How Whole Brain 3-D Magnetic Resonance Spectroscopy Is Advancing Exploration of Neuropsychiatric Disorders

Metabolites now measurable in large volumes of brain simultaneously


By Amit Anand, MD, and Pallab K. Bhattacharyya, PhD


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Mapping biochemical information in the brain has the potential to unlock the biochemical processes involved in neuropsychiatric disorders, which remain poorly understood.

Limitations of current techniques

Although techniques such as proton magnetic resonance spectroscopy (MRS) have yielded insight into the workings of the brain, these techniques are mostly restricted to single voxels (to obtain relatively large signal over a homogeneous area of brain) and thus to small areas of the brain that sometimes may not be relevant to psychiatric illness.

In addition to single-voxel spectroscopy, multivoxel MR spectroscopic imaging (MRSI) has long been used in spectroscopy studies, but MRSI studies often scan over a single slice and require long scan times to obtain useful information.

As imaging tools are refined, knowledge of brain neurochemistry in neuropsychiatric disorders will expand, promising better disease detection, superior therapy monitoring and improved drug development.

New imaging methods and techniques to map metabolites in larger volumes of the brain are being developed to accomplish these goals. Advances in hardware and pulse sequences have already made it possible to scan a much larger portion of the brain in three dimensions (3-D) with good signal-to-noise ratio and in reasonable scan time.1-3

This article highlights the advantage of building on these advances by performing 3-D MRSI to gain clinical insights and discusses the potential for future insights through 7-tesla (7T) MRI imaging.

Whole brain 3-D magnetic resonance spectroscopy

MRSI, also known as chemical shift imaging, records spectroscopic data for a group of voxels using an MRI scanner. To date, attempts to characterize the neurobiological basis of psychiatric illness have used proton MRSI to noninvasively measure the neurochemical environment within the brain. The neurochemicals most commonly visualized are:

  • Lactate
  • The metabolites N-acetylaspartate (NAA), creatine (Cr) and choline (Cho)
  • The amino acids γ-aminobutyric acid (GABA), glutamate and glutamine

Abnormalities in concentrations of these metabolites are indicators of abnormal neuronal energy metabolism, which is known to occur in several neuropsychiatric disorders.

Pros and cons of single- and multivoxel designs

For technical reasons, a single-voxel design that allows signal detection from a well-defined area and requires shorter measurement times typically has been employed. Unfortunately, measuring localization limits measurement to brain areas that may not be involved in psychiatric illness (e.g., the occipital cortex) and therefore does not provide a meaningful and comprehensive picture of whole brain metabolite concentrations.

Although acquisition times are shorter with single-voxel spectroscopy, that approach is best suited to imaging when a volume of interest is known. Multivoxel spectroscopic methods can present data in 2-D or 3-D images. Multivoxel spectroscopy is able to identify the metabolite profile in brain regions but suffers from long data acquisition times.

Building on insights from 2-D studies

In a recent study, Dr. Anand and colleagues,4 using a single-slice 2-D technique, reported different concentrations of glutamate in different brain regions among patients with bipolar depression, patients with bipolar mania and healthy controls, whereas concentrations of lactate were uniformly high in all regions.

This discovery has ignited a quest to study chemical changes in large volumes of brain simultaneously.


By using 3-D proton echo-planar spectroscopic imaging (PEPSI), brain metabolites can be measured simultaneously from multiple brain regions to accelerate spectra acquisition times. Using a high-spatial-resolution 3-D PEPSI pulse sequence at 3T field strength, high-quality spectra of the metabolites from a large part of the brain were obtained (Figure 1).

600x in story Whole Brain fig1

Figure 1. Single-slice spectra of N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) using three-dimensional proton echoplanar spectroscopic imaging (PEPSI). A total of eight slices were scanned for this study.

The scan also generated excellent 3-D maps of NAA, Cr and Cho (Figure 2).

600x in story Whole Brain fig2.jpg

Figure 2. Three-dimensional maps of N-acetylaspartate, creatine and choline using a 3-D PEPSI sequence.

Brave new world with 7T MRI scanning

Cleveland Clinic’s Center for Neuroimaging recently acquired a 7T Siemens MRI scanner to conduct state-of-the-art MRI/MRS studies (as detailed in this story), making ours one of the first institutions to use a 7T MRI scanner in a neuropsychiatric research setting.

The advantages of MRS at 7T include:

  • A high signal-to-noise ratio to enhance image quality by decreasing voxel size
  • Improved spatial resolution relative to other noninvasive imaging techniques

We will be working to develop MRSI sequences suited for ultra-high fields to take advantage of the increased spatial and spectral resolution they provide. With our new ability — made possible by ultra-high field strengths — to map metabolite distribution in the entire brain, we hope to gain further insight into the pathophysiology of neurological and psychiatric disorders.

Dr. Anandis Vice Chairman for Research and Director of the Mood Disorders Clinical and Research Program in Cleveland Clinic’s Center for Behavioral Health and Department of Psychiatry and Psychology.

Dr. Bhattacharyyais an assistant staff member in the Department of Diagnostic Radiology, Imaging Institute, and in the Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute.



1. Maudsley AA, Domenig C, Govind V, et al. Mapping of brain metabolite distributions by volumetric proton MR spectroscopic imaging (MRSI). Magn Reson Med. 2009;61(3):548-559.

2. Posse S, Otazo R, Dager SR, Alger J. MR spectroscopic imaging: principles and recent advances. J Magn Reson Imaging. 2013;37(6):1301-1325.

3. Otazo R, Tsai SY, Lin F H, Posse S. Accelerated short-TE 3D proton echo-planar spectroscopic imaging using 2D-SENSE with a 32-channel array coil. Magn Reson Med. 2007;58(6):1107-1116.

4. Xu J, Dydak U, Harezlak J, Nixon J, Dzemidzic M, Gunn AD, Karne HS, Anand A. Neurochemical abnormalities in unmedicated bipolar depression and mania: A 2D 1H MRS investigation. Psychiatry Res Neuroimag. 2013;213:235-241.

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