Dear Michael,

This great paper and its references should give you a good start into magnetic resonance spectroscopy:

Rae, Caroline D. „A Guide to the Metabolic Pathways and Function of Metabolites Observed in Human Brain (1)h Magnetic Resonance Spectra“. Neurochemical Research 39, Nr. 1 (Januar 2014): 1–36. doi:10.1007/s11064-013-1199-5.

Free Software exists, e.g. http://tarquin.sourceforge.net/

Many groups use LCmodel since it gives a high reprodicibility (unfortunately the price is quite high, too: http://s-provencher.com/pages/lcmodel.shtml)

All the best

Steffen

Dear Michael,

I agree with Steffen but would like to add that there are some inconsistencies in findings relating to brain functioning. The method is highly sensitive to noise and individual differences in physiology, depending on what neurochemicals/neurotransmitters you are looking for.

It is a relatively simple method to learn but I would always recommend to have a spectroscopy expert advice you about data quality evaluation and trouble shooting.

We have very interesting findings using MRS in combination with other measures, so I can recommend using it for such purposes.

Best wishes,

Bea

Michael,

I think that proton magnetic resonance spectroscopy is an extremely useful technique. In terms of the problems that it is suited for, it has widespread uses in my view. For instance, it has been used recently to illustrate changes in brain chemistry (e.g., reductions in GABA concentration) that accompany brain simulation using tDCS (Stagg et al., J Neurosci. 2009) and to illustrate that tDCS-induced changes in GABA predict individual levels of motor learning (Stagg et al., Current Biology, 2011). We have been using it to investigate differences in brain chemistry (Glutamate and GABA) in children presenting with neurodevelopmental hyperkinetic disorders thought to be related to excitatory-inhibitory imbalances within brain circuits.

Most people use the LCmodel software as mentioned already.

I can send you some papers if needed.

Good luck,

Stephen

Dear Michael,

I would recommend the article by Govinderaju et al.

Proton NMR chemical shifts and coupling constants for brain metabolites.

Govindaraju V, Young K, Maudsley AA.

NMR Biomed. 2000 May;13(3):129-53.

PMID: 10861994 [PubMed - indexed for MEDLINE]

that gives a good overview over the important brain metabolites, their chemical shift values and their function.

I perform MRS-measurements for the differential diagnosis in the context of neuroradiological questions (as useful additional information to imaging data), using a 3T Siemns scanner.

I use the LC-model program

http://s-provencher.com/pages/lcmodel.shtml

to validate the Syngo results ; but, as already mentioned, it is not free of charge (14700 $ for non-profit organizations).

I also would recommend to perform a manual shimming after the 3D-Shim to further improve the spectral resolution (to find under: Adjustment). Moreover, depending of the T2-characteristics of the metabolites you want to detect, you have to choose the correct echo times (20 ms for GABA, INS, LIPIDS) or 144 ms for the correct assignment of Lactate, hat is superimposed by Lipidsignals at short echo times).

In case of the compilation of metabolite pictures (from CSI data) you always should verify the underlying spectra, (especially in „hotspots“ of a definite matabolie) to get an information about the quality of the obtaines results.

Good luck and greatings from Germany,

Annett.

Dear Michael,

I'll jump in with with everyone else here who has said yes MRS is a useful tool to study brain function with. In addition to the excellent papers already suggested, several groups have been looking at neurometabolite change as a result of brain function - from changes in Glutamate in response to pain:

Mullins, P. G., Rowland, L. M., Jung, R. E., & Sibbitt, W. L. (2005). A novel technique to study the brain's response to pain: proton magnetic resonance spectroscopy. NeuroImage, 26(2), 642–646. doi:10.1016/j.neuroimage.2005.02.001;

Gussew, A., Rzanny, R., Erdtel, M., Scholle, H. C., Kaiser, W. A., Mentzel, H. J., & Reichenbach, J. R. (2009). Time-resolved functional 1H MR spectroscopic detection of glutamate concentration changes in the brain during acute heat pain stimulation. NeuroImage, 1–8. doi:10.1016/j.neuroimage.2009.09.007;

Gutzeit, A., Meier, D., Froehlich, J. M., Hergan, K., Kos, S., Weymarn, C., et al. (2012). Differential NMR spectroscopy reactions of anterior/posterior and right/left insular subdivisions due to acute dental pain. European Radiology, 23(2), 450–460. doi:10.1007/s00330-012-2621-0

to studying energetic changes in prolonged stimulation:

