ischemia from 20 min on following its onset.

The glucagon-like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents.

The incretin hormone, glucagon-like peptide 1 (GLP-1), regulates gastric emptying, glucose-dependent stimulation of insulin secretion and glucagon release, and GLP-1 analogs are therefore approved for treatment of type II diabetes. GLP-1 receptors are expressed in reward-related areas such as the ventral tegmental area and nucleus accumbens, and GLP-1 was recently shown to regulate several alcohol-mediated behaviors as well as amphetamine-induced, cocaine-induced and nicotine-induced reward. The present series of experiments were undertaken to investigate the effect of the GLP-1 receptor agonist, liraglutide, on several alcohol-related behaviors in rats that model different aspects of alcohol use disorder in humans. Acute liraglutide treatment suppressed the well-documented effects of alcohol on the mesolimbic dopamine system, namely alcohol-induced accumbal dopamine release and conditioned place preference in mice. In addition, acute administration of liraglutide prevented the alcohol deprivation effect and reduced alcohol intake in outbred rats, while repeated treatment of liraglutide decreased alcohol intake in outbred rats as well as reduced operant self-administration of alcohol in selectively bred Sardinian alcohol-preferring rats. Collectively, these data suggest that GLP-1 receptor agonists could be tested for treatment of alcohol dependence in humans.

Intraabdominal microdialysis - methodological challenges.

Microdialysis is used for in vivo sampling of extracellular molecules. The technique provides a continuous and dynamic view of concentrations of both endogenous released and exogenous administered substances. Microdialysis carries a low risk of complications and has proven to be a safe procedure in humans. The technique has been applied in several clinical areas, including gastrointestinal surgery. Microdialysis may be used for studies of tissue metabolism, and the technique is also a promising tool for pharmacological studies of drug penetration into abdominal organ tissue and the peritoneal cavity. The clinical significance of intraabdominal microdialysis in postoperative monitoring of surgical patients has yet to be proven. In this review, we introduce the microdialysis technique, and we present an overview of theoretical and practical considerations that should be taken into account when using microdialysis in intraabdominal clinical research.

Reducing adsorption to improve recovery and in vivo detection of neuropeptides by microdialysis with LC-MS.

Neuropeptides are an important class of neurochemicals; however, measuring their concentration in vivo by using microdialysis sampling is challenging due to their low concentration and the small samples generated. Capillary liquid chromatography with mass spectrometry (cLC-MS) can yield attomole limits of detection (LOD); however, low recovery and loss of sample to adsorptive surfaces can still hinder detection of neuropeptides. We have evaluated recovery during sampling and transfer to the cLC column for a selection of 10 neuropeptides. Adding acetonitrile to sample eliminated carryover and improved LOD by 1.4- to 60-fold. The amount of acetonitrile required was found to have an optimal value that correlated with peptide molecular weight and retention time on a reversed phase LC column. Treating AN69 dialysis membrane, which bears negative charge due to incorporated sulfonate groups, with polyethylenimine (PEI) improved recovery by 1.2- to 80-fold. The effect appeared to be due to reducing electrostatic interaction between peptides and the microdialysis probe because modification increased recovery only for peptides that carried net positive charge. The combined effects improved LOD of the entire method by 1.3- to 800-fold for the different peptides. We conclude that peptides with both charged and hydrophobic regions require combined strategies to prevent adsorption and yield the best possible detection. The method was demonstrated by determining orexin A, orexin B, and a novel isoform of rat ß-endorphin in the arcuate nucleus. Dialysate concentrations were below 10 pM for these peptides. A standard addition study on dialysates revealed that while some peptides can be accurately quantified, some are affected by the matrix.

Clinical performance of a low cost near infrared sensor for continuous glucose monitoring applied with subcutaneous microdialysis.

In this work we present a low cost, minimally invasive, and chip-based near infrared (NIR) sensor, combined with subcutaneous microdialysis, for continuous glucose monitoring (CGM). The sensor principle is based on difference absorption spectroscopy in the 1st overtone band known to be dominated by glucose-specific absorption features. The device comprises a multi-emitter LED and InGaAs-photodiodes, which are located on a single electronic board (non-disposable part), connected to a personal computer via Bluetooth. The disposable part consists of a chip containing the fluidic connections for microdialysis, two fluidic channels acting as optical transmission cells and total internally reflecting mirrors for in- and out-coupling of the light to the chip and to the detectors. The use of the sensor in conjunction with a subcutaneous microdialysis catheter to separate the glucose from the cells and proteins has been demonstrated to be extremely useful and advantageous for obtaining continuous glucose monitoring data and detecting glycemic levels in real time for a long period. Several in vitro and in vivo experiments were conducted to test the reliability of the device. In vitro measurements showed a linear relationship between glucose concentration and the integrated difference signal with a coefficient of determination of 99 % at the physiological concentration range. Clinical trial on 6 subjects with Type 1 diabetes showed that the NIR-CGM sensor data reflects the blood reference values adequately, if a proper calibration and signal drift compensation is applied. The MARD (mean absolute relative difference) value taken on retrospective data over all subjects is 8.5 % (range 6-11.5 %).

