In vivo Near Infrared Spectroscopy: a novel approach for simultaneously estimating molecules and hemodynamic parameters in the human and rat brain: a review Authors' affiliations

Abstract

There have been great advances in optical brain imaging over the last 50 years and the technique has grown into a richly diverse field. In vivo recording and imaging using light provides extraordinary sensitivity to functional changes through intrinsic contrast, blood, and can even exploit the growing availability of exogenous optical contrast agents. Light can be used to analyze microscopic structures and function in vivo in the exposed animal brain, while also allowing noninvasive imaging of hemodynamics and metabolism in a clinical setting. This review is an overview of approaches that have been applied in vivo optical brain recording, in both animals and humans. The basic principles of each technique are described, emphasizing the techniques used in our laboratory. Techniques include imaging of exposed cortex, in vivo functional spectroscopy of the living brain using optic fibers, and the broad range of noninvasive topography and tomography approaches to near-infrared imaging of the human brain. The basic principles of each technique are described, followed by examples of current applications to cutting-edge neuroscience research. In summary, it is shown that optical brain recording continues to grow and evolve, embracing new technologies and advancing to address ever more complex and important neuroscientific questions.

Full text

-Mora JL et al. Medical Research Archives, vol. 6, issue 2, February 2018 issue Page 1 of 20
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In vivo Near Infrared Spectroscopy: a novel approach for
simultaneously estimating molecules and hemodynamic
parameters in the human and rat brain: a review
-1*-1, Marcano Francisco1,
Salazar Pedro234
Authors’ affiliations:
1. Neurochemistry and Neuroimaging Group, Department of Basic Medical Sciences, and Instituto
Universitario de Neurociencias (IUNE), Universidad de La Laguna, Tenerife, (Spain).
2. Neurochemistry and Neuroimaging Group, (Laboratory of Sensors, Biosensors and Materials)
Faculty of Medical Sciences, Universidad de La Laguna, Tenerife, (Spain).
3. 
4. Departament of Applied Physics, Faculty of Sciences, Universidad de La Laguna, Tenerife,
(Spain).
* Corresponding author: -Mora JL, E-mail: jlgonzal@ull.edu.es
Abstract
There have been great advances in optical brain imaging over the last 50 years and the
technique has grown into a richly diverse field. In vivo recording and imaging using light
provides extraordinary sensitivity to functional changes through intrinsic contrast, blood, and
can even exploit the growing availability of exogenous optical contrast agents. Light can be
used to analyze microscopic structures and function in vivo in the exposed animal brain, while
also allowing noninvasive imaging of hemodynamics and metabolism in a clinical setting.
This review is an overview of approaches that have been applied in vivo optical brain
recording, in both animals and humans. The basic principles of each technique are described,
emphasizing the techniques used in our laboratory.
Techniques include imaging of exposed cortex, in vivo functional spectroscopy of the living
brain using optic fibers, and the broad range of noninvasive topography and tomography
approaches to near-infrared imaging of the human brain. The basic principles of each
technique are described, followed by examples of current applications to cutting-edge
neuroscience research. In summary, it is shown that optical brain recording continues to grow
and evolve, embracing new technologies and advancing to address ever more complex and
important neuroscientific questions.
KEY WORDS: Spectroscopy, optical imaging; two-photon microscopy; near-infrared
spectroscopy; diffuse optical tomography; neuroimaging; neurovascular coupling
REVIEW ARTICLE

-Mora JL et al. Medical Research Archives, vol. 6, issue 2, February 2018 issue Page 2 of 20
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1. Introduction
The interaction of light in tissue to
recognize disease has been widely
researched since the mid-19th century when
Joseph von Fraunhofer developed
diffraction grating. A large number of
scientists have brought optical spectroscopy
forward and enabled it to become a precise
and quantitative scientific technology.
     
