Nuclear magnetic resonance technology has been an integral part of radiologic imaging for more than 20 years. However, magnetic resonance spectroscopy (1H-MRS) has only recently been acknowledged as a useful diagnostic tool. Successful interpretation involves understanding the most basic principles of 1H-MRS and the clinically significant metabolites that it measures. This article is an introduction to 1H-MRS and its potential clinical applications in the field of neuroradiology.
Dr. Ballestero is a diagnostic radiology resident at the
University of Pittsburgh Medical Center, Pittsburgh, PA. She
received her MD in 1997 from the Medical College of
In 1973, nuclear magnetic resonance was first applied to the
field of medicine and, circa 1979, the first magnetic resonance
(MR) image was created on human pathology.
While magnetic resonance imaging (MRI) rapidly became an integral
part of diagnostic imaging, magnetic resonance spectroscopy (
H-MRS) lagged behind. However, since its 1995 Food and Drug
Administration (FDA) approval for neuroimaging,
H-MRS has flourished. The metabolic and biochemical information
that MRS provides, as well as its relative ease of acquisition and
interpretation, have made it a useful addition to the MRI sequences
that are now standard in all diagnostic radiology practices.
For many years, single-photon emission tomography (SPECT) and
positron emission tomography (PET) have been used to identify
metabolic changes involved in pathologic processes of the brain.
However, the radiation exposures inherent to these techniques have
limited their use. Many neurologic disorders are chronic in nature
and require serial imaging over long periods of time.
H-MRS can provide the same, if not more accurate, metabolic
information without the ionizing radiation associated with SPECT
and PET imaging. The ability to correlate anatomic and physiologic
information by coupling
H-MRS with MRI is an added advantage of this technique.
This article is intended to introduce the reader to some of the
most basic principles of
H-MRS and the most common clinically significant metabolites that
are essential to understanding and interpreting a human
H-MR spectrum. In addition, several cases will be presented to
demonstrate the clinical application of
H-MRS with respect to space-occupying lesions of the brain.
The fundamentals of
Volume of interest
--In order to produce a
H-MR spectrum, a single MR image is first acquired to be used as a
localizer. From this image, a volume of interest (VOI) is isolated.
H-MRS is to be performed, the selected VOI will ideally surround
only the tissue to be examined. For multi-voxel
H-MRS (see below), a larger volume is selected so that the spectra
from adjacent, more normal tissue can be simultaneously acquired
and compared to the anatomic region of interest. As with all MR
imaging, the larger the VOI, the greater the signal-to-noise ratio
(SNR) of the resultant spectrum. Similarly, signal averaging is
frequently invoked to increase the SNR to clinically usable levels.
--Three orthogonal slices are excited within the same pulse
sequence. Their common intersection defines the VOI from which the
H-MR spectrum will be obtained. This would represent single-voxel
H-MRS. Should the study be repeated numerous times with phase
encoding performed along two orthogonal axes, it would permit
spatial localization within the VOI itself. This technique would be
referred to as multi-voxel
H-MRS. The latter has the advantage of increased SNR and superior
in-plane spatial resolution of spectra within the targeted voxel.
However, it is accompanied by a scan time that is increased
proportional to the number of phase encoding steps performed.
H-MRS, the most commonly used techniques are the stimulated echo
acquisition mode (STEAM) and point resolved spectroscopy (PRESS).
STEAM has, historically, had the advantage of requiring shorter
echo time (TE) studies (e.g., 30 ms), a factor necessary to detect
the clinically significant neurometabolites with a higher SNR.
PRESS, on the other hand, has the predominant advantage of
producing greater spectral SNR (two-fold greater than with STEAM).
H-MRS technology has allowed the use of shorter TEs with the PRESS
technique. As a result, PRESS has become the
H-MRS method of choice in clinical use.
Repetition time and echo time
H-MRS use similar techniques for data acquisition but present the
data quite differently. MRI maps signal intensities to spatial
localization data. The result is an MR image.
H-MRS maps signal intensities to their component frequencies,
H-MR spectrum, or frequency map, of the examined tissue. It
therefore stands to reason that just as variations of repetition
time (TR) and TE will change signal intensities in an MR image,
they similarly affect signal intensities (i.e., spectral peak
heights), in a
H-MR spectrum (figure 1). The shorter the TR, the less the
longitudinal magnetization recovery of each metabolites'
magnetization and, therefore, the weaker the resultant signal
(i.e., smaller spectral peak heights). Similarly, the longer the
TE, the more transverse magnetization of each metabolite will have
decayed and, thus, the weaker the signal obtained, again resulting
in smaller and fewer peaks. TR and TE must be kept in mind when
H-MR study and interpreting a
H-MR spectrum. Valuable information can be obtained and/or lost
depending on the selection of such timing parameters.
