Unlocking Brain Secrets: Decoding Neurochemistry via Cerebral Microdialysis

By Michael Greenwood, M.Sc.Reviewed by Danielle Ellis, B.Sc.

Cerebral microdialysis is an invasive method of monitoring brain function usually only employed during neurocritical care. It allows physicians to observe changes in brain chemistry via semi-permeable dialysis tubing that exchanges fluids within the brain and transports them to detectors using dialysis pumps.

Cerebral microdialysis also presents a significant research opportunity, providing real-time information related to brain chemistry as a result of disease or treatment and a method through which drugs could potentially be delivered to specific brain regions in exact quantities with instantaneous feedback.

This article will discuss how cerebral microdialysis is currently utilized in the clinic and research and some potential future applications.

Unveiling Neurochemical Dynamics

Microdialysis catheters utilized in cerebral microdialysis consist of two inner channels connected by a U-turn at the tip, allowing fluids to be channeled down one side and up the other. A semi-permeable membrane allowing small molecule exchange is situated at the tip of the catheter, and the flow rate is carefully controlled to reach equilibrium with the concentration of analytes within the brain; thus, down-stream detectors provide a direct reading of concentration at the site of the catheter tip. Commercially available cerebral microdialysis tubing is available in various lengths, gauges, and membrane cut-off weights and can be combined with various types of microdialysis pumps.

Sterile perfusion fluid containing salts such as sodium, potassium, calcium, and magnesium chloride are used to maintain osmotic pressure within the brain, and may also contain protein binding agents that aid in sample recovery. Microdialysis catheters can be inserted through a single burr hole and frequently contain a gold filament within the tip to aid in positioning using computerized tomography or magnetic resonance imaging techniques.

Analytical Chemistry Meets the Brain

The recovered microdialysate may be collected and then subsequently analyzed following particular time intervals in a batch manner or, more recently, can be combined with on-line analysis apparatus. Various metabolites can be detected by enzymatic colorimetric methods, such as glucose, lactate, pyruvate, glycerol, glutamate, and urea, which each provide physicians with information about the brain's functioning.

For example, as glucose is the primary fuel source for cells in the brain, high levels may indicate impending delayed cerebral ischemia or low levels may alert of neuroglycopenia. Similarly, the lactate/pyruvate ratio provides information relating to the status of NADH/NAD⁺ redox and the balance between aerobic and anaerobic metabolism and is considered one of the most useful measurements relating to brain health monitoring.

A wide variety of additional brain biomarkers may be interpreted in relation to brain condition and disease state, including those related to neuroinflammation. During neuroinflammation, a complicated array of cytokines, chemokines, and other signaling molecules, such as tumor necrosis factor-α, interleukins -1b, -6, and -8, and monocyte chemoattractant proteins are generated, which generally require high molecular weight cut off catheters and the use of carrier agents within the perfusion fluid, such as human albumin or dextran, to ensure sufficient collection. Further, dedicated amplification arrays and assays are frequently employed to compensate for low analyte concentrations within the collected microdialysate. 

From Lab to Clinical Applications

The concentration of administered drugs reaching the brain can also be assessed by cerebral microdialysis, and the pharmacokinetics and pharmacodynamics of several neurotherapeutic agents are currently under investigation using this method in phase II clinical trials. Typically, collected samples are firstly separated using methods such as column chromatography, and the identity of the separated analytes is confirmed by appropriate analytical techniques, such as nuclear magnetic resonance spectroscopy or mass spectrometry.

As discussed, cerebral microdialysis could be used to deliver diagnostic or therapeutic agents directly to specific regions of the brain by retrodialysis, i.e., providing a positive concentration gradient against which the drugs will diffuse into the brain. This could be used both in the clinic during critical neuroinjury situations and during research into the interactions of medicines with specific brain regions.

Challenges and Future Prospects

The extremely fine microdialysis tubing used in cerebral microdialysis is very fragile and, when inserted via cranial access devices, may fail to penetrate the dura mater, the dense membrane surrounding the brain and spinal cord. As discussed, subsequent computed tomography scans confirm correct positioning, though this significantly slows the process.

Further, reliance on batch-based methods of sample collection and analysis significantly reduces the resolution of data temporally, limited to only hourly or less frequent collection, which may be late or missed. At this time, on-line analysis of microdiasylate is limited, and often cannot perform an assessment of the important lactate/pyruvate ratio. Additionally, owing to the interpretation of brain metabolite concentrations only in the local vicinity of the microdialysis probe, results often cannot be extrapolated to the condition of the whole brain.

In any case, cerebral microdialysis is currently the only method of continuously and relatively non-invasively sampling molecules within the extracellular fluid of the brain, allowing real-time indication of brain health and local drug efficacy.

Conclusion

Cerebral microdialysis has been quickly adopted in the clinic and research during brain health monitoring and is particularly useful in interpreting glucose concentrations and the lactate/pyruvate ratio in emergency situations. Those living with long-term brain conditions such as epilepsy may, in the future, benefit from cerebral microdialysis apparatus, which could be semi-permanently installed and used to monitor brain metabolism and administer drugs if needed.

Currently, cerebral microdialysis apparatus is too ungainly to be installed in any patients besides those requiring critical care or immediate neurosurgery, but in the future, smaller, more convenient, and wireless devices could be implanted for long-term use.