new optical method in an original article(1),
near-infrared spectroscopy (NIRS) was seen
as the technique which could deliver a
solution to a clinical need. In 1977, this
author demonstrated the possibility of
detecting changes in adult cortical
oxygenation during hyperventilation(2).
NIRS has become an established research
and clinical tool for measuring changes in
cerebral oxygenation, in particular, changes
in oxygenated (HbO2) and deoxygenated
(HbR) hemoglobin concentration.
The technology has gained interest in the
medical field in numerous biomedical
applications for its advantages over existing
conventional techniques. Optical
spectroscopy at infrared and visible
wavelengths avoids the use of ionizing
radiation, is non-destructive, utilizes
relatively inexpensive equipment, and can
be performed near real-time without
pharmaceutical means to enhance contrast,
i.e., contrast agents.
Different optical recording techniques, both
in visible and near infrared, have been used
in animal experimentation. One of the most
widely used techniques has been the
exposed-cortex imaging; its use in animal
studies has been widespread. Although it
has been widely used by many groups,
optical imaging in experimental animals has
been only one step towards the study of
imaging in clinical diagnosis and an
excellent tool to learn much more about the
basic mechanisms of brain function both in
physiology and in pathology. These results
can be useful to help the development of
new drugs and treatments. These studies
can also contribute to the interpretation and
better comprehension of results from other
imaging modalities such as functional
magnetic resonance imaging (fMRI) or
positron emission tomography (PET). Some
of these applications of animal imaging
have included   
disease(3), stroke(4), epilepsy(5) and
published by our group, the mechanisms of
neurovascular coupling(6).
The obvious advantage of optical imaging
over other modalities is its reduced cost and
infrastructure requirements (such as
shielded rooms, synchrotrons etc...).
This review describes a selection of optical
approaches to detect functional brain
activity. The basic principles of each
technique are described, highlighting the
techniques used in our laboratory, 1)
Invasive optical brain techniques,
including: a) optical techniques for exposed
cortex imaging, b) recording functional
activity using optic fibers, 2) noninvasive
clinical optical imaging of the living brain.
2. Invasive optical brain techniques.
2.1. Optical techniques for exposed-
cortex imaging.
The exposed-cortex imaging in animals
rather than humans provides significantly
more flexibility, since preparations can be
much better controlled and all types of
experiments can be systematically
compared. Extrinsic dyes and cross-
validation techniques such as voltammetry,
amperometry or electrophysiology can even
be used simultaneously(6).
This technique therefore also offers
significant technical advantages for small
animals, allowing higher resolution imaging
and improved sensitivity. The cortex can be

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surgically exposed to obtain high resolution
imaging, allowing direct optical imaging of
     
disturbance to brain activity. Exposed
cortex is highly accessible, and most
commonly performed in experimental
animals, although it has also been achieved
on the intra operatory human brain(7)(8).
In the neuroscience literature, the exposed-
cortex is the simplest optical imaging
techniques. The most useful are, HbO2 and
HbR dynamics(6); imaging extrinsic
voltage sensitive dyes(9); speckle-flow
imaging(4), capable of imaging the blood
flow dynamics in the superficial cortex.
Exposed-cortex imaging has been applied
to an extensive range of research areas.
These can be summarized as: 1. functional
imaging to improve understanding of the
basic mechanisms of the hemodynamic and
neuronal response to stimulus, 2. functional
imaging to investigate the sensory and
cognitive processing functions of the brain,
and 3. a study of the effects of diseases and
treatments on normal brain behavior.
2.1.1. Technical procedure.
Surgical preparation for exposed-cortex
recordings, the experimental subject,
commonly a rat, mouse, cat or primate is
anesthetized while the scalp is retracted and
the skull is carefully removed from over the
brain area of interest. In some cases, the
skull may be carefully thinned to obtain a
       