Influence of surface modification and static pressure on microdialysis protein extraction efficiency.

There is growing interest in using microdialysis (MD) for monitoring larger and more complex molecules such as neuropeptides and proteins. This promotes the use of MD membranes with molecular weight cut off (MWCO) of 100 kDa or above. The hydrodynamic property of the membrane goes to ultrafiltration or beyond, making the MD catheters more sensitive to pressure. In the meantime, despite the large pore size, studies have shown that membrane biofouling still lead to unstable catheter performance. The objective is to study in vitro how 500 kDa dextran and Poloxamer 407 surface modification affect the fluid recovery (FR) and extraction efficiency (EE) of 100 kDa MWCO MD catheters. A pressure chamber was designed to facilitate the tests, using as MD sample a protein standard with similar concentrations as in human cerebral spinal fluid, comparing native and Poloxamer 407 modified MD catheters. The collected dialysate fractions were examined for FR and protein EE, employing Dot-it Spot-it Protein Assay for total protein EE and targeted mass spectrometry (MS) for EE of individual proteins and peptides. The FR results suggested that the surface modified catheters were less sensitive to the pressure and provide higher precision, and provided a FR closer to 100%. The surface modification did not show a significant effect on the protein EE. The average total protein EE of surface modified catheters was slightly higher than that of the native ones. The MS EE data of individual proteins showed a clear trend of complex response in EE with pressure.

A review of the effects of FSCV and microdialysis measurements on dopamine release in the surrounding tissue.

Microdialysis is commonly used in neuroscience to obtain information about the concentration of substances, including neurotransmitters such as dopamine (DA), in the extracellular space (ECS) of the brain. Measuring DA concentrations in the ECS with in vivo microdialysis and/or voltammetry is a mainstay of investigations into both normal and pathological function of central DA systems. Although both techniques are instrumental in understanding brain chemistry each has its shortcomings. The objective of this review is to characterize some of the tissue and DA differences associated with each technique in vivo. Much of this work will focus on immunohistochemical and microelectrode measurements of DA in the tissue next to the microdialysis probe and mitigating the response to the damage caused by probe implantation.

Online electrochemical systems for continuous neurochemical measurements with low-potential mediator-based electrochemical biosensors as selective detectors.

This study demonstrates a new strategy to develop online electrochemical systems (OECSs) for continuously monitoring neurochemicals by efficiently integrating in vivo microdialysis with an oxidase-based electrochemical biosensor with low-potential electron mediators to shuttle the electron transfer of the oxidases. By using thionine and xanthine oxidase (XOD) as examples of low-potential mediators and oxidases, respectively, we demonstrate that the use of low-potential mediators to shuttle the electron transfer of oxidases would offer a new approach to the development of oxidase-based biosensors with theoretical and technical simplicity. To construct the XOD-based biosensor, thionine was adsorbed onto carbon nanotubes and used to shuttle the electron transfer of XOD. The XOD-based biosensor was positioned into an electrochemical cell that was directly coupled with in vivo microdialysis to form an online electrochemical system (OECS) for continuous and selective measurements of the substrate of XOD (with hypoxanthine as an example). The OECS based on the low-potential mediators is highly selective against the species endogenously existing in the brain system, which is attributed to the low operation potential benefited from the low redox potentials of the mediators. Moreover, the OECS demonstrated here is stable and reproducible and could thus be envisaged to find some interesting applications in physiological and pathological investigations. This study essentially offers a new strategy to develop online electrochemical systems, which is of great importance in understanding the molecular basis of physiological and pathological events.

Cerebral microdialysis in traumatic brain injury and subarachnoid hemorrhage: state of the art.