--The concentrations of the clinically significant metabolites can
be 10,000 to 100,000 times smaller than that of free water. As a
result, the area-under-the-water portion of the
H-MR spectrum (at 4.7 ppm) tremendously overshadows the spectral
peaks of the metabolites of interest (figure 2). Therefore, water
suppression techniques are routinely employed in an attempt to
eliminate the signal from free water.
The most commonly employed water suppression technique is the
chemical shift selective (CHESS) radiofrequency (RF) pulse. This
works in much the same way as the water and fat suppression pulses
used in MRI. Prior to initiating a
H-MRS sequence, the CHESS method will place a narrow, frequency
selective RF pulse at the water resonance frequency, resulting in
saturation of free water. When performed properly, this can lower
the resultant water peak by up to 1,000 times, enabling the smaller
metabolite peaks to be successfully detected and differentiated.
Magnetic field homogeneity
--Within a selected VOI, heterogeneities in the magnetic field will
result in broadening and lowering of the individual component
peaks. This results in poor spectral resolution (i.e., decreased
ability to detect and differentiate individual peaks) while
simultaneously worsening the SNR of the study. As in MRI, shim
coils are used to correct for magnetic field distortions to yield
narrow line widths and improved SNR; all in clinically feasible
H-MRS of the normal brain
MRS is used to identify and quantify metabolites in and around
the tissues being examined. In order to detect pathology and
differentiate it successfully from normal tissue, one must
understand how a
H-MR spectrum is read and be able to recognize normal spectral
patterns. The roles of the clinically significant metabolites must
also be addressed, as changes in their concentrations will provide
biochemical/metabolic information about the tissue in question.
With this knowledge,
H-MRS can be used to develop or narrow a differential diagnosis of
pathologic and/or normal entities.
H-MR spectrum is essentially a graphic representation of the
quantity and variety of metabolites present in a particular volume
of tissue (figure 3). Each metabolite is plotted as a total
quantity, mapped to its particular resonant frequency. The vertical
axis is used to measure concentration. In simplest terms, the area
under a peak represents a given metabolite's concentration. The
greater the concentration, the taller and/or wider the peak. Poor
magnetic field homogeneities will result in a lower peak height.
Because the metabolite concentration is constant, the area under
the peak will be spread over a broader range, thus resulting in
lowered spectral resolution (the broader the peak, the greater the
chance of overlap with other peaks). The horizontal axis is
referred to as the frequency, or chemical shift, axis. It defines
characteristic resonant frequencies of the detected metabolic
moieties. The metabolite peak positions (typically reported as
chemical shifts of parts per million (ppm) will not vary from
subject to subject, as long as the same primary magnetic field is
used (Table 1).
--As there are hundreds of metabolites produced by the human brain,
the concept of mapping these out, using
H-MRS, can be very daunting. However, because only a handful of
these occur in significant quantities in both healthy and diseased
states, most of the neurometabolites can be eliminated, making the
H-MRS a much less complex task. The clinically significant
neurometabolites that one may encounter in clinical practice are as
Found solely in the brain, NAA is a measure of neural tissue
viability. As it is present in both gray and white matter, it is
considered a marker of neuronal and axonal integrity. NAA creates
what is typically the tallest peak in the normal brain spectrum.
Because its decrease or disappearance can be due to either cell
death or axonal injury, correlation with the patient's clinical
history is essential. Decreased NAA can be seen in numerous
pathologic processes including neoplasm, infection, ischemic
injury, and demyelinating diseases. Elevation of the NAA peak is
rare but may be seen in hyperosmolar states and axonal
Phosphotidylcholine, the most common choline neurometabolite, is
found in lipid-containing structures such as myelin and cell
membranes. When pathologic processes alter or destroy these
structures, phosphotidylcholine is released and, thus, elevations
of the choline peak will occur. Some of these processes include
neoplasm, ischemic injury, and acute demyelinating diseases.
Decreased choline peaks can also be seen, raising suspicion for
In normal brain metabolism, phosphocreatine supplies phosphate to
adenosine diphosphate (ADP), resulting in the production of an
adenosine triphosphate (ATP) molecule and the release of creatine.
