<s>
Functional	B-Algorithm
magnetic	I-Algorithm
resonance	I-Algorithm
spectroscopy	I-Algorithm
of	I-Algorithm
the	I-Algorithm
brain	I-Algorithm
(	O
fMRS	B-Algorithm
)	O
uses	O
magnetic	O
resonance	O
imaging	O
(	O
MRI	O
)	O
to	O
study	O
brain	O
metabolism	O
during	O
brain	O
activation	O
.	O
</s>
<s>
The	O
data	O
generated	O
by	O
fMRS	B-Algorithm
usually	O
shows	O
spectra	O
of	O
resonances	O
,	O
instead	O
of	O
a	O
brain	O
image	O
,	O
as	O
with	O
MRI	O
.	O
</s>
<s>
fMRS	B-Algorithm
is	O
based	O
on	O
the	O
same	O
principles	O
as	O
in	B-Algorithm
vivo	I-Algorithm
magnetic	I-Algorithm
resonance	I-Algorithm
spectroscopy	I-Algorithm
(	O
MRS	O
)	O
.	O
</s>
<s>
However	O
,	O
while	O
conventional	O
MRS	O
records	O
a	O
single	O
spectrum	O
of	O
metabolites	O
from	O
a	O
region	O
of	O
interest	O
,	O
a	O
key	O
interest	O
of	O
fMRS	B-Algorithm
is	O
to	O
detect	O
multiple	O
spectra	O
and	O
study	O
metabolite	O
concentration	O
dynamics	O
during	O
brain	O
function	O
.	O
</s>
<s>
Therefore	O
,	O
it	O
is	O
sometimes	O
referred	O
to	O
as	O
dynamic	O
MRS	O
,	O
event-related	O
MRS	O
or	O
time-resolved	O
MRS	O
.	O
A	O
novel	O
variant	O
of	O
fMRS	B-Algorithm
is	O
functional	O
diffusion-weighted	O
spectroscopy	O
(	O
fDWS	O
)	O
which	O
measures	O
diffusion	O
properties	O
of	O
brain	O
metabolites	O
upon	O
brain	O
activation	O
.	O
</s>
<s>
Unlike	O
in	O
vivo	O
MRS	O
which	O
is	O
intensively	O
used	O
in	O
clinical	O
settings	O
,	O
fMRS	B-Algorithm
is	O
used	O
primarily	O
as	O
a	O
research	O
tool	O
,	O
both	O
in	O
a	O
clinical	O
context	O
,	O
for	O
example	O
,	O
to	O
study	O
metabolite	O
dynamics	O
in	O
patients	O
with	O
epilepsy	O
,	O
migraine	O
and	O
dyslexia	O
,	O
and	O
to	O
study	O
healthy	O
brains	O
.	O
</s>
<s>
fMRS	B-Algorithm
can	O
be	O
used	O
to	O
study	O
metabolism	O
dynamics	O
also	O
in	O
other	O
parts	O
of	O
the	O
body	O
,	O
for	O
example	O
,	O
in	O
muscles	O
and	O
heart	O
;	O
however	O
,	O
brain	O
studies	O
have	O
been	O
far	O
more	O
popular	O
.	O
</s>
<s>
The	O
main	O
goals	O
of	O
fMRS	B-Algorithm
studies	O
are	O
to	O
contribute	O
to	O
the	O
understanding	O
of	O
energy	O
metabolism	O
in	O
the	O
brain	O
,	O
and	O
to	O
test	O
and	O
improve	O
data	B-Algorithm
acquisition	I-Algorithm
and	O
quantification	O
techniques	O
to	O
ensure	O
and	O
enhance	O
validity	O
and	O
reliability	O
of	O
fMRS	B-Algorithm
studies	O
.	O
</s>
<s>
Like	O
in	O
vivo	O
MRS	O
,	O
fMRS	B-Algorithm
can	O
probe	O
different	O
nuclei	O
,	O
such	O
as	O
hydrogen	O
(	O
1H	O
)	O
and	O
carbon	O
(	O
13C	O
)	O
.	O
</s>
<s>
The	O
natural	O
abundance	O
of	O
13C	O
in	O
the	O
brain	O
is	O
only	O
about	O
1%	O
;	O
therefore	O
,	O
13C	O
fMRS	B-Algorithm
studies	O
usually	O
