In vivo magnetic resonance (MR) spectroscopy is a noninvasive imaging modality useful for obtaining metabolic information complementary to conventional MR imaging. By studying the biochemical and metabolic changes in brain lesions, it is possible to diagnose a multitude of diseases involving the central nervous system and provide information that can be helpful in clinical decision making. This review focuses on the basic proton MR spectroscopy physics, spectroscopy pulse sequences, and the clinical relevance of this modality in neuroradiology. This report discusses its role in neoplastic and non-neoplastic intracranial lesions.
is the Chief Resident in Diagnostic Radiology, William Beaumont
Hospital, Royal Oak, MI. He will start a fellowship in July 2003 in
Abdominal Imaging and Interventional Radiology at Massachusetts
General Hospital in Boston, MA.
is Chief of the Neuroradiology Division, William Beaumont Hospital,
Royal Oak, MI.
is a Neuroradiologist, Department of Radiology, William Beaumont
Hospital, Royal Oak, MI.
In vivo magnetic resonance (MR) spectroscopy is a
noninvasive imaging modality useful for obtaining metabolic
information complementary to conventional MR imaging. By studying
the biochemical and metabolic changes in brain lesions, it is
possible to diagnose a multitude of diseases involving the
central nervous system and provide information that can be
helpful in clinical decision making. This review focuses on the
basic proton MR spectroscopy physics, spectroscopy pulse
sequences, and the clinical relevance of this modality in
neuroradiology. This report discusses its role in neoplastic and
non-neoplastic intracranial lesions.
Imaging is routinely used for the diagnosis and follow-up of
patients with brain lesions of indeterminate etiology. The standard
imaging modalities, such as magnetic resonance (MR) and computed
tomography (CT), provide excellent spatial and contrast resolution
but are frequently unable to distinguish neoplastic from
non-neoplastic conditions, such as radiation necrosis and abscess.
In vivo proton spectroscopy is a reliable technique that overcomes
the problem of tissue characterization of intracranial lesions.
Both positron-emission tomography (PET) with
fluorodeoxyglucose and hydrogen-1 (H-1) MR spectroscopy provide
unique physiologic and metabolic information based on different
physical principles. The former is based on the glucose metabolism
in the tissue of interest and the latter involves identification of
metabolites based on the difference in resonance frequency of
The MR spectroscopy technique aims at determining the
concentration of certain nuclei in metabolites and is most
frequently based on the resonance frequency of hydrogen protons.
Because the concentration of tissue, water, and lipids is several
times the concentration of other metabolites, the signal from water
and lipids is suppressed to uncover signal from low-concentration
Whereas MR imaging provides morphological information, MR
spectroscopy allows quantification of various metabolites and the
study of their distribution in different tissues. It opens a new
frontier in imaging in which the distribution of various
metabolites can be used for tissue characterization.
Why hydrogen-1 MR spectroscopy?
The different metabolites that can be used with MR spectroscopy
include H-1, phosphorus 31, carbon 13, fluorine 19, and sodium 23.
The hydrogen and phosphorus concentration in central nervous system
tissue is high enough to be useful in clinical MR spectroscopy. At
this time, hydrogen is best suited for MR spectroscopy because of
its high concentration, favorable relaxation time, and high
The relatively lower gyromagnetic ratio and concentration make
phosphorus 31 MR spectroscopy less popular than H-1 MR
spectroscopy. Using phosphorus 31 on a conventional 1.5 T MR
scanner, it is not possible to obtain adequate signal-to-noise
ratio (SNR) on a voxel size routinely used in H-1 MR spectroscopy.
The minimal voxel size needed to get adequate SNR for phosphorus 31
MR spectroscopy is 30 mL at 1.5 T magnetic fields.
Physics of MR spectroscopy
The spectroscopy technique is based on the principle of chemical
shift in which the frequency of precession of a nucleus is directly
proportional to the strength of magnetic field experienced by it.
The frequency domain spectrum is generated by Fourier
transformation of the time domain signal. The resonance frequency
of each metabolite is represented on a graph and is expressed as
parts per million (ppm). This is because the resonance frequency is
in MHz or 10
Hz, whereas the difference between various metabolites is only a
few Hz. The ratio between the resonance frequency of metabolites is
of the order of 10
During MR spectroscopy, as the nuclei are exposed to the 90°
radiofrequency pulse, the protons rotate (nutate) from the Z axis
to the X axis. When the radiofrequency pulse is discontinued, they
return to their equilibrium positions at different rates. The decay
rate of different nuclei is dependent on the chemical environments
they experience, and it allows the visualization of various
metabolites as separate spectroscopy peaks.