Cerebral microdialysis (CMD) is a laboratory tool that provides on-line analysis of brain biochemistry via a thin, fenestrated, double-lumen dialysis catheter that is inserted into the interstitium of the brain. A solute is slowly infused into the catheter at a constant velocity. The fenestrated membranes at the tip of the catheter permit free diffusion of molecules between the brain interstitium and the perfusate, which is subsequently collected for laboratory analysis. The major molecules studied using this method are glucose, lactate, pyruvate, glutamate, and glycerol. The collected substances provide insight into the neurochemical features of secondary injury following traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) and valuable information about changes in brain metabolism within a short time frame. In this review, the authors detail the CMD technique and its associated markers and then describe pertinent findings from the literature about the clinical application of CMD in TBI and SAH.

Characterizing Diffusion from Microdialysis Catheters in the Human Brain: A Magnetic Resonance Imaging Study With Gadobutrol.

Cerebral microdialysis (CMD) catheters allow continuous monitoring of patients' cerebral metabolism in severe traumatic brain injury (TBI). The catheters consist of a terminal semi-permeable membrane that is inserted into the brain's interstitium to allow perfusion fluid to equalize with the surrounding cerebral extracellular environment before being recovered through a central non-porous channel. However, it is unclear how far recovered fluid and suspended metabolites have diffused from within the brain, and therefore what volume or region of brain tissue the analyses of metabolism represent. We assessed diffusion of the small magnetic resonance (MR)-detectible molecule gadobutrol from microdialysis catheters in six subjects (complete data five subjects, incomplete data one subject) who had sustained a severe TBI. Diffusion pattern and distance in cerebral white matter were assessed using T1 (time for MR spin-lattice relaxation) maps at 1 mm isotropic resolution in a 3 Tesla MR scanner. Gadobutrol at 10 mmol/L diffused from cerebral microdialysis catheters in a uniform spheroidal (ellipsoid of revolution) pattern around the catheters' semipermeable membranes, and across gray matter-white matter boundaries. Evidence of gadobutrol diffusion was found up to a mean of 13.4 ± 0.5 mm (mean ± standard deviation [SD]) from catheters, but with a steep concentration drop off so that ≤50% of maximum concentration was achieved at ∼4 mm, and ≤10% of maximum was found beyond ∼7 mm from the catheters. There was little variation between subjects. The relaxivity of gadobutrol in human cerebral white matter was estimated to be 1.61 ± 0.38 L.mmol-1sec-1 (mean ± SD); assuming gadobutrol remained extracellular thereby occupying 20% of total tissue volume (interstitium), and concentration equilibrium with perfusion fluid was achieved immediately adjacent to catheters after 24 h of perfusion. No statistically significant change was found in the concentration of the extracellular metabolites glucose, lactate, pyruvate, nor the lactate/pyruvate ratio during gadobutrol perfusion when compared with period of baseline microdialysis perfusion. Cerebral microdialysis allows continuous monitoring of regional cerebral metabolism-the volume of which is now clearer from this study. It also has the potential to deliver small molecule therapies to focal pathologies of the human brain. This study provides a platform for future development of new catheters optimally designed to treat such conditions.

Pharmacological mitigation of tissue damage during brain microdialysis.

Microdialysis sampling in the brain is employed frequently in the chemical analysis of neurological function and disease, but implanting the probes, which are substantially larger than the size and spacing of brain cells and blood vessels, is injurious and triggers ischemia, gliosis, and cell death at the sampling site. The nature of the interface between the brain and the microdialysis probe is critical to the use of microdialysis as a neurochemical analysis technique. The objective of the work reported here was to investigate the potential of two compounds, dexamethasone, a glucocorticoid anti-inflammatory agent, and XJB-5-131, a mitochondrially targeted reactive oxygen species scavenger, to mitigate the penetration injury. Measurements were performed in the rat brain striatum, which is densely innervated by axons that release dopamine, an electroactive neurotransmitter. We used voltammetry to measure electrically evoked dopamine release next to microdialysis probes during the retrodialysis of dexamethasone or XJB-5-131. After the in vivo measurements, the brain tissue containing the microdialysis probe tracks was examined by fluorescence microscopy using markers for ischemia, neuronal nuclei, macrophages, and dopamine axons and terminals. Dexamethasone and XJB-5-131 each diminished the loss of evoked dopamine activity, diminished ischemia, diminished the loss of neuronal nuclei, diminished the appearance of extravasated macrophages, and diminished the loss of dopamine axons and terminals next to the probes. Our findings confirm the ability of dexamethasone and XJB-5-131 to mitigate, but not eliminate, the effects of the penetration injury caused by implanting microdialysis probes into brain tissue.