Fast magnetic resonance spectroscopic imaging techniques in human brain- applications in multiple sclerosis
© The Author(s). 2017
Received: 14 July 2016
Accepted: 8 February 2017
Published: 28 February 2017
Multi voxel magnetic resonance spectroscopic imaging (MRSI) is an important imaging tool that combines imaging and spectroscopic techniques. MRSI of the human brain has been beneficially applied to different clinical applications in neurology, particularly in neurooncology but also in multiple sclerosis, stroke and epilepsy. However, a major challenge in conventional MRSI is the longer acquisition time required for adequate signal to be collected. Fast MRSI of the brain in vivo is an alternative approach to reduce scanning time and make MRSI more clinically suitable.
Fast MRSI can be categorised into spiral, echo-planar, parallel and turbo imaging techniques, each with its own strengths. After a brief introduction on the basics of non-invasive examination (1H-MRS) and localization techniques principles, different fast MRSI techniques will be discussed from their initial development to the recent innovations with particular emphasis on their capacity to record neurochemical changes in the brain in a variety of pathologies.
The clinical applications of whole brain fast spectroscopic techniques, can assist in the assessment of neurochemical changes in the human brain and help in understanding the roles they play in disease. To give a good example of the utilities of these techniques in clinical context, MRSI application in multiple sclerosis was chosen. The available up to date and relevant literature is discussed and an outline of future research is presented.
KeywordsFast MRSI Spiral EPSI Human In vivo Multiple Sclerosis
MRS and MRSI
Magnetic resonance spectroscopy (MRS) is a technique used to identify and quantify metabolites in vivo, giving chemical and quantitative information rather than anatomical information, as in routine MR imaging. MRS interrogates a three dimensional volume of tissue within the body positioned in a MR scanner, to produce a “spectrum” of information about existing chemicals and their relative concentrations. Most applications and technical developments of MRS have focused on the human brain, including clinical studies and increased understanding of the pathology of Parkinson’s disease , Alzheimer’s disease , stroke  and multiple sclerosis (MS) [4, 5]. MR spectra can be acquired from many chemical elements. However, proton (1H) spectroscopy provides a large sensitivity advantage over other nuclei used in MRS (e.g. 31P and 13C). This is because it has the greatest gyromagnetic ratio (γ) of non-radioactive nuclei and a high natural abundance. This sensitivity is augmented compared to other nuclei, due to propitious metabolite relaxation times and because several essential brain metabolites have multiple protons.
In 1985, Bottomley et al., used a slice-selective spin-echo excitation and frequency-selected water suppression (at 1.5 tesla (T)) to obtain the first spatially localised human brain spectrum, at a time when spatial localisation and spectral resolution were limited . Many spatial localisation techniques were developed in the 1980s, when the technology was in its elementary stages and faced many difficulties in implementation and efficiency. Presently, the two most basic and common techniques used in spectroscopy are Stimulate Echo Acquisition Mode (STEAM) [7, 8] and Point RESolved Spectroscopy (PRESS) [9, 10] which are based on three slice-selective pulses applied in orthogonal planes.
MRSI can also be used in an MR scanner to fully cover an organ, e.g. brain, by giving a spectroscopic signature from each part of this organ. It is a method used to collect spectroscopic data and spatial distribution of metabolites using multiple-voxel locations within a single measurement. Multi-voxel spectroscopy (2 or 3 dimensional (2D or 3D)) plays a particularly prominent role, not only in increasing the spatial coverage, but also in improving the efficiency of data collection. Major disadvantages of the technique are long acquisition times, lack of adequate signal-to-noise ratio (SNR), insufficient water and lipid suppression and limited spatial coverage; these elements pose major constraints and limitations. Despite these disadvantages, MRSI has the potential to play a significant role to assist in clinical diagnosis and treatment planning. Many different MRSI acquisition methods have been developed, including conventional and fast MRSI methods, each of which has its own advantages and disadvantages.
MRSI was initially conceptually proposed and implemented in a phantom with varying phosphorus chemical shift composition by Brown et al. in 1982  . The method used a sequence of radio-frequency (RF) and magnetic field gradient pulses to measure chemical shift distribution across a rectangular grid. Simple Fourier transformation was applied to recover the original chemical shift distribution. The first in vivo application was carried out on a human forearm on a 1.5 T magnet by Pykett et al. .