Thus, the total creatine (creatine plus phosphocreatine) is a very
reliable marker of brain metabolism. Creatine is generally seen as
the constant, central peak in a
H-MR spectrum. Lower creatine peaks may be seen in primary cerebral
lesions such as neoplasm, ischemic injury, and infection. However,
decreased creatine peaks may also be encountered in systemic
diseases. Creatine, phosphocreatine, and their main precursor,
guanidinoacetate, are synthesized in extracerebral tissues
(primarily liver and kidney) and then transported to the brain.
Therefore, any metabolic defect resulting in decreased production
of creatine/phosphocreatine (e.g., he-patic or renal diseases) will
lower the total creatine peak. Absence of the creatine peak can
also be seen. Most neoplastic tissues that metastasize to the brain
do not possess creatine kinase, and, thus, cannot produce creatine.
H-MR spectrum lacks a creatine peak, metastatic tumor should be
When oxygen supplies are depleted, the brain responds by switching
to anaerobic glycolysis. One end product of this metabolic pathway
is lactate production. Therefore, the presence of a lactate peak in
H-MR spectrum is a sign of hypoxic tissue. The etiology of
decreased oxygen supply may include: decreased oxygen delivery,
increased oxygen demand, or a combination of the two. Decreased
oxygen delivery may be encountered as the result of vascular
insults (thromboembolism, vasculitis, etc.) or hypoventilation
(e.g., asphyxiation). Increased oxygen demand is generally seen in
hypermetabolic tissues such as neoplasms and infections.
Found primarily in astrocytes, mI is a glucose-like metabolite that
helps regulate cell volume. If one considers mI an astrocyte
marker, then elevation of the mI
H-MR spectral peak would be seen in areas of glial cell
proliferation, as can be seen in Alzheimer's disease or gliosis.
Conversely, lower mI spectral peaks would be observed in conditions
producing astrocyte destruction (e.g., neoplasm, ischemic injury,
Lipids are found generally in the form of fatty acids,
triglycerides, and phospholipids incorporated into cell membranes
and myelins. They are not generally detectable on
H-MRS until released by destructive processes of the brain
including necrosis, inflammation, or infection. Care must be taken
when selecting the volume to be studied such that extracerebral
sources of lipids do not appear on the
H-MR spectrum and complicate its interpretation.
Clinical Application of
--A 32-year-old man presented to the Emergency Department (ED) with
a generalized seizure. His work-up led to the diagnosis of a left
frontoparietal lobe oligodendroglioma. At the time of diagnosis, he
received external beam radiation therapy and was placed on
anticonvulsants. For the following 8 years, he was neurologically
and radiologically stable, experiencing only occasional focal
seizures involving the right lower extremity. At the time of his
most recent presentation, he had been experiencing more frequent
focal seizures as well as mild expressive aphasia and memory loss.
MRI examination, at that time, revealed a slight increase in the
size of the left frontoparietal lobe lesion with no significant
change in its contrast enhancement pattern. A Thallium-201 SPECT
study (figure 4A) was performed which revealed no areas of abnormal
uptake. PET imaging (figure 4B) showed the left frontoparietal
lesion to be hypometabolic. Both of these studies were essentially
equivocal as their results could be due to postradiation scarring
and/or low-grade neoplasm. Therefore, single-voxel
H-MRS was obtained (figure 4C).
In this spectrum, the Cho peak is increased and the NAA peak is
decreased. In addition, there is an abnormal lipid/lactate peak.
These findings, together, are consistent with the presence of
neoplastic tissue. The spectra obtained with a TE of 144 ms (not
shown) revealed similar findings except for inversion of the
lactate/lipid peak. The patient had his recurrent tumor surgically
--A 36-year-old woman had a biopsy-proven oligodendroglioma
resected from the left frontal lobe. Routine follow-up MRI revealed
blood products and minimal enhancement in the resection bed.
Concern was raised for recurrent or residual neoplastic tissue. A
H-MRS was then obtained (figure 5).
These spectra demonstrate the use of multi-voxel
H-MRS. The multiple spectra obtained from the VOIs outside of the
resection bed (numbers 16, 17, 21, 22) clearly show normal
metabolite peaks; in other words, normal brain parenchyma. As the
VOIs approach the lesion, there is a noticeable drop in the normal
metabolite concentrations. Once in the center of the resection bed
(numbers 9, 10, 14, 15), no discernible peaks are identified, a
finding consistent with debris/hematoma. In all of the spectra,
there are no elevated Cho peaks or decreased NAA peaks to suggest
the presence of neoplastic tissue. Finally, spectra obtained with
TE of 288 (not shown) did reveal small lactate/lipid peaks,
indicating dead or dying tissue.
