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.

In-vitro gadolinium retro-microdialysis in agarose gel-a human brain phantom study.

Rationale and objectives: Cerebral microdialysis is a technique that enables monitoring of the neurochemistry of patients with significant acquired brain injury, such as traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH). Cerebral microdialysis can also be used to characterise the neuro-pharmacokinetics of small-molecule study substrates using retrodialysis/retromicrodialysis. However, challenges remain: (i) lack of a simple, stable, and inexpensive brain tissue model for the study of drug neuropharmacology; and (ii) it is unclear how far small study-molecules administered via retrodialysis diffuse within the human brain. Materials and methods: Here, we studied the radial diffusion distance of small-molecule gadolinium-DTPA from microdialysis catheters in a newly developed, simple, stable, inexpensive brain tissue model as a precursor for in-vivo studies. Brain tissue models consisting of 0.65% weight/volume agarose gel in two kinds of buffers were created. The distribution of a paramagnetic contrast agent gadolinium-DTPA (Gd-DTPA) perfusion from microdialysis catheters using magnetic resonance imaging (MRI) was characterized as a surrogate for other small-molecule study substrates. Results: We found the mean radial diffusion distance of Gd-DTPA to be 18.5 mm after 24 h (p < 0.0001). Conclusion: Our brain tissue model provides avenues for further tests and research into infusion studies using cerebral microdialysis, and consequently effective focal drug delivery for patients with TBI and other brain disorders.

Modified MRI Anonymization (De-Facing) for Improved MEG Coregistration.

Localising the sources of MEG/EEG signals often requires a structural MRI to create a head model, while ensuring reproducible scientific results requires sharing data and code. However, sharing structural MRI data often requires the face go be hidden to help protect the identity of the individuals concerned. While automated de-facing methods exist, they tend to remove the whole face, which can impair methods for coregistering the MRI data with the EEG/MEG data. We show that a new, automated de-facing method that retains the nose maintains good MRI-MEG/EEG coregistration. Importantly, behavioural data show that this "face-trimming" method does not increase levels of identification relative to a standard de-facing approach and has less effect on the automated segmentation and surface extraction sometimes used to create head models for MEG/EEG localisation. We suggest that this trimming approach could be employed for future sharing of structural MRI data, at least for those to be used in forward modelling (source reconstruction) of EEG/MEG data.

Phosphorus spectroscopy in acute TBI demonstrates metabolic changes that relate to outcome in the presence of normal structural MRI.

Metabolic dysfunction is a key pathophysiological process in the acute phase of traumatic brain injury (TBI). Although changes in brain glucose metabolism and extracellular lactate/pyruvate ratio are well known, it was hitherto unknown whether these translate to downstream changes in ATP metabolism and intracellular pH. We have performed the first clinical voxel-based in vivo phosphorus magnetic resonance spectroscopy (31P MRS) in 13 acute-phase major TBI patients versus 10 healthy controls (HCs), at 3T, focusing on eight central 2.5 × 2.5 × 2.5 cm3 voxels per subject. PCr/γATP ratio (a measure of energy status) in TBI patients was significantly higher (median = 1.09) than that of HCs (median = 0.93) (p < 0.0001), due to changes in both PCr and ATP. There was no significant difference in PCr/γATP between TBI patients with favourable and unfavourable outcome. Cerebral intracellular pH of TBI patients was significantly higher (median = 7.04) than that of HCs (median = 7.00) (p = 0.04). Alkalosis was limited to patients with unfavourable outcome (median = 7.07) (p < 0.0001). These changes persisted after excluding voxels with > 5% radiologically visible injury. This is the first clinical demonstration of brain alkalosis and elevated PCr/γATP ratio acutely after major TBI. 31P MRS has potential for non-invasively assessing brain injury in the absence of structural injury, predicting outcome and monitoring therapy response.

The effect of succinate on brain NADH/NAD+ redox state and high energy phosphate metabolism in acute traumatic brain injury.