Multiple sclerosis (MS)
MS is an immune-mediated neuronal disorder in which inflammatory cells attack the myelin of the central nervous system (CNS), leading to varying extents of neuroaxonal injury, demyelination and gliosis by affecting both the brain and spinal cord [13, 14]. Typically, symptoms of MS are based on the location of the plaque and most patients experience initially exacerbations and remissions due to inflammation and recovery with remyelination which, in the later stages, is exhausted and then leads to persistent symptoms. Clinically, MS can be classified into: (a) relapsing remitting MS (RRMS) that accounts for 85% of MS patients, and is characterised with remission phases (stability) and relapse or exacerbation , (b) chronic progressive MS is divided into primary progressive MS (PPMS), secondary progressive MS (SPMS) and progressive relapsing (PRMS). However, the new classification by Lublin  aims to characterise progressive disease according to its clinical and MRI activity. PPMS is defined by slowly progressing disability from onset, characterised by localised subpial inflammation without blood brain barrier disruption . The diagnosis and management of MS is increasingly reliant on non-invasive MR modalities. Indeed, the current diagnostic criteria for MS  includes specific MR imaging features which provides evidence of dissemination in space and time of brain and spinal cord lesions. Recent guidelines regarding the frequency of MRI protocols and frequency of MR evaluations  suggest MR imaging be undertaken between every 6 months and 2 years for all RRMS patients, to monitor new and enhancing lesions and contribute to the medical management of the relapsing form of the disease. However, in contrast, there are no current reliable markers to evaluate therapeutic efficacy in the progressive forms of MS, which has been a major obstacle in the development of new disease-modifying therapies.
1H-MRS might add to the specificity of diagnosis and clinical management by the potential identification of new disease biomarkers [20, 21]. 1H-MRS provides a unique potential to evaluate biochemical alteration in MS. In light of this, neurochemical changes of the brain are related to the metabolite concentration levels. For instance, a reduction of N-acetylaspartate (NAA) level, which is an amino acid derivative and has a high concentration in the brain, reflects axonal degeneration or loss, [20, 22] while increased Creatine (Cr) levels, known to play an important role in cellular energy metabolism, can be indicative of gliosis in MS patients . Furthermore, increased resonance intensity of Choline (Cho) indicates an altered turnover of cell membranes level in steady state, and finally, alteration in myo-inositol (mI) concentration can indicate increased glial cell activity or changes in the inflammatory cells .
While existing MR protocols used in MS focus on changes in white matter lesions it is evident that there is a disparity between lesion load and clinical disability  and current MR protocols have limited sensitivity in detecting changes in gray matter. This leaves neuroradiologists with the dilemma on how to best accurately evaluate pathological changes occurring across the entire MS brain .
Several reports have primarily studied MS patients using single-voxel spectroscopy (SVS) methods to evaluate spectroscopic changes of brain metabolites and their ratios in several ROI including normal appearing white matter (NAWM) and (gray matter) GM [27, 28], in addition to whole brain NAA (WBNAA)  at different fields strengths (1.5–3 T) and echo time (TE) values (20–70 ms) . However, these techniques have successfully collected data from a limited region of the brain, within acceptable acquisition times, the real challenge for these methods is to be able to perform a metabolite mapping covering the whole brain, with high spatial resolution and short TE in order to estimate neurochemical changes within larger brain regions in one session. The potential usefulness for such techniques in a clinical setting is also dependent on the acquisition time for the MRS or MRSI profile. If the intention is to run these novel MR metrics in parallel to the standard MS MR protocols, acquisition times and quantification procedures need to be optimised to make this application feasible.
Scope of the review
In this article, the underlying principles of MRS will be described and the different MRSI techniques compared, focussing on recent advances in high-speed MRSI methods. MS will be used as an example pathology in a clinical setting where MRSI techniques are being applied to map brain metabolic changes in different areas of the brain and at different disease stages to evaluate the potential use of the technique as a tool in disease diagnosis and clinical management.
Data acquisition techniques
Conventional multi-voxel techniques
Single-voxel techniques are invariably used in clinical settings, however, SVS techniques are restricted by their limited coverage and coarse spatial resolution. These constraints can be overcome by MRSI techniques . For more global coverage, MRSI can also be extended to 3D-MRSI [35–37].
To overcome the above challenges, fast MRSI techniques were introduced as an improved alternative to facilitate implementation of this technique in the clinic, and to eliminate challenges associated with conventional MRSI techniques.
Parallel imaging techniques, such as sensitivity encoding (SENSE) , simultaneous acquisition of spatial harmonics (SMASH)  and generalised auto-calibrating partial parallel acquisition (GRAPPA) , have been introduced and commonly used to accelerate MRI techniques and can also be applied to improve the temporal performance of conventional MRSI [45–47]. In parallel imaging, signal sensitivity and spatial encoding can be improved by using multiple receiver coils, whereby the number of needed k-space lines decreases with considerable acceleration in the image acquisition.