Mangia, S., Tkáč, I., Gruetter, R., Van de Moortele, P.-F., Maraviglia, B., & Ugurbil, K. (2007). Sustained neuronal activation raises oxidative metabolism to a new steady-state level: evidence from 1H NMR spectroscopy in the human visual cortex. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 27(5), 1055–1063. doi:10.1038/sj.jcbfm.9600401

Lin, Y., Stephenson, M. C., Xin, L., Napolitano, A., & Morris, P. G. (2012). Investigating the metabolic changes due to visual stimulation using functional proton magnetic resonance spectroscopy at 7 T. Journal of Cerebral Blood Flow & Metabolism, 1–12. doi:10.1038/jcbfm.2012.33

and even combining it with EEG

Siniatchkin, M., Sendacki, M., Moeller, F., Wolff, S., Jansen, O., Siebner, H., & Stephani, U. (2011). Abnormal Changes of Synaptic Excitability in Migraine with Aura. Cerebral Cortex. doi:10.1093/cercor/bhr248

Lally, N., Mullins, P. G., Roberts, M. V., Price, D., Gruber, T., & Haenschel, C. (2013). Glutamatergic correlates of gamma-band oscillatory activity during cognition: A concurrent ER-MRS and EEG study. NeuroImage, 1–11. doi:10.1016/j.neuroimage.2013.07.049

Having mentioned all that, Beatrix is correct in suggesting contacting an expert to help with issues of data quality and fitting. Additionally there are several different software suites in use for fitting MRS spectra. One that has not yet been mentioned is jMRUI (http://www.mrui.uab.es/mrui/). Also free, and very useful.

Hope this helps.

Paul.

Michael you have asked several questions, directly or indirectly. I will try to handle them somehow. Whether you have a 1.5 or 3 T MRI system, roughly the detectable metabolites must have a concentration of 0,5 mM or more. This leaves several important substances out of detection. Nevertheless the few detected substances (NAA, Creatine/phosphocreatine, Cholines, Myo-Inositol, glycine, taurine, lactate, lipids, citrate in the prostate, other amino acids etc. in abscesses) allow significant diagnostic conclusions. What can you examine? For focal lesions signal/noise ratio considerations and time limitations put a lower limit on the voxel size, especially on single voxel MRS, let's say 0,5 cc. Obviously the goal is to differentially diagnose a focal lesion which MRI fails or the differential list is too large. For non- focal diseases that you have enough "material" things are technically easier but you need a lot of expereinece to interpret the spectrosopic findings. What can you examine? Temporal lobe epilepsy, Dementia, depression, metabolic diseases, name it. You can't howver start from scratch and expect to be able to explain and exploit the acquired spectra. You need knowledge in many special areas. In summary here are the steps:

1. Spectral acquisition. You need to be able to guarantee well-shimmed spectra, which means that if the machine fails to "find" good shim values you have to do it manually. Therefore you must become a good shimmer, otherwise you cannot always guarantee good quality and diagnostic spectra. This becomes a must for 2D and 3D CSI spectral acquisition if you want to have huindreds of good quality spectra.

2. Spectral processing for 2D and 3D CSI spectra. In this second stage you might need to phase better some spectra in case your software fails.

3. Quantitative evaluation, for example absolute concetrations determination. This helps answer many questions. For example if you have an abnormal Cho/Cr the questions are: is it higher than normal because Choline is increased (the usual) or because Cr is decreased or both choline increase and Cr decrease. Each answer might lead to a different diagnosis.

4. Diagnosis!!! Here you look at the lines (the spectral lines of course!) but you must learn to read between the lines. I.e., you must include in your consideration everyting you know about the patient in addition to the spectra. Patient history and symptoms, MRI, IV contrast information, etc., etc! In order to go to stage 4 you must have done all other stages perfectly!!!

I have another recommendation for an excellent overview over technical/methodological considerations to a large variety of applications:

https://www.elsevier.com/books/magnetic-resonance-spectroscopy/stagg/978-0-12-401688-0

This is currently the best comprehensive book on the market and contains chapters by various leading analysis and application experts in the field.

