# A Review of Neurotransmitters Sensing Methods for Neuro-Engineering Research
## 3 Neurotransmitter Detection Techniques' Guidelines
If we compare the electrochemical research for glucose sensors and brain electrochemical sensing, the environment itself is very different. The glucose sensors are adapted to blood which is a very non-homogeneous liquid, but available in important quantities, while, in the case of the brain, the opposite is true: the cerebrospinal fluid volume is available in less volume, but it is more homogeneous. Moreover, brain volume samples are less reachable than blood because of the complexity to access the sampling zone, and when an electrode is implanted into the brain, the tissue can react with \begin{table}
\begin{tabular}{l l l l} \hline \hline
**Techniques** & **Advantages** & **Shortcomings** & **Reported LOD** \\ \hline PET & High spacial resolution & Complex manipulation & Dopamine: 200 nM [216] \\ SPECT & High spacial resolution & Complex manipulation & \\  & & Very high cost & \\ SERS & Very high sensitivity and & Can be inapplicable in vivo & \begin{tabular}{l} Choline: 2 uM \\ Acetylcholine: 4 uM \\ Dopamine: 100 nM \\ Epinephrine: 100 uM \\ \end{tabular} \\ FSCV & High sensitivity & Low selectivity & Dopamine: 50 nM \\ \end{tabular} \begin{tabular}{l} Hyperometry \\ HPLC \\ manipulation \\ \end{tabular} \\  & & High sensitivity and & High cost and complex & \\ Fluorescence & High sensitivity and selectivity & May not be usable in vivo & Dopamine: 10 pM \\ \end{tabular} \begin{tabular}{l} Optical Fiber Sensing \\ \end{tabular} \\  & & & Low sensitivity & Glutamate: 0.22 uM \\ \end{tabular} \
\begin{tabular}{l} Colorimetric \\  & & & Dopamine: 1.8 nM \\  & & Not usable in vivo &
\begin{tabular}{l} Noradrenaline: 20 uM \\ Adrenaline: 2.5 uM \\ \end{tabular} \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Summary of neurotransmitters’ detection techniques. the implanted devices. All of these aspects make the use of electrochemical methods problematic for brain research. Still, some research uses this technique, whereas other techniques are being developed. Optical sensing techniques are suitable for miniaturization, thanks to rapidly advancing optoelectronic and MEMS (micro-electromechanical systems ) micro-fabrication technologies, and the possibility to automate chemical reactions with micro-reactors. With adequately selected functionalized quantum dots (QDs), enhanced surfaces by noble metals particles or aptamers, this emerging technology is among the most promising for neurotransmitter detection with high accuracy. One of the known optical sensing weaknesses is the limitations due to Debye length. While aptamer modified surfaces provide high selectivity in SERS based biomolecule detection, Raman signal is only enhanced within the physiological Debye length, which is approximately 1 nm. Hence, this may complicate the detection of small molecules such as neurotransmitters. However, [PERSON] et al. proposed using aptamer modified field-effect transistors (FET), which can overcome this limitation [218]. Their strategy of combining both high sensitive FET and high selective aptamer may open another branch of neurotransmitter detection based on electronics in parallel to the known optical techniques. Another weakness of optical sensing techniques is that some of the sensing elements may be toxic and thus unusable for in vivo neurotransmitters detection. Furthermore, these techniques rely on the optical properties of neurotransmitter molecules. The approach is acceptable when experiments are performed in a laboratory environment and in vitro experiments. However, when molecules in the brain are targeted, the tissue interaction with and growth around the sensor should be considered. It is technically impossible to guarantee that the sensor environment will not be changed when in contact with the cerebral tissue. Knowing that most of optical sensors are based on optical stimulation of molecules, the optical path between the light source and the target molecule must remain clear, which is impossible to guarantee with actual technology, even if we use biocompatible materials.