Fast multi-voxel techniques
In order to study the whole brain, there must be a decrease in the scanning time and motion sensitivity. MRSI methods can be accelerated using time-varying gradients during the readout of spectroscopic imaging data [51–54]. Efficient spatial and spectral k-space sampling with time-varying gradients is a mechanism that can be used to address time limitations. The majority of k-space trajectories that are widely used in spectroscopic imaging are echo-planar and spiral trajectories [55–57]. Recent developments in the gradients hardware design made it possible to traverse the k-space within a shorter period of time within each repetition . For this reason, spiral imaging has shown to be useful in specific applications such as cardiovascular and functional brain imaging applications .
A number of fast MRSI acquisition techniques designed to collect k-space data in three spatial dimensions have been reviewed elsewhere [48, 60]. Their main aim is not only to reduce acquisition time but also to minimise voxel signal contamination and improve metabolite mapping of the whole brain .
Many different strategies for fast MRSI have been used to gain high spatial resolution and to improve the time efficiency of MRSI experiments. The most common and effective of these approaches applied to the human brain are briefly described in this article.
Due to this ability, a sequence with spiral trajectory has a much quicker acquisition time compared to conventional MRSI methods . This single-shot spiral-imaging technique sets a remarkable new standard for fast spectroscopic imaging.
Spiral MRSI was originally introduced by Adalsteinsson et al.  to evaluate the neurochemical change of metabolites in GM in patients with SPMS . However, this technique has limitations in certain clinical applications (i.e. increased blurring and hardware limitation), and thus never became a widely used tool despite its advantages.
Data sampled in spiral spectroscopic imaging sequences are usually non-uniform, and thus acquired data has to be re-gridded to reconstruct the data onto a Cartesian k-space, where Fourier transformation can be applied [57, 59]. Due to the data collection being completely symmetric and sampled around the centre of k-space, several artefacts that are influenced by external variables such as motion or other instabilities are reduced . As a result spiral MRSI offers shorter imaging time, higher spatial resolution, improved point spread function (PSF) and SNR.
Spiral spectroscopic imaging can be readily and effectively combined with other imaging-based techniques such as parallel imaging methods leading to Mayer et al. proposing their accelerated version of this technique for human brain at 3 T .
SENSE-based spiral MRSI  has been applied to address the challenges associated with their clinical application, e.g. volumetric coverage and evaluation of the neurochemical change of the whole human brain .
Turbo spectroscopic imaging (turbo-MRSI)
Even though turbo-MRSI techniques have successfully mapped and assessed uncoupled brain metabolite distributions with long TE, mapping of coupled resonance metabolites (e.g. glutamine + glutamate (Glx)) proved to be a challenge. Fortunately, Yahya et al.  proposed modifications that allow the quantitation of Glx at TE of 100 ms and 170 ms in addition to halving acquisition time.
Turbo-MRSI can be combined with parallel imaging techniques such as SENSE to improve acquisition rate to obtain higher resolution (high sensitivity). Dydak et al. was able to design a turbo-SENSE-MRSI sequence that uses an echo train length of four to acquire spectroscopic data within two to three minutes and reduced acquisition times by about eight folds compared to conventional MRSI techniques .
Due to combining multiple-echo MRSI methods with parallel imaging techniques, high spatial resolutions MRSI become clinically feasible. Many challenging clinical applications have been achieved through the use of the turbo-SENSE-MRSI technique  involving high spatial encoding train (i.e. long multiple-echoes train) which only becomes feasible at 3 T. For instance, acquisition times are significantly reduced (~1 min) to obtain brain metabolites ratios Cho/NAA and Cr/NAA with a TE of 144 ms, even though SNR is reduced because of the longer echo train. In addition to these clinical successes, turbo-MRSI techniques  have made it possible to evaluate brain metabolite levels within the pons, accumulating spectroscopic data within very short periods of time (1 min 20 s) using long TE (288 ms) at 1.5 T.
The advent of the turbo-MRSI technique has made faster data acquisition possible, although with a major drawback of lowering spectral resolution, due to the short time between consecutive refocusing pulses [70, 73]. The second disadvantage is the drop in SNR as a consequence of the increase in spatial encoding trains of more than two, as the spatial encoding maintains a balance between the output of acquisition scan time and SNR [50, 72].
Echo-planar spectroscopic imaging (EPSI)
The introduction of echo-planar imaging (EPI) originally proposed by Mansfield  has facilitated the development of EPSI on conventional clinical MRI scanners. The latter technique made the mapping of spatial metabolite distributions in the brain possible, accelerating spectral data acquisition compared to conventional MRSI, therefore creating an exceptionally fast imaging technique. New improvements to the readout frame of EPI techniques meant that an oscillating readout gradient can be reproducibly used in EPSI. EPSI encoding method that uses multiple-slice or PRESS excitation in 2D or 3D-MRSI [75, 76] became the method of choice. These improvements led to the advent of EPSI to change how MRSI is applied in a clinical setting.