A key pathophysiological process and therapeutic target in the critical early post-injury period of traumatic brain injury (TBI) is cell mitochondrial dysfunction; characterised by elevation of brain lactate/pyruvate (L/P) ratio in the absence of hypoxia. We previously showed that succinate can improve brain extracellular chemistry in acute TBI, but it was not clear if this translates to a change in downstream energy metabolism. We studied the effect of microdialysis-delivered succinate on brain energy state (phosphocreatine/ATP ratio (PCr/ATP)) with 31P MRS at 3T, and tissue NADH/NAD+ redox state using microdialysis (L/P ratio) in eight patients with acute major TBI (mean 7 days). Succinate perfusion was associated with increased extracellular pyruvate (+26%, p < 0.0001) and decreased L/P ratio (-13%, p < 0.0001) in patients overall (baseline-vs-supplementation over time), but no clear-cut change in 31P MRS PCr/ATP existed in our cohort (p > 0.4, supplemented-voxel-vs-contralateral voxel). However, the percentage decrease in L/P ratio for each patient following succinate perfusion correlated significantly with their percentage increase in PCr/ATP ratio (Spearman's rank correlation, r = -0.86, p = 0.024). Our findings support the interpretation that L/P ratio is linked to brain energy state, and that succinate may support brain energy metabolism in select TBI patients suffering from mitochondrial dysfunction.

Corrigendum: Assessing Metabolism and Injury in Acute Human Traumatic Brain Injury with Magnetic Resonance Spectroscopy: Current and Future Applications.

[This corrects the article on p. 426 in vol. 8, PMID: 28955291.].

Assessing Metabolism and Injury in Acute Human Traumatic Brain Injury with Magnetic Resonance Spectroscopy: Current and Future Applications.

Traumatic brain injury (TBI) triggers a series of complex pathophysiological processes. These include abnormalities in brain energy metabolism; consequent to reduced tissue pO2 arising from ischemia or abnormal tissue oxygen diffusion, or due to a failure of mitochondrial function. In vivo magnetic resonance spectroscopy (MRS) allows non-invasive interrogation of brain tissue metabolism in patients with acute brain injury. Nuclei with "spin," e.g., 1H, 31P, and 13C, are detectable using MRS and are found in metabolites at various stages of energy metabolism, possessing unique signatures due to their chemical shift or spin-spin interactions (J-coupling). The most commonly used clinical MRS technique, 1H MRS, uses the great abundance of hydrogen atoms within molecules in brain tissue. Spectra acquired with longer echo-times include N-acetylaspartate (NAA), creatine, and choline. NAA, a marker of neuronal mitochondrial activity related to adenosine triphosphate (ATP), is reported to be lower in patients with TBI than healthy controls, and the ratio of NAA/creatine at early time points may correlate with clinical outcome. 1H MRS acquired with shorter echo times produces a more complex spectrum, allowing detection of a wider range of metabolites.31 P MRS detects high-energy phosphate species, which are the end products of cellular respiration: ATP and phosphocreatine (PCr). ATP is the principal form of chemical energy in living organisms, and PCr is regarded as a readily mobilized reserve for its replenishment during periods of high utilization. The ratios of high-energy phosphates are thought to represent a balance between energy generation, reserve and use in the brain. In addition, the chemical shift difference between inorganic phosphate and PCr enables calculation of intracellular pH.13 C MRS detects the 13C isotope of carbon in brain metabolites. As the natural abundance of 13C is low (1.1%), 13C MRS is typically performed following administration of 13C-enriched substrates, which permits tracking of the metabolic fate of the infused 13C in the brain over time, and calculation of metabolic rates in a range of biochemical pathways, including glycolysis, the tricarboxylic acid cycle, and glutamate-glutamine cycling. The advent of new hyperpolarization techniques to transiently boost signal in 13C-enriched MRS in vivo studies shows promise in this field, and further developments are expected.