Because the brain is composed of a multitude of tissues, MR
spectroscopy must be obtained from a localized volume of tissue to
be useful clinically. The metabolic information is obtained from a
localized volume of tissue known as a voxel. In clinical practice,
the voxel size can vary from 1 to 8 mL. The spectrum from smaller
voxel sizes has the inherent disadvantage of poorer SNR. In
practice, a compromise between voxel size and SNR is reached and is
most often 1 to 2 mL.
Water and lipid suppression
The normal water concentration is 100,000 times the
concentration of other metabolites. To detect these metabolites
successfully, the signal from water must be suppressed adequately.
The water peak located at
4.7 ppm can be suppressed using chemical shift selective excitation
(CHESS) or water elimination Fourier transform technique.
At present, CHESS is the most frequently used technique and
involves presaturation of water signal using one or more 90°
presaturation pulses centered over the water resonance frequency.
Using this technique, the water signal can be suppressed by a
factor of up to 1000. In contrast, water elimination Fourier
transform technique involves a 180° pulse centered over water and
is less efficient than CHESS for water suppression.
During MR spectroscopy, lipid signals in neuroimaging can be
eliminated by avoiding excitation of lipid-containing regions.
Other methods include the use of radiofrequency presaturation
pulses and inversion pulses. The shorter T2 relaxation times of
water and lipids result in better suppression using long echo time
(TE) compared with short TE pulse sequences.
The two most popular localization methods for MR spectroscopy
are point-resolved spectroscopy (PRESS) and stimulated echo
acquisition method (STEAM).
The STEAM technique provides more effective water suppression and
shorter TE, thereby allowing visualization of a greater number of
metabolic peaks. The disadvantages of STEAM are poorer SNR and
increased sensitivity to motion.
The PRESS technique allows better SNR compared with STEAM but
shows only the four major peaks, ie, N-acetylaspartate (NAA),
choline (Cho), creatine (Cr), and lactate. For long TEs of >135
ms, PRESS is the localization method of choice. The water
suppression using CHESS cannot be used with PRESS. Point-resolved
spectroscopy for localization and a TE of 135 ms to obtain brain MR
spectroscopy scans are used routinely at the author's
A highly homogeneous magnetic field having width of water peak
at half maximal height of <0.2 ppm is required for high-quality
spectra. A uniform magnetic field also decreases the acquisition
time by increasing the SNR. In practice, either manual or automatic
shimming can be used to achieve a uniform magnetic field. Table 1
compares single-voxel technique and chemical-shift imaging for
obtaining spectroscopic data.
The number of metabolic peaks seen on MR spectroscopy varies
with the TE used. At higher TEs, such as
136 ms or 272 ms, a smaller number of peaks are seen because of the
short T2 relaxation times and/or dephasing effects of J-coupling
(Figure 1). At shorter TEs, a greater number of metabolites can be
seen (Cho, Cr, NAA, myoinositol [mI], gamma-aminobutyric acid
[GABA], glutamate/glutamine) and the spectrum has better SNR. It is
difficult to calculate the absolute concentration of various
metabolites, so the relative concentrations of these metabolites
are often used for interpretation. Table 2 summarizes the location
of various metabolites seen on MR spectroscopy.
The largest peak seen on MR spectroscopy is due to NAA and
occurs at 2.0 ppm. The 2 other minor peaks of NAA are located at
2.5 and 2.6 ppm. In general, NAA is a marker of mature neuronal
density and is therefore decreased in many disease states in which
neurons are destroyed.
These diseases include neoplasm, infarct, demyelinating disease,
etc. The only condition where NAA is increased is Canavan's
disease. A smaller contribution to the NAA peak is from
non-neuronal cell types such as mast cells and
The Cr peak is located at 3.03 ppm and has contributions from
Cr, Cr phosphate, GABA, lysine and glutathione. A secondary peak
for Cr is at 3.94 ppm. The Cr compounds are involved in energy
metabolism via Cr kinase reaction and probably serve as reserves
for high-energy phosphates in cell metabolism.
Because the Cr peak is relatively resistant to change during
disease states when compared with other metabolites, it is usually
used in the denominator of Cho/Cr and NAA/Cr ratios. The Cr
concentration is increased in hypometabolic disease states and is
decreased in hypermetabolic disease states.