Echo-planar encoding has proved particularly useful in 1H-MRSI applications. Its application has improved performance in covering large volumes due to its improved spatial and temporal resolution, compared to typical conventional phase-encoded MRSI.
The spectroscopic images for distribution of the major metabolites in the human brain were first obtained with 3D-EPSI technique by Posse et al.  and later with fully automated analysis by Ebel et al. . A comparison between EPSI and conventional MRSI spectra indicated a similarity in SNR per unit volume and unit time [60, 77]. However, an outstanding feature of the two-dimensional EPSI method  is the improvement of spatial resolution and SNR for a number of metabolites at short TE (13 ms) and acquisition time (64 s). In addition to evaluating and detecting the three major metabolite maps (NAA, Cho, Cr), 2D-EPSI was also applied to measure the changes in brain lactate at long TE (272 ms) and 1.5Tesla .
New EPSI methods were developed where the quantity of k-space lines are reduced. When 2D-spatial selective RF (2DRF) are incorporated within EPSI sequences, a new type of 2DRF-EPSI is obtained . 2DRF-EPSI addresses the poor image quality that results from artefacts and low spatial resolution, by shortening echo-train length, and doubling the spatial resolution along the direction of phase-encoding.
The implementation of EPSI techniques at high field (3 to 7 T) has enabled not only to linearly gain SNR per unit volume and time but has also allowed for the evaluation of J-coupled metabolites such as glutamate (Glu) and glutamine (Gln) . 3D-EPSI was successfully applied to assess the concentrations of major metabolites, including J-coupled, at 4 T and 3 T in GM and WM  of healthy volunteers. This is an important development as it has greatly increased the spectral resolution and SNR associated with shortened experimental time (<10 min) and has thus sparked interest in clinical studies of MS and stroke for the potential benefits of this methodology .
Short TE EPSI was recently introduced by Ding et al.  to evaluate the neurochemical variation of major metabolites as well as Glx and mI in conjunction with parallel imaging acquisition. NAA, tCr, Cho, Glx and mI were found to have different mapping concentrations in WM and GM in comparison with other short TE (15 ms) studies . Mapping of whole brain metabolites was also achieved by implementation of 3D-EPSI at short TE (20 ms) . An improvement in short TE EPSI applications with high spatial resolution and improved SNR was increasing spatial sensitivity using multiple coils [84, 85].
The significant development of advanced gradient hardware has resulted in the emergence of a new EPSI method that focuses on high spatial resolutions with a large coverage of the human brain at 3 T. The flyback 3D-EPSI technique  was presented to improve the spatial resolution and SNR for different metabolites (NAA, Cr, Cho and lactate). Zierhut et al. employed flyback EPSI for a detailed analysis of the data from a human glioma patient with an acquisition time of less than 9.5 min, with a spatial resolution of 1 cc .
The developments in whole brain coverage have shown that the efficiency of spatial and spectral encoding can be improved by applying volumetric EPSI techniques. However, these improvements are still limited by long acquisition times, which are considered to be a crucial factor in many clinical studies . The first modification to enhance the acceleration of data collection was the use of SENSE-EPSI. This strategy combined the spatial and spectral encoding capabilities and has been investigated by Lin et al.  to obtain major brain metabolites maps. In this particular study, the data acquisition time was halved to 32 s for 32 × 32 image matrix with high spatial-temporal resolution, using SENSE acceleration factor of two. However, SNR declines with faster acceleration, which can affect the usefulness of these techniques clinically. 3D-EPSI and 2D-SENSE  are combined to acquire higher spatial resolution data that covers the whole brain in a shorter acquisition time (1 min) for 32 × 32 × 8 spatial matrix and TE (15 ms) at high field (3 T).
Another method that can be used to map metabolite distribution in the whole brain is the 3D GRAPPA-EPSI techniques . The spectral quality, brain metabolite concentrations and SNR values from 3D GRAPPA-EPSI were obtained with an acceleration factor of 1.5 shows similar results to the 3D-EPSI technique . Reduction of SNR has become a major challenge for implementing 2D GRAPPA-EPSI  techniques with a 32 channel coil array , which improves SNR values due to the large numbers of small sized coils . In addition to this, 2D GRAPPA-EPSI allows for the mapping of most metabolites within a much shorter time.
Dydak et al. incorporated the MEscher-GArwood (MEGA) editing scheme  within the EPSI technique [92, 93] for mapping of the main inhibitory neurotransmitter γ-aminobutyric acid (GABA) levels. The MEGA-EPSI method can perform data acquisition of GABA level activity in less than 10 min in a 2D slice. The short acquisition time and high sensitivity of the 2D MEGA-EPSI lead to the creation of 3D MEGA-EPSI technique due to its increased spatial resolution with an acquisition times of 17 min for eight slices at 3 T, which is a major improvement compared to other techniques .