surface, avoiding contact with the brain
cortex. Many imaginative tricks have been
developed to ensure that correct brain
function is not affected. Most often, these
techniques are performed with anesthetized
animals. However, in many other cases a
cranial window can be implanted in the
animal to perform chronic optical studies.
While the techniques described above make
it possible to obtain information from the
cortex (2D-imaging), there is the possibility
of recording images with tomographic
information (3D) using Optical Coherence
Tomography (OCT)(10) of functional brain
activation, Laminar Optical
Tomography(LOT)(11), Fluorescence
Lifetime Imaging and Microscopy
(FLIM)(12) and Two-Photon
Tomography(13)(14).
Brain in vivo imaging for research using
Two-Photon Tomography has also found
applications in areas of functional
mechanisms, functional processing and
pathology/treatment research(13)(14).
These applications exploit a variety of
methods to introduce fluorescent contrast
into the brain, including intravenous
injection of dextran-conjugated dyes to
show blood vessels, topical application, or
pressure injection of dyes into the cortex,
transgenic mutation of cells to express
fluorescent proteins and systemic delivery
of dyes.
2.2. Recording functional activity using
optic fibers.
We will now review fiber optic probe
scattering spectroscopy of turbid tissues
using visible and infrared light. A
spectroscopic system incorporates a light
source, an optical analyzer with a detector,
and a light transport conduit, which, in
many cases, is made of optical fibers, figure
1. The excitation or illumination light
source is usually a laser or a white light
source, such as a xenon or incandescent
lamp. The coupling optics adapts the
f-number of the light source to the
numerical aperture of the fiber and
guarantees optimal irradiance into the fiber.

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Figure 1. Fiber optic-based spectroscopy system, with separate illumination (excitation source,
LED or incandescent light bulb). Optical elements couple the excitation light into the flexible
probe, a probe collects the emitted light, coupling optics adapt the numerical aperture of the
probe to the miniature spectrometer and an optical detector (CCD, or CMOS linear element) is
read out and digitized.
Single fiber solutions are used and well-
aligned coupling optics to achieve the
smallest probe diameters. Single-fiber
solutions are the most commonly used
because of the small diameter 50-
and the fact that single fiber-based probes
require a minimal amount of components
for the probe and can be used to create the
smallest illumination spots as well as
having excellent light collection efficiency.
The simplest way to setup is Y-shaped
assemblies with two fibers of the same
diameter side-by-side in the common end,
which then diverges into two separate legs.
The fibers in the assembly may be UV-VIS,
VIS-NIR or one of each in a mixed
bifurcated assembly(15). See figure 2 for
more details.

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Figure 2. A. Y-shaped assembly with two fibers of the same diameter side-by-side in the
common end implanted in brain, which then diverge into two separate legs. B. Zoom of
distalendtips of fiber optic in dual angle-polished fibers configuration. The arrangement of the
fibers and their angle of polishing try to prevent damage to the cerebral parenchymaas much as
possible.
Another of the additional advantages of
simultaneously using optical fibers is the
possibility of using other neurotechniques
(voltammetry(6), amperometry(16), electro-
physiology(17), microdialysis(18), etc.),
that complement the obtained information.
The optical registration techniques do not
generate interferences or electronic noise
that could alter the results.
As an example of what was said above,
using microdialysis and fNIRS, we found
that intracerebral infusions of amphetamine
increase the extracellular concentration of
glutamate, dopamine, aspartate, GABA, and
taurine. This study(18) also shows that an
alpha-noradrenergic receptor antagonist is
able to attenuate the effects of amphetamine
on the release of glutamate, dopamine,
GABA and taurine, which further suggests
a vasoconstrictor effect of amphetamine as
a result of which hypoxia could develop.
2.2.1. In vivo spectroscopy: for simulta-
neously estimating nitric oxide and
hemodynamic parameters
Nitric oxide (NO) is a well-known signaling
molecule involved in a wide range of
biological processes. Under physiological
conditions, NO reacts with HbO2 to form
methemoglobin (MetHb) at a very high
rate. Microdialysis studies have used
hemoglobin solutions as a trapping method
to quantify NO in vivo. The methodology
described here uses the microcapillary
network (capillary bed) with endogenous