The Cho peak is located at 3.2 ppm and contains contributions
from glycerophosphocholine, phosphocholine, and free Cho. The
molecules are located in the cell membranes and reflect the
phospholipid membrane turnover, and the peak is elevated in
neoplastic and acute demyelinating diseases. The Cho peak elevation
in acute demyelinating diseases is due to rapid cell membrane
breakdown, whereas in neoplasms it is caused by rapid cell membrane
turnover and increased cellular density.
The lactate peak is located at 1.32 ppm and represents the end
product of anaerobic metabolism. Usually, lactate is not detectable
on human brain MR spectroscopy. Its concentration is increased in
certain neoplasms, radiation necrosis, abscesses, mitochondrial
diseases, acute infarcts, and cysts. The lactate peak overlaps with
lipid peak on STEAM and can be separated from it at a TE of 135 ms
when it inverts. The inverted double peak is due to the J-coupling
effect from adjacent protons. A second lactate peak at 4.1 ppm is
not well seen because it is close to water and is suppressed by the
water suppression pulses.
The mI peak is located at 3.56 ppm and is known to decrease in
patients with hepatic encephalopathy. It has been suggested that mI
be used as a glial cell marker
and is increased in Alzheimer's disease and demyelinating
The other metabolites identified at low TEs include glutamate,
glutamine, alanine, and lipids (Table 2). The cerebral levels of
glutamine are increased in patients with hepatic encephalopathy and
Developmental and morphologic variations
A newborn shows low NAA, high Cho, and high mI levels on MR
spectroscopy. These metabolites gradually approach the adult
pattern by 1 to 2 years of age.
The Cho and NAA concentrations are higher in white matter than in
gray matter. With aging, the Cho concentration in gray matter is
significantly increased. The concentration of Cr is much higher in
gray matter than in white matter and is significantly higher in
older rather than in younger subjects.
The cerebellar levels of Cho are higher than the supratentorial
Unlike PET, MR spectroscopy does not suffer from the
disadvantage of ionizing radiation and, therefore, can be used to
perform serial studies to monitor disease progression. By avoiding
surgical/ stereotactic biopsy, MR spectroscopy provides a possible
noninvasive investigation in the management of neoplastic and
non-neoplastic brain lesions. A typical chemical shift imaging
sequence takes approximately 12 minutes to complete and can be
incorporated with MR examination under the supervision of a
The overwhelming number of MR spectroscopy applications in
clinical practice is in neuroradiology because of the lack of
motion artifacts, absence of free lipids in the brain, and ease of
magnetic field shimming. The protean practical and research
applications of MR spectroscopy are for neoplasm, radiation
necrosis, temporal lobe epilepsy, stroke, Alzheimer's disease,
multiple sclerosis, Parkinson's disease, AIDS, and a number of
The MR spectroscopy data are often useful in confirming the
diagnosis, grading the malignancy, and distinguishing radiation
necrosis from residual/recurrent neoplasm (Figures 2 through 5).
The accuracy of MR spectroscopy in distinguishing neoplastic from
non-neoplastic lesion is greatest when the spectra are obtained
from voxels at the enhancing edge of a lesion.
A typical astrocytoma shows decreased NAA, decreased Cr, and
increased Cho levels.
The degree of elevation of Cho correlates with the histologic grade
of malignancy and is helpful in distinguishing tumors from
non-neoplastic disease processes. An elevated lactate level is
frequently found in high-grade malignancies.
In a study of 55 patients with focal brain lesions conducted by
the author, MR spectroscopy had an overall accuracy of 90.9% in
distinguishing neoplastic from non-neoplastic lesions.
The MR spectroscopy spectra of metastases shows increased Cho/Cr
and decreased NAA/Cr ratios. The lactate and lipid levels are more
likely to be elevated in metastases than in primary brain
The MR spectroscopy of peripherally located neoplasm is more
technically difficult to perform because of contamination from fat
and susceptibility artifacts. A typical cerebellopontine angle
schwannoma will show the absence of NAA along with elevation of
phosphoinositide peak at 3.6 ppm. The absence of NAA along with
elevation of alanine peak (1.3 to 1.4 ppm) is often seen in
The MR spectroscopy detection of a decrease in NAA coupled with
an occasional increase in lactate is useful in detection of the
seizure focus in patients with temporal lobe epilepsy.