A further benefit to the EPSI technique is its flexibility to adapt to a wide range of techniques to improve speed of data collection in certain specialised areas across a wide-range of MRSI and MRI techniques, including: Flyback, GRAPPA, and SENSE in 2D and 3D modes, that would otherwise be relying on slow conventional MRSI methods.
Some disadvantages regarding EPSI need to be mentioned. The speed of data collection is the root cause for EPSI’s major technical problems with the gradient system, especially when recording data with disequilibrium of positive and negative gradient lobes . This leads to further contraction of spectral bandwidth which poses a problem considering EPSI has less SNR than traditional phase-encoded MRSI. Therefore, multiple averages are required to improve SNR. Regardless, when the above challenges are suitably addressed, EPSI can be considered one of the best techniques for whole brain 3D-MRSI .
Comparison of MRSI techniques
Advances on MRSI techniques have focussed on either improving the temporal resolution or investigating the relationship between spatial resolution and SNR. To achieve these aims, work has been carried out to improve the MRSI techniques and increase spatial coverage e.g. 2D-3D MRSI.
Detecting various brain metabolites in vivo, using different parameters for 3D PRESS-MRSI [36, 40], showed variable NAA concentrations in different acquisitions at 3 T. Recently, the 3D PRESS-MRSI has been improved by using 4 slices in PRESS box and outer volume suppression pulses to cover the whole brain with an acquisition time of 9 min, leading to spectral data of NAA, Cho and Cr . Multiple 2D-MRSI has significant improvements for spatial resolution, SNR and whole brain metabolite mapping at long TE .
Brain metabolite concentration and acquisition time of various MRSI techniques
Brain region/ FOV/ voxel size/Bo (Tesla)
NAA: 10.1 ± 0.64
Centre of brain/ 12 × 12 × 8 cm3/1 cm3/3 T
NAA: 6.9 ± 1.3, Cho: 6.5 ± 1.4 Cr: 6.1 ± 1.2
Not reported/ 12x12x8 and 16x16x8 cm3/1 cm3/3 T
Not reported/ 12 × 12 × 8 cm3/ 1 cm3/3 T
NAA:2.5 ± 4.47, Cho:2.94 ± 9.71, Cr:7.3 ± 4.09
Whole brain scans/ Not reported
MS patients: NAA:9.48 ± 0.73
Controls: NAA:11.58 ± 0.37
WM and GM/ 16 × 16 cm2/ 2 cm3/1.5 T
3D PRESS-MRSI with OVS
Whole brain/ 16 × 16 × 16, 18x18x16 cm3/1 cm3/3 T
Brain metabolite concentrations obtained in fast MRSI techniques
Brain region/ FOV/ voxel size/ Cohort/ Bo (Tesla)
GM in frontal lobe left: NAA:11.10 ± 0.32, tCho:2.04 ± 0.16, Glx:10.22 ± 0.53
WM in frontal lobe left: NAA:9.51 ± 0.27, tCho:1.95 ± 0.16, Glx:6.43 ± 0.34
whole brain/ 28 × 28 × 18 cm3/1 cm3/ 20 HCs/ 3 T
EPSI with OVS
GM: NAA:8.6 ± 0.7, Glu:12.8 ± 1.5, tCho:1.4 ± 0.2.
WM: NAA:7.2 ± 0.7, Glu:7.0 ± 1.1, tCho:1.4 ± 0.2
WM and GM/ 26 cm/ 1 cm3/ 9 HCs/ 3 T
aNAA: 595 ± 37.9, Cr: 346 ± 23.9
Cho: 100 ± 9.7
Whole brain/ 28 × 28 × 18 cm3/ 0.31 cm3/ 25 patients with mild traumatic brain injuries (mTBI) & 25 HCs/ 3 T
GM: NAA:15.36 ± 2.62, Glx:18.40 ± 3.19, Cho:3.19 ± 0.58
WM: NAA: 14.46 ± 1.79, Glx: 11.01 ± 3.20, Cho:3.19 ± 0.45
WM and GM/ 24 cm/ 0.85 cm3/ 5 HCs/ 3 T
NAA:9.5 ± 4.3, Cho:1.4 ± 0.9, Glu:8.8 ± 5.2, Cr:7.2 ± 2.8
WM and GM/ 24 × 24 × 10 cm/ 0.7 cm3/ HCs/ 3 T
bGM: NAA:4948 ± 75, Cr: 3461 ± 53,
Cho: 544 ± 13 in Occipital
WM: NAA:5165 ± 81, Cr: 3048 ± 48,
Cho: 671 ± 12 in Occipital
WM and GM/ 28 × 28 × 18 cm3/ 0.31 cm3/ 88 HCs/ 3 T
Concentration for age groups (25–32)
NAA/Cr:1.8 in Frontal lobe
NAA/Cr : 1.9 in Occipital lobe
Whole brain/ 32 cm /1 cm3/ 8 HCs/ 1.5 T
Whole brain was also studied by GRAPPA-EPSI short TE technique, where NAA (15.36 ± 2.62), mI (6.11 ± 1.14), tCr (11.97 ± 1.67) and Glx (18.40 ± 3.19) mM where found to be more abundant in GM than WM . In addition, GRAPPA-EPSI sequence at TE of 70 ms  found that WM NAA concentration to be (595 ± 37.9) which is higher than Cr (346 ± 23.9) and Cho (100 ± 9.7) institutional units (IU) for HCs. A summary of fast MRSI studies in human brain and their results are shown in Table 2.