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HbO2 instead of a microdialysis probe with
exogenous HbO2 for monitoring MetHb as
an indirect index of NO levels by in vivo
spectroscopy using optical fibers.
This method has been validated using in
vivo voltammetry and selective NO
microelectrodes. We have used in vivo
local infusion of NO into the tissue
surrounding the probe (optodes) in both
methods, NOS inhibitors to decrease the
NO production and local infusion of
NMDA agonists to increase NO production
in the cerebral cortex. Thus, the association
between in vivo voltammetry and in vivo
spectroscopy as we have described for our
group could be very advantageous, because
by using both methodologies it is possible
to measure the NO directly in the
extracellular fluid (voltammetry) and its
deactivation by its principal in vivo
scavenger (spectroscopy). Moreover, the
latter technique makes simultaneous
measurements of hemodynamic parameters
such as oxygenation rate and blood volume
(cerebral blood flow) possible, see figure 3.
NO is extremely unstable in vivo and its
half-life has been estimated as a few
seconds(18). In accordance with its role as a
paracrine mediator, NO can travel to reach
target cells in neighboring areas of the NO-
generating cell. During the paracrine
migration, in particular at high
concentrations, this reactive molecule can
interact with molecular oxygen to form
higher nitrogen oxides (e.g. NO2 andN2O3),
which can either react with other
biomolecules such as thiols and amines or
be hydrolyzed to nitrite (NO2- ) and nitrate
(NO3-)(16). However, the most important
reactions are with ferrous hemoproteins and
especially with hemoglobin (Hb)(19),
(figure 3A), such as those which yield
nitrosylhemoglobin or methemoglobin.
Nitrosylhemoglobin formation has a very
low rate(16), whereas the interaction with
HbO2 is characterized by a very high rate
even under saturating oxygen
concentrations, and it has been estimated to
be at least 26 times faster than the auto-
oxidation of NO in aqueous solution. Thus,
MetHb levels are proportional to the NO
concentration and they can be used as an
indirect index of NO (20)(21)(22), as we
can observe when this technique is
compared with another technique, see
figure 3, C and D.
Many results indicate that this spectroscopy
technique is able to record large increases
in MetHb levels and to detect reductions of
its basal levels(16)(17)(23)(24)(22). In
addition, data show that similar changes
and kinetics can be observed with both
techniques. Thus, intravascular MetHb can
be used as an indirect index of NO levels. It
is proposed that in vivo spectroscopy may
be a useful tool to gain insight into the roles
of NO in hemodynamic parameters and in
other physiological processes such as the
regulation of the mitochondrial respiratory
chain(18)(16).
Finally, this technique offers the possibility
of monitoring the neuronal activity, bearing
in mind that it is widely accepted that
changes or alterations in regional cerebral
blood flow and cerebral oxygen
consumption rate can be used as an index of
neuronal activity. Other groups have made
interesting contributions using our
method(23)(24).
3. Non-invasive optical imaging of the
human brain
Functional near infrared spectroscopy
(fNIRS) commonly used the topography
approach in brain research covering
different fields such as physiology (25),
psychiatry (26), alterations in disease (27),
and its application in the brain computer
interface (BCI) (28),in neuroimaging
studies has recently been developed.
However, the method has some