involve	O
the	O
isotope	O
enrichment	O
via	O
infusion	O
or	O
ingestion	O
.	O
</s>
<s>
In	O
the	O
literature	O
13C	O
fMRS	B-Algorithm
is	O
commonly	O
referred	O
to	O
as	O
functional	O
13C	O
MRS	O
or	O
just	O
13C	O
MRS	O
.	O
</s>
<s>
fMRS	B-Algorithm
differs	O
from	O
MRS	O
by	O
acquiring	O
not	O
one	O
but	O
multiple	O
spectra	O
at	O
different	O
time	O
points	O
while	O
the	O
participant	O
is	O
inside	O
the	O
MRI	O
scanner	O
.	O
</s>
<s>
Thus	O
,	O
temporal	B-General_Concept
resolution	I-General_Concept
is	O
very	O
important	O
and	O
acquisition	O
times	O
need	O
to	O
be	O
kept	O
adequately	O
short	O
to	O
provide	O
a	O
dynamic	O
rate	O
of	O
metabolite	O
concentration	O
change	O
.	O
</s>
<s>
To	O
balance	O
the	O
need	O
for	O
temporal	B-General_Concept
resolution	I-General_Concept
and	O
sufficient	O
SNR	O
,	O
fMRS	B-Algorithm
requires	O
a	O
high	O
magnetic	O
field	O
strength	O
(	O
1.5	O
T	O
and	O
above	O
)	O
.	O
</s>
<s>
fMRS	B-Algorithm
is	O
continuously	O
advancing	O
as	O
stronger	O
magnets	O
become	O
more	O
available	O
and	O
better	O
data	B-Algorithm
acquisition	I-Algorithm
techniques	O
are	O
developed	O
providing	O
increased	O
spectral	O
and	O
temporal	B-General_Concept
resolution	I-General_Concept
.	O
</s>
<s>
Temporal	B-General_Concept
resolution	I-General_Concept
has	O
increased	O
from	O
7	O
minutes	O
in	O
the	O
first	O
fMRS	B-Algorithm
studies	O
to	O
5	O
seconds	O
in	O
more	O
recent	O
ones	O
.	O
</s>
<s>
In	O
fMRS	B-Algorithm
,	O
depending	O
on	O
the	O
focus	O
of	O
the	O
study	O
,	O
either	O
single-voxel	O
or	O
multi-voxel	O
spectroscopic	O
technique	O
can	O
be	O
used	O
.	O
</s>
<s>
In	O
single-voxel	O
fMRS	B-Algorithm
the	O
selection	O
of	O
the	O
volume	O
of	O
interest	O
(	O
VOI	O
)	O
is	O
often	O
done	O
by	O
running	O
a	O
functional	B-Algorithm
magnetic	I-Algorithm
resonance	I-Algorithm
imaging	I-Algorithm
(	O
fMRI	B-Algorithm
)	O
study	O
prior	O
to	O
fMRS	B-Algorithm
to	O
localize	O
the	O
brain	O
region	O
activated	O
by	O
the	O
task	O
.	O
</s>
<s>
Single-voxel	O
spectroscopy	O
requires	O
shorter	O
acquisition	O
times	O
;	O
therefore	O
it	O
is	O
more	O
suitable	O
for	O
fMRS	B-Algorithm
studies	O
where	O
high	O
temporal	B-General_Concept
resolution	I-General_Concept
is	O
needed	O
and	O
where	O
the	O
volume	O
of	O
interest	O
is	O
known	O
.	O
</s>
<s>
Multi-voxel	O
spectroscopy	O
provides	O
information	O
about	O
group	O
of	O
voxels	B-Algorithm
and	O
data	O
can	O
be	O
presented	O
in	O
2D	O
or	O
3D	O
images	O
,	O
but	O
it	O
requires	O
longer	O
acquisition	O
times	O
and	O
therefore	O
temporal	B-General_Concept
resolution	I-General_Concept
is	O
decreased	O
.	O
</s>
<s>
Multi-voxel	O
spectroscopy	O
usually	O