MRSI in multiple sclerosis
MRSI was applied to MS patients at 1.5 T with long TE values [96–99] and at 2 T with short TE values . Some studies focused on lesions compared to NAWM and GM . Other studies compared distinct different clinical groups such as RRMS [101, 102], SPMS and PPMS [103, 104].
Conventional MRSI techniques have identified changes in metabolite concentration in limited regions within NAWM or GM affected by the disease process [105–107]. For this purpose, Tiberio et al. used 3D PRESS-MRSI at TE of 30 ms and 1.5 T. Statistically significant metabolic differences between RRMS patients and HCs were found in NAWM total NAA and cortical gray matter (CGM) Glx and Cho . This technique was also used at TE of 40 ms and 3 T by Ratiney et al.  to investigate mI concentration level in normal appearing white and gray matter (NAGM). mI concentration was significantly increased in both NAWM and NAGM of MS patients compared to control subjects. Changes in the above metabolites have been associated with clinical impairment or/and neuronal dysfunction in MS patients.
In another study, RRMS patients and age-matched controls were recruited to investigate abnormal metabolic changes in GM and WM by using conventional 3D-MRSI techniques at 3 T . With an MRSI scan lasting 34 min, it was found that the concentrations of Cr, Cho and mI in WM of RRMS group were higher (p ≤ 0.01) compared to controls, while WM NAA was lower (p = 0.07). NAA reduction reflects neuronal and glial loss or impairment at early stage of RRMS, whereas brain inflammation leads to increase of mI and Cr concentration levels due to intense gliosis. Additionally, increase in Cho levels is usually associated with abnormal membrane turnover from myelin breakdown.
Suhy et al.  found that NAA was reduced in RRMS and PPMS from NAWM compared to HCs WM. Similarly, the normalized value of brain metabolites in NAWM of RRMS and PPMS patients shows that there is a significant decrease in NAA/Cr ratio (p = 0.027). These results were achieved by applying a 2D PRESS-MRSI at long TE (135 ms) at 1.5Tin RRMS and PPMS groups. However, by applying a 2D PRESS-MRSI at TE (135 ms) at 3 T no statistically significant difference of absolute concentrations of Cr, NAA and NAA/Cr ratio was found in NAWM between RRMS vs control group , but significant reduction was found for NAA/Cr (p < 0.0003 and p < 0.001) in SPMS compared to RRMS and control groups. The above work suggested reduction in NAA and NAA/Cr as potential indicators for irreversible damage in MS. NAA Reduction is usually associated with neuroaxonal injury. Astrocytic proliferation reflects increased levels of Cr. NAA and NAA/Cr are constantly reported with lower level values from NAWM and lesion of MS patients. Recently, Khan et al. showed that tNAA/tCr (1.88 ± 0.19 mM, p < 0.05) has strong and statistically significant inverse correlation with total disability score in a group of 39 RRMS patients .
Spectroscopic data from early RRMS in NAWM, CGM and lesions have been reported by Kapeller et al. . This study focused primarily on quantifying the concentration of the NAA, Cr and mI using PRESS-MRSI technique at short TE (30 ms). Lower NAA concentration (p < 0.01) was found in RRMS in CGM and NAWM compared to controls. Shorter TE is more sensitive to coupled metabolites than longer TE spectroscopy.
Recently, in vivo proton MRSI technique at long TE (135 ms) and 3 T has been reported by Rahimian et al.  not only to measure brain metabolite concentration of NAA, Cho and Cr, NAA/Cr and NAA/Cho in RRMS and PPMS groups but also to differentiate between MS subtypes. Comparing the results obtained shows that there was a significant increase in Cr concentration in non-enhancing lesions of RRMS patients compared to the PPMS patients (p = 0.008) whilst the concentration of NAA/Cr was significantly reduced (p = 0.03) in PPMS compared with RRMS. However, there was no statistically significant difference in concentrations of Cho, NAA and NAA/Cho between the two groups.