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disadvantages as the relative positions of
the measurement channels to brain anatomy
vary between subjects or fNIRS
measurements in cortical areas are always
affected by the hemodynamic changes in
the scalp layer affecting the interpretation
of results in cortical activity(29)(30).
Figure 3. A, Absorbance in arbitrary units of oxyhemoglobin (HbO2), deoxyhemoglobin (HbR),
carboxyhemoglobin (HbCO) and methemoglobin (MethHb) as a function of wavelength. B,
Mechanical device for selective microelectrode brain implantation for nitric oxide (NO) and fiber
optics. Schematic drawing and photography. C and D, Kinetic effects of the manipulation of NO
synthesis on MetHb band and free NO levels in rat cerebral cortex determined by in vivo
spectroscopy (D) and in vivo voltammetry (C), respectively. Absorbance values at 635 nm (A)
were averaged every 30 s (scan rate: 40 spectra min-1. Voltammetric peaks of NO (oxidation peak
at approximately 650 mV) were recorded every 2 min and percentages of modification from basal
values were calculated. Data represent mean +SEM (n = 5-8 rats per group) and arrows indicate
the infusion of drugs close to the microsensor (see publication 17 for more detail) As illustrated
in C and D, NO and MetHb levels were decreased by the potent NO-synthase inhibitor L-NAME,
white squares, but were not modified by vehicle solution (PBS), black triangles. In addition, NO
and MetHb levels were markedly enhanced by the administration of NMDA, black squares. Time
scales for spectroscopic and voltammetric studies differ due to the differences in scan rate
between both techniques.

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3.1. Advantages of optical techniques
Functional brain imaging has provided
substantial information about how dynamic
neural processes are distributed in space
and time. A large number of brain studies
based on task or resting state imaging
studies of neural networks through healthy
subjects have been reported(31)(32)(33).
Some imaging modalities to study brain
functioning use fMRI which require costly
infrastructure, while optical imaging
instruments are less expensive. Moreover,
technique limitations in fMRI devices such
as a fixed scanner, contraindication with
metal implants, scanner noise and stress
associated with fear are avoided or reduced
in optical imaging devices.
fMRI measures changes in the blood
oxygen level dependence (BOLD) signal
associated with hemodynamic changes after
the neural activity to visualize functional
changes in the brain. Although the BOLD
signal has been associated to a decrease of
HbR(34), an increase of BOLD signal could
be associated to an increase of HbO2(35) or
a combination of both. Initially, the HbR
decreases and then the HbO2 increases due
to the vasodilatation that washes the local
HbR. The above controversy disappears
with the use of optical imaging techniques,
which measure each hemoglobin state
separately (HbR & HbO2), using at least
two wavelengths to measure each
hemoglobin state. Moreover, the optical
imaging techniques provide more
comprehensive information of
hemodynamic and metabolism than the
BOLD signal, due to the complicated
connection of the BOLD signal to the
neurovascular coupling.
Optical imaging techniques can measure
changes in HbO2, HbR and HbT at a much
higher sampling rate than fMRI, and this
could be a fundamental tool for the study of
the neurovascular coupling in humans,
especially when the neurovascular coupling
is either unknown or altered. The principal
advantage of fMRI measurements is that
they can cover the whole brain, while
optical measurements only reach the
cerebral cortex because its penetration
depth is around of 3-4 centimeters could
anatomically reach the gyral level(36).
Finally, unlike other imaging modalities
such as the PET(37) or x-ray computed
tomography(38), functional brain
measurements using optical imaging do not
need a contrast agent, whose doses are
limited in infants and could induce
anaphylactic reactions in certain
populations.
All these aforementioned circumstances
have potentiated the use and developments
of optical imaging techniques in recent
years for research, diagnosis and prognostic
studies.
3.2. Instrumentation
A wide variety of NIRS instruments has
been created for different types of
measurements, with the most common
being the following: continuous wave
(CW), time domain (TD) and frequency
domain (FD).
 In CW measurements, the light is
emitted at a constant intensity by
sources into the tissue, and the same
device detects the transmitted light
intensities. CW uses frequency-
encoded intensities to acquire data
and can simultaneously measure
wavelength(39) or light sources(40).
 TD uses ultrashort laser pulses to
irradiate the tissue, and the light
intensity detected is recorded over
time to show a temporal point spread
function (TPSF) with a resolution of
picoseconds (41)(42).