is	O
performed	O
when	O
the	O
specific	O
volume	O
of	O
interest	O
is	O
not	O
known	O
or	O
it	O
is	O
important	O
to	O
study	O
metabolite	O
dynamics	O
in	O
a	O
larger	O
brain	O
region	O
.	O
</s>
<s>
fMRS	B-Algorithm
has	O
several	O
advantages	O
over	O
other	O
functional	B-Algorithm
neuroimaging	I-Algorithm
and	O
brain	O
biochemistry	O
detection	O
techniques	O
.	O
</s>
<s>
Unlike	O
push-pull	O
cannula	O
,	O
microdialysis	O
and	O
in	O
vivo	O
voltammetry	O
,	O
fMRS	B-Algorithm
is	O
a	O
non-invasive	O
method	O
for	O
studying	O
dynamics	O
of	O
biochemistry	O
in	O
an	O
activated	O
brain	O
.	O
</s>
<s>
It	O
is	O
done	O
without	O
exposing	O
subjects	O
to	O
ionizing	O
radiation	O
like	O
it	O
is	O
done	O
in	O
positron	B-Application
emission	I-Application
tomography	I-Application
(	O
PET	O
)	O
or	O
single-photon	O
emission	O
computed	O
tomography	O
(	O
SPECT	O
)	O
studies	O
.	O
</s>
<s>
fMRS	B-Algorithm
gives	O
a	O
more	O
direct	O
measurement	O
of	O
cellular	O
events	O
occurring	O
during	O
brain	O
activation	O
than	O
BOLD	B-Algorithm
fMRI	I-Algorithm
or	O
PET	O
which	O
rely	O
on	O
hemodynamic	O
responses	O
and	O
show	O
only	O
global	O
neuronal	O
energy	O
uptake	O
during	O
brain	O
activation	O
while	O
fMRS	B-Algorithm
gives	O
also	O
information	O
about	O
underlying	O
metabolic	O
processes	O
that	O
support	O
the	O
working	O
brain	O
.	O
</s>
<s>
However	O
,	O
fMRS	B-Algorithm
requires	O
very	O
sophisticated	O
data	B-Algorithm
acquisition	I-Algorithm
,	O
quantification	O
methods	O
and	O
interpretation	O
of	O
results	O
.	O
</s>
<s>
This	O
is	O
one	O
of	O
the	O
main	O
reasons	O
why	O
in	O
the	O
past	O
it	O
received	O
less	O
attention	O
than	O
other	O
MR	O
techniques	O
,	O
but	O
the	O
availability	O
of	O
stronger	O
magnets	O
and	O
improvements	O
in	O
data	B-Algorithm
acquisition	I-Algorithm
and	O
quantification	O
methods	O
are	O
making	O
fMRS	B-Algorithm
more	O
popular	O
.	O
</s>
<s>
Main	O
limitations	O
of	O
fMRS	B-Algorithm
are	O
related	O
to	O
signal	O
sensitivity	O
and	O
the	O
fact	O
that	O
many	O
metabolites	O
of	O
potential	O
interest	O
can	O
not	O
be	O
detected	O
with	O
current	O
fMRS	B-Algorithm
techniques	O
.	O
</s>
<s>
Because	O
of	O
limited	O
spatial	O
and	O
temporal	B-General_Concept
resolution	I-General_Concept
fMRS	B-Algorithm
can	O
not	O
provide	O
information	O
about	O
metabolites	O
in	O
different	O
cell	O
types	O
,	O
for	O
example	O
,	O
whether	O
lactate	O
is	O
used	O
by	O
neurons	O
or	O
by	O
astrocytes	O
during	O
brain	O
activation	O
.	O
</s>
<s>
The	O
smallest	O
volume	O
that	O
can	O
currently	O
be	O
characterized	O
with	O
fMRS	B-Algorithm
is	O
1cm3	O
,	O
which	O
is	O
too	O
big	O
to	O
measure	O
metabolites	O