The multi-slice EPSI technique was introduced by Mathiesen et al.  as a response to the limitations of VOI in conventional MRS techniques. The introduction of this technique made it possible to measure brain metabolites in specific regions such as MS lesions, NAWM, CGM and to estimate WBNAA which is generally considered an indicator of disease progression and treatment efficiency. Decreases in global ratios (NAA/Cr and Cho/Cr) were noticed for early MS patients compared with healthy subjects, however, no statistically significant differences were noticed in NAA/Cr between these two groups .
Brain metabolite concentration were acquired for MS patients and HCs by applying PRESS-MRSI and fast MRSI methods
Tacq a (min)
Brain region/ FOV/voxel size/Cohort/Bo (Tesla)
Controls, tNAA: 8.3 ± 1.0, Cr: 5.9 ± 0.8
RRMS, tNAA: ↓, Cr: ↓
NAWM, CGM/ 30 cm/2.34 mL/ 16 RRMS, 12 HCs/1.5 T
Controls, NAA/Cr: 2.22 ± 0.19
RRMS, NAA/Cr: ↓
PPMS, NAA/Cr: ↓
WM, NAWM/ 21 × 21 cm/ 2.4 cm3/ 15 PPMS, 13 RRMS & 20 HCs/ 1.5 T.
Controls, tNAA: 8.82, Cr: 4.87
RRMS, tNAA: ↓, Cr : ↓
NAWM, CGM/ 30x30 cm/ 2.3 mL/ 25 RRMS, 28 HCs/ 1.5 T
Controls, NAA:10.63 ± 0.6, Cr:6.13 ± 0.31 PPMS, NAA: ↓, Cr: ↓
Controls, NAA:11.48 ± 0.37, Cr: 5.35 ± 0.45
PPMS, NAA: ↓, Cr: ↓
WM and GM/ 16 ×16 cm2/ 2 cm3/ 4 PPMS & 4 HCs/ 1.5 T
NAWM: Controls, tNAA: 9.18 ± 0.6
RRMS, tNAA: ↓
CGM: Controls, tNAA: 9.28 ± 1.02
RRMS, tNAA: ↓
NWWM and CGM/ 30x30 cm/ 20 RRMS, 10 HCs /1.5 T
GM: Controls, NAA:8.5 ± 0.6, Cr: 6.8 ± 0.6
RRMS, NAA: ↑, Cr: ↑
WM: Controls, NAA:7.9 ± 0.6, Cr: 4.9 ± 0.2
RRMS, NAA: ↓, Cr: ↑
WM and GM/ 16x16 cm/ 0.75 cm3, 18 RRMS, 10 HCs/ 3 T
RRMS, NAA: 8.45 ± 0.88, Cr: 5.2 ± 0.73
PPMS, NAA: ↓, Cr:↑
MS lesion for RRMS & PPMS/ 16×16/ 1.2 cm3/ 15 RRMS, 15 PPMS/ 3 T
Controls, NAA: 12.3 ± 0.4, Cr: 8.4 ± 0.4
RRMS, NAA: ↑, Cr: ↑
SPMS, NAA: ↓, Cr: ↓
Fronto-parietal WM/ 16x16 cm/1 cm3/ 27 RRMS, 10 SPMS & 8 HCs/ 3 T
Normal VEP, NAA: 7692 ± 632
Abnormal VEP NAA: ↓
Mid-thalamus / 24 cm/ 9 MS with abnormal VEP& 8 MS normal VEP/ 1.5 T
Controls, NAA/Cr: 1.963 ± 0.167
MS patients, NAA/Cr: ↓
Corpus callosum, STB/ 24x24x16 cm/ 1 cm3/ 9 RRMS, 21 SPMS, 18 PPMS & 10 HCs/ 1.5 T
NAA/Cr: 1.55 ± 0.1 from RRMS
Whole brain/ not reported /1 cm3, 20 RRMS & 75 HCs/ 1.5 T
Controls, NAA: 159 A.U. (mean conc.)