The decrease in NAA corresponds to neuronal loss on histology in
these patients. The localization of the seizure focus is helpful in
the surgical planning of temporal lobectomy in patients with
intractable seizure disorder.
This condition typically develops in brain neoplasms that have
been irradiated with 4000 or more rads. It is often impossible to
distinguish it from viable residual/recurrent neoplasm based on MR
imaging. In these patients, MR spectroscopy shows promising
sensitivity and selectivity for differentiation of radiation
necrosis from recurrent/ progressive brain tumor.
The MR spectroscopy spectrum of radiation necrosis shows a broad
peak because of fatty acids, lactate, and amino acids centered at
approximately 1.5 ppm. MR spectroscopy and PET play a complementary
role in classifying indeterminate brain lesions into non-
neoplastic and neoplastic.
In acute multiple scleroses, there is a decrease in the NAA
levels that correlates well with the neurologic impairment. In
these patients, there is an increase in the Cho concentration from
accelerated myelin destruction. The increase in lactate level seen
in these patients is the result of inflammatory infiltrates. In
hyperacute demyelinating disease, there is a transient decrease in
Cr that returns to normal in subacute and chronic stages.
In chronic multiple sclerosis, there is an irreversible decrease
in NAA and inositol levels.
The decrease in NAA in the white matter surrounding the
demyelinating plaque correlates best with clinical impairment in
There is potential for detection of a decrease in NAA and an
increase in Cho even before the development of abnormalities on MR
imaging. The metabolic abnormalities increase as the severity of
the disease increases.
In immunocompromised patients, MR spectroscopy can often be used to
distinguish between neoplasm and opportunistic infection. For
example, the spectra of toxoplasmosis show large lipid and lactate
peaks with virtual absence of normal metabolites.
This can be distinguished from lymphoma, which shows marked
elevation of Cho and lipids and significant reduction of NAA. MR
spectroscopy may play a future role in monitoring the results of
antiretroviral therapy and predicting the usefulness of drug
In early stages of stroke, lactate elevation can be identified
in absence of MR imaging abnormalities. These areas may represent
ischemic zones at risk for infarction.
In acute infarcts, there is a decrease in NAA and an increase in
lactate concentrations. There is a progressive decrease in NAA and
lactate up to 1 week after infarct, indicating the reversibility of
neuronal damage during this period. In chronic infarcts, there is a
decrease in NAA, Cr, and Cho levels.
In patients with Alzheimer's disease, there is a decrease in NAA
levels and hippocampus atrophy, which may be useful in
distinguishing this disease from normal aging. There are reports of
a decrease in NAA levels and an increase in mI in patients with
In patients with hepatic encephalopathy, there is an increase in
glutamine, a decrease in Cho, and a decrease in mI concentration.
In Parkinson's disease, NAA, Cr, and Cho levels are unchanged but
lactate levels are elevated.
The MR spectroscopy feature of brain abscess includes increased
acetate and succinate levels at 1.92 and 2.42 ppm, respectively
(Figures 6 and 7). Currently, there are a number of MR spectroscopy
research frontiers that include inherited, idiopathic, and
metabolic brain disorders.
Hydrogen-1 MR spectroscopy is a technically demanding
investigation and produces low SNR.
The possible causes of poor spectral quality on MR spectroscopy
include hemorrhage, postoperative changes, less than 200
acquisitions, small voxel size, and automatic shimming. These
causes either result in poor homogenity of the magnetic field or
poor SNR, making the interpretation of spectroscopy data
unreliable. The presence of hemorrhage and postoperative changes
within the volume of interest often leads to poor-quality
measurements due to susceptibility effects caused by hemosiderin.
The cortical brain lesions located close to the calvaria are often
difficult to image on MR spectroscopy because of susceptibility
artifacts and contamination from lipids located outside the
Although MR spectroscopy allows detection of only a few of the
cellular metabolites at moderate spatial resolution, it remains a
unique modality available to neuroradiologists that provides
biochemical information not obtainable with CT or MR imaging.
Hydrogen-1 MR spectroscopy can be implemented on the widely
available 1.5 T MR scanners. With its recent improvements in
techniques, MR spectroscopy is already playing an important role in
the management of neurologic diseases.
With the advent of high-field MR imaging scanners, it is
possible to improve SNR as well as reduce acquisition time and
voxel size. In the future, MR spectroscopy research is likely to
result in smaller voxel size and improved acquisition time.
The author wishes to thank Dr. Duane Mezwa for continuous
support and guidance.