in	O
different	O
cell	O
types	O
.	O
</s>
<s>
Many	O
brain	O
areas	O
are	O
not	O
suitable	O
for	O
fMRS	B-Algorithm
studies	O
because	O
they	O
are	O
too	O
small	O
(	O
like	O
small	O
nuclei	O
in	O
brainstem	O
)	O
or	O
too	O
close	O
to	O
bone	O
tissue	O
,	O
CSF	O
or	O
extracranial	O
lipids	O
,	O
which	O
could	O
cause	O
inhomogeneity	O
in	O
the	O
voxel	B-Algorithm
and	O
contaminate	O
the	O
spectra	O
.	O
</s>
<s>
To	O
avoid	O
these	O
difficulties	O
,	O
in	O
most	O
fMRS	B-Algorithm
studies	O
the	O
volume	O
of	O
interest	O
is	O
chosen	O
from	O
the	O
visual	O
cortex	O
–	O
because	O
it	O
is	O
easily	O
stimulated	O
,	O
has	O
high	O
energy	O
metabolisms	O
,	O
and	O
yields	O
good	O
MRS	O
signals	O
.	O
</s>
<s>
Unlike	O
in	O
vivo	O
MRS	O
which	O
is	O
intensively	O
used	O
in	O
clinical	O
settings	O
,	O
fMRS	B-Algorithm
is	O
used	O
primarily	O
as	O
a	O
research	O
tool	O
,	O
both	O
in	O
a	O
clinical	O
context	O
,	O
for	O
example	O
,	O
to	O
study	O
metabolite	O
dynamics	O
in	O
patients	O
with	O
epilepsy	O
,	O
migraine	O
and	O
dyslexia	O
,	O
and	O
to	O
study	O
healthy	O
brains	O
.	O
</s>
<s>
fMRS	B-Algorithm
can	O
be	O
used	O
to	O
study	O
metabolism	O
dynamics	O
also	O
in	O
other	O
parts	O
of	O
the	O
body	O
,	O
for	O
example	O
,	O
in	O
muscles	O
and	O
heart	O
;	O
however	O
,	O
brain	O
studies	O
have	O
been	O
far	O
more	O
popular	O
.	O
</s>
<s>
The	O
main	O
goals	O
of	O
fMRS	B-Algorithm
studies	O
are	O
to	O
contribute	O
to	O
the	O
understanding	O
of	O
energy	O
metabolism	O
in	O
the	O
brain	O
,	O
and	O
to	O
test	O
and	O
improve	O
data	B-Algorithm
acquisition	I-Algorithm
and	O
quantification	O
techniques	O
to	O
ensure	O
and	O
enhance	O
validity	O
and	O
reliability	O
of	O
fMRS	B-Algorithm
studies	O
.	O
</s>
<s>
fMRS	B-Algorithm
was	O
developed	O
as	O
an	O
extension	O
of	O
MRS	O
in	O
the	O
early	O
1990s	O
.	O
</s>
<s>
Its	O
potential	O
as	O
a	O
research	O
technology	O
became	O
obvious	O
when	O
it	O
was	O
applied	O
to	O
an	O
important	O
research	O
problem	O
where	O
PET	B-Application
studies	I-Application
had	O
been	O
inconclusive	O
,	O
namely	O
the	O
mismatch	O
between	O
oxygen	O
and	O
glucose	O
consumption	O
during	O
sustained	O
visual	O
stimulation	O
.	O
</s>
<s>
The	O
1H	O
fMRS	B-Algorithm
studies	O
highlighted	O
the	O
important	O
role	O
of	O
lactate	O
in	O
this	O
process	O
and	O
significantly	O
contributed	O
to	O
the	O
research	O
in	O
brain	O
energy	O
metabolism	O
during	O
brain	O
activation	O
.	O
</s>
<s>
1H	O
fMRS	B-Algorithm
measurements	O
were	O
instrumental	O
in	O
achieving	O
the	O
current	O
consensus	O
among	O
most	O
researchers	O
that	O
lactate	O
levels	O
increase	O
during	O
the	O
first	O
minutes	O
of	O
intense	O