Good luck!

Bea

Dear All: Thanks very much for all your answers: some excellent leads from the literature, some encouragement, and some good advice. My conclusions so far: to follow up your leads from the literature, to explore the free software (we don't have £10K at present for LCModel) and then to design a study that follows published methods and is within our technical capabilities (we have a 3T TiM Trio). I think Estafthios' comment adds a realistic note of caution "You can't however start from scratch and expect to be able to explain and exploit the acquired spectra. You need knowledge in many special areas", and that means learning from others who have already acquired practical knowledge.I'm quite impressed with the quantity and quality of replies that have come through so I'll ask again when I have a more focused question.

Dear Michael,

as a fellow Trio user, let me add some small suggestions for data acquisition. They might save you some time and frustration that I went through when I dug myself into MR spectroscopy on the Trio.

- When performing the manual shim, stick to the X, Y and Z channels. From my experience, the higher order shim channels rarely have a positive effect on linewidth, if at all. So save yourself some valuable time that can be used for a few more acquisitions. As mentioned before, FWHM values below 20 Hz should suffice for in-vivo studies, in-vitro you may reach

I suppose 1.5 Tesla magnets have better homogeity. I always get 3-6 Hz resolution for my 3D CSI spectra, allowing me to have excellent metabolite maps in addition to good spectra. And yes I only use x y and z shimming. And yes I use 6 saturation slabs in hexagon shape that I saturate completely the skull, allowing only for brain spectra.

In response to Efstathios's answer I would like to add that it may depend on what metabolites you are interested in. If you are interested in brain activity, you would probably want to investigate GABA and glutamate (or glutamate+glutamine = glx), in which case anything less than 3T is not advisable. There are also different spectroscopy sequences, such as MEGA-PRESS (as mentioned before) and SPECIAL (Mlynarik, V., Gambarota, G., Frenkel, H., & Gruetter, R. (2006). Localized short-echo-time proton MR spectroscopy with full signal-intensity acquisition. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, 56(5), 965-970. doi: 10.1002/mrm.21043). SPECIAL has a good capacity to separate GABA from glutamate (not glx) and give you measures of both. The method however, has the disadvantage that it requires a shim volume that is larger than the voxel (e.g. 3x3x3cm for a 2x2x2cm voxel) and can make voxel placement very difficult in certain areas or populations, as you need to stay away from the dura and CSF. We now use other sequences with more manual shimming and VAPOR flip angle application, which don't require the extra shim volume. The choice of scanner (field strength), sequence and tools should be based on your specific hypothesis. I hope you find this useful and I would also be happy to provide more specific information if you need anything.

You can also use the jMRUI Software Package

http://www.mrui.uab.es

This package is free and is in use by more than 3500 research groups and hospitals worldwide.

This package is also well-suited for quantification of 1H-MRS and you can simulate the metabolite basis-sets as well.

Yes, the MRS is suitable for studying brain function and yes, there are many aspects that are to be taken into account, like the other responders have highlighted. I also think it would be useful/easier to get in contact with an MRS scientist to set up an MRS study.

Besides the high quality papers that were mentioned before, there is a very good recent review article (October 2013) about using dynamic 1H and 13C MRS for assessing brain function: B Lanz, R Gruetter and JMN Duarte, Frontiers in Endocrinology: "Metabolic flux and compartmentation analysis in the brain in vivo", doi: 10.3389/fendo.2013.00156. It is complex and comprises, among other useful considerations and information, mathematic/kinetic models for estimation of conversion rates of metabolism.

In terms of software, there are several packages and most of them have already been named: jMRUI, LCModel, Tarquan, NUTS, Matlab.

jMRUI software package can be used for several nuclei such as 1H, 13C, 31P, etc., for post-processing of the spectra and for estimation of metabolites concentration. For the quantification process, there are several methods incorporated, like AMARES for simple, peak by peak, quantitation, or QUEST, for estimation of the concentration of metabolites with more complex structure/spectral signature. QUEST requires a basis set of the metabolites to be supplied to the quantification algorithm, basis set which can be simulated, as Danielle suggested, or acquired on the scanner for each one of the metabolites of interest. There are pros and cons for both acquired and simulated basis sets, so each user decides what is the best option for his/her specific study.

I hope this was helpful.

Best wishes,

Adriana.