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 In FD measurements, the light source
is modulated at radio frequencies
(100-1000 MHz)(43), and measures
the phase delay of the light detected
from the tissue(44). The parameters
of FD measurements are phase shift,
the intensity of light (DC component)
and the amplitude of the intensity
oscillations (AC component) at given
wavelengths and for different
distances between the light source and
detector. The FD instrumentation is
more complex and expensive than
CW systems, thus a combination of
CW measurements and small
frequency-domain measurements
have been proposed to provide good
spatial resolution and quantitative
accuracy(45).
3.3. Tomography approach
The most significant improvements in
optical imaging came when image
reconstruction techniques were proposed in
the 1990s using diffusive photons(46)(47).
Diffuse optical tomography (DOT) is an
fNIRS approach that transforms the
detected light from different measuring
distances on the surface of the head into
depth information providing three-
dimensional images of cerebral
activations(48). DOT uses the multi-
distance approach with the purpose of
increasing spatial resolution and positional
accuracy of optical brain imaging(49).
Unlike the topography approach which
directly maps the changes in optical
properties from the midway between a
source and detector into a 2-D image(50).
3.3.1. Image reconstruction
The forward model is used by DOT to
model light migration processes to create
functional images. The forward model
relates the activity inside the head tissue
with the measured light intensity changes,
using the radiative transfer equation (RTE)
or diffusion approximation (DA).The
mathematical forward model must be
implemented in computational models.
There are three types of computational
modeling approach, which are the
following: analytical modeling, stochastic
modeling and deterministic modeling.
 Analytical modeling uses 
function for the solution of partial
differential equations such as the RTE
or DA in a homogeneous semi-
infinite medium(51) and simple
geometries. It has been used to
validate stochastic and deterministic
models.
 Stochastic modeling whose
distribution of optical properties is
calculated by Monte Carlo
simulations which model the light
propagation inside a 3-D realistic
head obtained from MRI scans, where
heterogeneous structures are
incorporated to the simulation(52).
This method allows heterogeneity and
a flexible shape of the medium.
 Deterministic modeling is based on
the finite element method to solve the
DA. FEM is capable of dealing with
heterogeneity in arbitrary geometries.
This is the most commonly used
system in diffuse optical imaging.
The relationship between the measurement
of light intensity and optical property is
non-linear. However, the relationship is
assumed to be linear for DOT images, and
is known as the inverse problem. Two
approaches are used to solve the inverse
problem: linearization and nonlinear
iterative approaches.
The linearization approach does not
correctly predict changes in the optical
properties, showing as results qualitative

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image reconstructed of measured changes
in the brain(53). This approach is good
enough for neuroimaging studies, but not
for clinical studies because, for it, it
necessary to have quantitative images of
hemoglobin states, whereas the nonlinear
iterative approach applies an iterative
optimization method to minimize the
differences between the calculated and
measured data of the distribution of optical
properties. In addition, a Jacobian matrix or
sensitivity is found as a product of both
approaches, which relates the number of
measurements on the surface and changes
in the optical properties, and must be
computed. Methods have been proposed
such as the perturbation method(54) or the
gradient-based method(55) to compute the
Jacobian matrix
Finally, the inverse problem is ill
conditioned suggesting that the
reconstructed images are sensitive to noise
during the measurements. Some research
groups have attempted to solve this using
regularization methods(56)(57) such as the
use of decomposition singular values(58).
In addition, anatomical information of a
subject can be a problem during the image
reconstruction. The DOT technique cannot
provide anatomical information making it
difficult to solve the forward model, unlike
fMRI or x-ray CT which provide
anatomical information. In neuroimaging
studies using DOT technology, the optical
model is constrained to the tissue geometry
through segmented MRI scans. In order to
solve this problem, some research groups
have proposed other methods to perform
DOT studies without MRI scans such as
MNI-guided DOT(59) or DOT images
reconstructed on a generic head model(60).
The same problem occurs when NIRS
technology is applied on other tissues such
as prostate or breast. X-ray CT(61) or
ultrasound(62) or MRI scans can be used to
improve the image reconstruction.
3.4. Applications in functional brain
imaging
Optical measurements can play a role in
determining underlying brain physiology,
especially when investigating the
relationship between neural activity and
hemodynamic changes known as
neurovascular coupling from animals(63) to
humans(64). fNIRS has been used in a wide
variety of applications in neuroimaging
studies to measure functional changes
associated to a stimuli or paradigm. Some
examples are listed below:
 Cognitive stimuli based on go/no-go
paradigms(65). Different letters are
presented on a screen for a few
seconds followed by an inter-stimulus
period of 1-2 seconds. On the one
hand, the participants are instructed to
press a button with their right index
finger each time a letter appears on
the screen (during the go). On the
other hand, the participants are
instructed to push the button for all
letters except X (during the no-go).
Although, the go/no-go paradigm is
one of the most used in cognitive
studies, some authors, as is the case of
our laboratory, have used other
cognitive tasks such as mental
arithmetic tasks(66), see figure 4.
 Somatosensory and motor stimuli
based on finger tapping(67), tactile
stimulation(68) or finger
flexion/extension(69) tasks are some
of the most used examples in
neuroimaging studies. Due to the fact
that cerebral activation amplitudes are
higher than the amplitudes given by
other paradigms e.g. cognitive, the
cerebral activations are reproducible
and spatial localizations of the motor