brain	O
activation	O
.	O
</s>
<s>
13C	O
MRS	O
is	O
a	O
special	O
type	O
of	O
fMRS	B-Algorithm
particularly	O
suited	O
for	O
measuring	O
important	O
neurophysiological	O
fluxes	O
in	O
vivo	O
and	O
in	O
real	O
time	O
to	O
assess	O
metabolic	O
activity	O
both	O
in	O
healthy	O
and	O
diseased	O
brains	O
(	O
e.g.	O
,	O
in	O
human	O
tumor	O
tissue	O
)	O
.	O
</s>
<s>
13C	O
MRS	O
can	O
provide	O
detailed	O
quantitative	O
information	O
about	O
glucose	O
dynamics	O
that	O
can	O
not	O
be	O
obtained	O
with	O
1H	O
fMRS	B-Algorithm
,	O
because	O
of	O
the	O
low	O
concentration	O
of	O
glucose	O
in	O
the	O
brain	O
and	O
the	O
spread	O
of	O
its	O
resonances	O
in	O
several	O
multiplets	O
in	O
the	O
1H	O
MRS	O
spectrum	O
.	O
</s>
<s>
This	O
finding	O
has	O
an	O
important	O
implication	O
for	O
the	O
interpretation	O
of	O
BOLD	B-Algorithm
fMRI	I-Algorithm
data	O
where	O
this	O
high	O
baseline	O
activity	O
is	O
generally	O
ignored	O
and	O
response	O
to	O
the	O
task	O
is	O
shown	O
as	O
independent	O
of	O
the	O
baseline	O
activity	O
.	O
</s>
<s>
13C	O
MRS	O
studies	O
indicate	O
that	O
this	O
approach	O
can	O
misjudge	O
and	O
even	O
completely	O
miss	O
the	O
brain	B-Application
activity	I-Application
induced	O
by	O
the	O
task	O
.	O
</s>
<s>
13C	O
MRS	O
findings	O
together	O
with	O
other	O
results	O
from	O
PET	O
and	O
fMRI	B-Algorithm
studies	O
have	O
been	O
combined	O
in	O
a	O
model	O
to	O
explain	O
the	O
function	O
of	O
resting	O
state	O
activity	O
called	O
default	O
mode	O
network	O
.	O
</s>
<s>
Usually	O
,	O
in	O
1H	O
fMRS	B-Algorithm
the	O
water	O
signal	O
is	O
suppressed	O
to	O
detect	O
metabolites	O
with	O
much	O
lower	O
concentration	O
than	O
water	O
.	O
</s>
<s>
Though	O
,	O
an	O
unsuppressed	O
water	O
signal	O
can	O
be	O
used	O
to	O
estimate	O
functional	O
changes	O
in	O
the	O
relaxation	O
time	O
T2*	B-Algorithm
during	O
cortical	O
activation	O
.	O
</s>
<s>
This	O
approach	O
has	O
been	O
proposed	O
as	O
an	O
alternative	O
to	O
the	O
BOLD	B-Algorithm
fMRI	I-Algorithm
technique	O
and	O
used	O
to	O
detect	O
visual	O
response	O
to	O
photic	B-Algorithm
stimulation	I-Algorithm
,	O
motor	O
activation	O
by	O
finger	O
tapping	O
and	O
activations	O
in	O
language	O
areas	O
during	O
speech	O
processing	O
.	O
</s>
<s>
Recently	O
functional	O
real-time	O
single-voxel	O
proton	O
spectroscopy	O
(	O
fSVPS	O
)	O
has	O
been	O
proposed	O
as	O
a	O
technique	O
for	O
real-time	O
neurofeedback	O
studies	O
in	O
magnetic	O
fields	O
of	O
7	O
tesla	O
(	O
7	O
T	O
)	O
and	O
above	O
.	O
</s>
<s>
This	O
approach	O
could	O
have	O
potential	O
advantages	O
over	O
BOLD	B-Algorithm
fMRI	I-Algorithm
and	O
is	O
the	O
subject	O
of	O
current	O
research	O
.	O
</s>