RRMS, NAA: ↓ SPMS, NAA: ↓
NAWM, GM in supratentorial brain/ 24 cm/ 1.2 mL/ 5 RRMS, 5 SPMS & 9 HCs/ 1.5 T
Controls, NAA/Cr: 1.5 ± 0.09
MS patients, NAA/Cr: ↑
Whole brain/ not reported/ 1 cm3, 18 RRMS & 18 HCs/ 1.5 T
Controls, NAA: 10 ± 0.85, Glx: 6.5 ± 1.1
MS patients, NAA: ↓, Glx: ↓
Whole brain/ 28×28×18 cm/ 1 cm3, 19 RRMS & 19 HCs / 3 T
Reproducibility of MRSI of MS patients
Reproducibility of fast MRSI techniques has not been evaluated. It is important that MRSI techniques have good reproducibility and recent studies have shown good correlation between time points. Mostert et al. tested MRSI reproducibility with stable MS patients 4 week apart and found good short term reproducibility of NAA/Cr measurement . Vafaeyan et al. also validated the reproducibility of NAA/Cr and NAA/Cho in MS as they found high correlation of these ratios at different time points .
In recent years, the evolution of MR technologies has led to developments of brain 1H-MRS and clinical MR imaging procedures which enabled the collection of morphometric and biochemical information in a single imaging session. There are a variety of 1H-MRS techniques that are used to detect and evaluate the biochemical changes of whole brain, where whole brain coverage requires improving spatial resolution and SNR. Fast MRSI is more suited to a clinical setting, mainly due to faster acquisition time, improved SNR and spatial resolution.
The short acquisition time of fast MRSI requires advanced and robust design in the hardware and software systems to improve and modify sequences for these techniques, making them more adaptable, especially when there is a need to combine them with other acceleration techniques by either increasing field strength or modifying coil design.
EPSI has brought about revolutionary improvement in the technological capacity of MRSI, compared to conventional MRSI methods. This development has improved the time efficiency of data collection and enhanced the recording brain metabolite distribution. Data acquisition has seen the biggest improvement, with speeds more than two to three times faster than that of traditional MRSI methods. This has provided the opportunity for clinical research to be done on whole brain in acquisition times of less than 16 min.
This article has shown the benefits and ability of the EPSI to adapt to a diverse range of techniques, leading to: flyback-EPSI, MEGA-EPSI, GRAPPA-EPSI, SENSE-EPSI 1H-MRSI techniques and 2D and 3D echo-planar techniques. This also enables the detection of J-coupled brain metabolites like: GABA, Glu, Gln and mI. Moreover, it can be concluded that the echo-planar imaging sequence has proven to be a successful and accelerated technique in clinical studies not only in multiple sclerosis  but also in Parkinson’s disease , Alzheimer’s disease  and stroke .
In vivo spectroscopy has the potential to play an important role in biomarker discovery and disease activity prediction in MS. MRSI studies confirmed that NAA/Cr can distinguish MS from HCs independent from the ROI. NAA can also be a potential marker of neuronal function in NAWM, CGM for different clinical groups identifying the progressive stage of the disease. Longitudinal studies with techniques applicable in clinical setting are required to determine if MRSI can close the gap in MRI imaging by defining the disease course for the individual patient. The larger ROI afforded by MRSI compared to conventional MRS has provided evaluations of neurometabolite changes to be assessed across a much larger area, thereby assessing whole brain pathological changes occurring in MS. The improvements in achieving shorter acquisition times for MRSI now provide a greater likelihood of clinical application of these techniques.
Static magnetic field
Cortical gray matter
Chemical shift selective suppression pulses
Echo planar imaging
Echo planar spectroscopic imaging
Field of view
Glutamine + glutamate
Generalised autocalibrating partially parallel acquisitions
Magnetic resonance imaging
Magnetic resonance spectroscopic
Magnetic resonance spectroscopic imaging
Normal appearing gray matter
Normal appearing white matter
Outer volume suppression
Parts per million
Primary progressive multiple sclerosis
Point resolved spectroscopy
Point spread function
Region of interest
Relapsing-remitting multiple sclerosis
Simultaneous acquisition of spatial harmonics
Secondary progressive multiple sclerosis
Stimulated echo acquisition mode
Volume of interest
Whole brain N-acetylaspartate
This research was supported by the Imaging Centre of the University of Newcastle and Hunter Medical Research Institute.
SR received research funding from Hunter Medical Research Institute.
Availability of data and materials
“Not applicable” (The present paper is a review article, it describes published data).
OA has been involved in writing, compiling and revising the manuscript critically to suit publication standards. JLS, KR and SR contributed significantly on revising, literature and critical suggestions to reshape the manuscript. All authors read and approved the final version of manuscript.
OA and KR declare that they have no competing interests. JLS has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support as well as research grants from Bayer Health Care, Biogen, CSL, Genzyme Sanofi, Merck, Novartis and TEVA.
Consent for publication
“Not applicable” (The present paper does not contain any individual persons data).
Ethics approval and consent to participate
“Not applicable” (The present paper is a review article and thus it does not involve performing research on human subjects but it describes published data).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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