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activity are known, the motor
paradigms are especially used in the
new method applications such as
image reconstruction algorithms(56),
filtering procedures(70) or
corroboration of simulated
models(57).
Figure 4. Spatial conjunction of HbO (yellow), HbR (red), HbT (blue) and BOLD (cyan) signals
during a mental arithmetic task based on easy count<difficult count, performance by a subject in
6 sessions on subsequent days. Easy count refers to counting backwards from a 3-digit number
-digit number for
riod. Each condition was repeated twelve times
in both DOT and fMRI devices with a random order of the instructions. All resulting t-images of
contrast selected were fitted a normalized anatomical space. Threshold p-value < 0.05, FDR
corrected.
 Visual stimuli based on random dot
stereo pairs where the stimuli are
presented as a pair of images, one to
each eye, then when viewed
binocularly a strongly fused
perception of depth is produced(71).
A visual paradigm is used because
binocular vision allows the fusion of

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each image presented from our retinas
using the difference between them to
estimate relative depths. A wide
variety of studies to measure the
relationship of HbO2/HbR with
perception have been
performance(72).
 Resting-state based on the study of
the functional architecture of the
brain(73). Monitoring HbO2 and HbR
using fNIRS during a rest state of the
participants can exhibit patterns of
functional connectivity. Given that
fNIRS uses a sampling rate higher
than classical fMRI, optical
measurements allow the study of low
frequency components (aim of
resting-state studies), thereby
avoiding the mix with high frequency
components(74).
3.4.1. Applications in infants and
neonates
Portable and noninvasive measurements are
characteristic of NIRS devices, which allow
blood flow and oxygenation monitoring in
infants and neonates especially in brain
injuries. It is essential to control
hemodynamic changes during the
development of neurological disorders in
these patients. Various studies have
reported the suitability of fNIRS to measure
changes in saturation, blood volume and
relative cerebral metabolic rate of
oxygen(75), even in hemorrhage in a
premature baby(76).
3.4.2. Clinic applications
NIRS has been used in populations for
which other imaging modalities are
impractical, such as the elderly and infants,
because fNIRS devices are flexible,
minimally invasive and can be portable.
Despite its limited depth penetration and
difficulty to apply on darker skins or hairs,
fNIRS devices can still be used for
neurologic and psychiatric disorders studies
such as the following:
Neurologic disorders such as
Parkinson(77), Alzheimer(78),
epilepsy(79), ischemia(80) or aging(81),
have been evaluated using fNIRS devices.
Moreover, psychiatric disorders such as
schizophrenia(82) or anxiety disorders(83),
have also been monitored by fNIRS
devices.
In spite of the wide use of fNIRS devices
for brain imaging, an essential application
is, without doubt, for breast cancer imaging,
one the most common cancers in women.
Currently, the most usual screening is x-ray
mammography combined with physical
examination. Tumors are normally
associated with an increase in
vascularization. In these cases, NIRS can
play an important role because it can
measure blood volume and oxygenation to
determine the presence of a tumor. A
variety of studies have shown the capability
and feasibility of fNIRS to identify the
increased vascularization associated with a
tumor(84)(85), despite the fact that the poor
spatial resolution is still insufficient for a
diagnosis.
3.4.3. Other applications
fNIRS not only offers potential applications
in diagnosis and evaluation of diseases, but
can also be used to monitor the saturation of
oxygen in the blood during the
neurorehabilitation in stroke patients,
allowing the evaluation of the recovery
degree. Some research reports the use of
fNIRS devices to monitor functional
changes during neurorehabilitation
processes in cognitive disabilities(86),
motor disabilities(87) or aphasia(88). A
new application of fNIRS is being
developed based on the application of
transcranial magnetic stimulation (TMS)