<s>
fMRS	B-Algorithm
has	O
been	O
used	O
in	O
migraine	O
and	O
pain	O
research	O
.	O
</s>
<s>
Here	O
the	O
ability	O
of	O
fMRS	B-Algorithm
to	O
measure	O
chemical	O
processes	O
in	O
the	O
brain	O
over	O
time	O
proved	O
crucial	O
for	O
confirming	O
that	O
repetitive	O
photic	B-Algorithm
stimulation	I-Algorithm
causes	O
higher	O
increase	O
of	O
the	O
lactate	O
level	O
and	O
higher	O
decrease	O
of	O
the	O
N-acetylaspartate	O
(	O
NAA	O
)	O
level	O
in	O
the	O
visual	O
cortex	O
of	O
MwA	O
patients	O
compared	O
to	O
migraine	O
without	O
aura	O
(	O
MwoA	O
)	O
patients	O
and	O
healthy	O
individuals	O
.	O
</s>
<s>
In	O
pain	O
research	O
fMRS	B-Algorithm
complements	O
fMRI	B-Algorithm
and	O
PET	O
techniques	O
.	O
</s>
<s>
Although	O
fMRI	B-Algorithm
and	O
PET	O
are	O
continuously	O
used	O
to	O
localize	O
pain	O
processing	O
areas	O
in	O
the	O
brain	O
,	O
they	O
can	O
not	O
provide	O
direct	O
information	O
about	O
changes	O
in	O
metabolites	O
during	O
pain	O
processing	O
that	O
could	O
help	O
to	O
understand	O
physiological	O
processes	O
behind	O
pain	O
perception	O
and	O
potentially	O
lead	O
to	O
novel	O
treatments	O
for	O
pain	O
.	O
</s>
<s>
fMRS	B-Algorithm
overcomes	O
this	O
limitation	O
and	O
has	O
been	O
used	O
to	O
study	O
pain-induced	O
(	O
cold-pressure	O
,	O
heat	O
,	O
dental	O
pain	O
)	O
neurotransmitter	O
level	O
changes	O
in	O
the	O
anterior	O
cingulate	O
cortex	O
,	O
anterior	O
insular	O
cortex	O
and	O
left	O
insular	O
cortex	O
.	O
</s>
<s>
These	O
fMRS	B-Algorithm
studies	O
are	O
valuable	O
because	O
they	O
show	O
that	O
some	O
or	O
all	O
Glx	O
compounds	O
(	O
glutamate	O
,	O
GABA	O
and	O
glutamine	O
)	O
increase	O
during	O
painful	O
stimuli	O
in	O
the	O
studied	O
brain	O
regions	O
.	O
</s>
<s>
The	O
use	O
of	O
fMRS	B-Algorithm
for	O
this	O
purpose	O
is	O
at	O
present	O
mainly	O
at	O
an	O
experimental	O
level	O
but	O
is	O
rapidly	O
increasing	O
.	O
</s>
<s>
Cognitive	O
tasks	O
where	O
fMRS	B-Algorithm
has	O
been	O
used	O
and	O
the	O
major	O
findings	O
of	O
the	O
research	O
are	O
summarized	O
below	O
.	O
</s>
<s>
In	O
this	O
study	O
fMRS	B-Algorithm
was	O
used	O
simultaneously	O
with	O
EEG	B-Application
and	O
positive	O
correlation	O
between	O
gamma-band	B-Algorithm
activity	O
and	O
glutamate	O
level	O
changes	O
was	O
observed	O
.	O
</s>
<s>
Stroop	O
task	O
Anterior	O
cingulate	O
cortex	O
(	O
ACC	O
)	O
Demonstration	O
of	O
phosphocreatine	O
dynamics	O
with	O
12s	O
temporal	B-General_Concept
resolution	I-General_Concept
.	O
</s>
<s>
The	O
main	O
implication	O
of	O
this	O
study	O
was	O
that	O
reliable	O
fMRS	B-Algorithm
measures	O
are	O
possible	O
in	O
the	O
ACC	O
during	O
cognitive	O
tasks	O
.	O
</s>