This patient was felt to have no evidence of residual or
recurrent neoplasm. She received no further aggressive treatment
and has continued with her routine follow-up.
--A 32-year-old, HIV-positive man presented to the ED with a
3-month history of intermittent headaches, dizziness, and possible
seizures associated with olfactory auras. In the few days prior to
his presentation, he developed increasing confusion, slurred
speech, and a low-grade fever. An initial computed tomography (CT)
scan revealed multiple, bilateral, space-occupying lesions.
Subsequent MRI showed numerous ring-enhancing lesions with
associated surrounding edema. The largest of these was in the left,
anterior temporal lobe. Single-voxel
H-MRS was obtained through this region (figure 6).
There is substantial loss of height of the NAA peak as well as a
very pronounced lactate/lipid peak. There is no significant
elevation of the Cho peak. These findings, while not definitive,
are strongly suggestive of an infectious process associated with
tissue destruction. They do not support the diagnosis of
Given the patient's HIV status, toxoplasmosis was suspected;
primary central nervous system lymphoma was felt to be unlikely.
Although no biopsy was performed, the patient was started on
anti-toxoplasma therapy with resultant improvement of his
--A 35-year-old woman presented to the ED with a 1-week history of
bronchitis and a 2-day history of progressive neurologic decline,
including aphasia and hemiplegia. An initial CT scan revealed a
large, low-density, space-occupying lesion in the left frontal
lobe. MRI was performed for assessment of a suspected underlying
tumor. This showed a large, ring-enhancing lesion of the left
frontal lobe, which crossed the midline via the superior corpus
callosum. Associated edema and mass effect were also seen (figure
H-MRS was obtained for further evaluation (figure 7B).
Interpretation of this spectrum is not straightforward due to
suboptimal water suppression. This is manifested as a rise in the
spectrum's baseline as it moves towards the water peak (4.7 ppm).
H-MRS of a tumor would be expected to demonstrate an elevation of
the choline peak. In this case, because of the poor water
suppression, there appears to be a slight elevation of the choline
peak; but this rise is, in fact, artifactual. Essentially, both the
choline and creatine peaks are
normal and there is no significant decrease of the NAA peak. The
most important finding is the elevated lipid/lactate peak,
indicating the presence of byproducts of anaerobic respiration.
This constellation of findings speaks against neoplasm and,
instead, is suggestive of an inflammatory/ encephalitic
Subsequent stereotactic brain biopsy confirmed the presence of
an acute inflammatory, demyelinating process; no neoplastic cells
were identified. Despite appropriate treatment, the patient
deteriorated rapidly and succumbed to her disease approximately 1
week following her presentation. At autopsy, the final diagnosis
was acute demyelinating encephalomyelitis.
--A 72-year-old man presented to the ED with a several month
history of personality changes. During the week prior to his
presentation, he had experienced progressively worsening headaches.
On the morning of his presentation, he experienced new right-sided
weakness. An initial CT scan (figure 8A) revealed a hypodense,
space-occupying lesion in the left thalamus. MRI was requested for
evaluation of a suspected tumor. It revealed abnormal T2
prolongation throughout the basal ganglia and thalami, bilaterally,
extending into the deep white matter of both cerebral hemispheres
(figure 8B). It also revealed thromboses of the Vein of Galen,
internal cerebral veins, left transverse, and straight sinuses
(confirmed by MR angiogram/MR venogram). In addition, there was
evidence of new hemorrhage in the region of the left thalamus. No
significant enhancing lesions were identified. Single-voxel
H-MRS was performed (figure 8C).
H-MR spectrum demonstrates considerable loss of the NAA, choline,
and creatine peaks. In addition, there is an overwhelming
lactate/lipid peak (notice the reversal of this peak on the TE of
144 spectrum when compared with the TE of 288 spectrum). These
findings are strongly suggestive of infarction, not tumor.
The etiology of the patient's multiple thromboses was never
established. However, his diffuse, acute infarctions were felt to
have resulted from them. He died several days after
Relative ease of acquisition has made
H-MRS a useful tool for the evaluation of neurologic disease. Its
interpretation is based on current knowledge of the complex
metabolic and biochemical processes associated with pathology. As
understanding of these processes becomes clearer, interpretation of
H-MR spectra will become more complex; but the spectra will also
have the ability to provide more specific information.
Additionally, applications of
H-MRS will likely extend to involve other organ systems.
The author would like to thank Dr. Emanuel Kanal for his support
and assistance with this manuscript.