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B)
A)
whose electrical changes produced inside
the brain lead to hemodynamic changes
which can be monitored by fNIRS.
Electroencephalography (EEG) has been
used to monitoring the cerebral changes
generated during the TMS (89). The EEG
allows the measurement of changes in the
bioelectric activity while the TMS is
applied, with a good temporal resolution
but does not provide hemodynamic
information. Some authors have stimulated
previous to or between intervals of radio
frequency pulses inside fMRI(90) to
measure cerebral functional changes
generated by TMS. It is not possible to
monitor functional changes during the
stimulation period because of the
electromagnetic incompatibility with fMRI.
In these cases, NIRS offers the possibility
of functional change monitoring while the
TMS is applied without interferences that
can affect the results, an example of this,
recorded in our laboratory can be seen in
figure 5.
Although, there are some discrepancies
about the hemodynamic changes measured
by fNIRS during the TMS application,
which depending on the cerebral area
stimulated, TMS coil angulation, intensity,
and frequency of the stimulation, the results
are variable. In spite of these discrepancies,
simultaneous fNIRS and TMS are potential
tools for the study of the physiology that
underlies the stimulation, neurovascular
coupling and as clinic tools.
Figure 5. T-maps of brain activation during rTMS at high-frequency (>10Hz) vs resting period,
simultaneously measured by DOT on A) the middle of the prefrontal cortex and B) the right

p < 0.001; p < 0.05 corrected FDR, at the voxel level for HbO signals. Color bars show HbO
changes during rTMS.
In summary, for clinical applications,
noninvasive optical imaging can provide
complimentary information to other
modalities such as fMRI and provide a low-
cost alternative in some cases. This is in
addition to serving populations often unable
to receive MRI or PET scans such as young
infants or the critically ill. Clinical optical
brain imaging is generally noninvasive and
uses NIR light to obtain improved
penetration through the scalp, skull, and
brain. To conclude   
advantage is the ability to measure a range of
functional contrasts, it can readily be
exploited in functional brain imaging via a
wide range of approaches from animal
studies of the intricate cellular mechanisms
of normal and diseased brain to in vivo
noninvasive clinical brain imaging.
In addition, optical recordings or brain
imaging is finding widespread applications
as a research tool for both clinical and
animal studies of basic brain function and

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Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra
disease. At present, so little is known about
the way that the normal brain functions, in
part due to the difficulties of measuring such
a complex organ without disturbing or
  s in vivo functioning.
Optical imaging allows the living brain to be
closely observed, as well as investigation
into many functional interactions and
changes over many length scales.
4. Acknowledgements
This work was supported by the grant
MACbioIdi Project, co-funded by the
European Union program INTERREG V-A
MAC 2014-    
Desarrollo Regional-. The authors
would like to thank Patrick Dennis for the
English revision.
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