Computational Models and Simulators of Functional MRI: February 2015

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Computational Models and Simulators of functional MRI
Technical Report · February 2015

DOI: 10.13140/RG.2.2.24990.33600
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Computational Models and Simulators of functional MRI
Marwan Abdellah
[email protected]
Blue Brain Project (BBP)
École Polytechnique Fédérale de Lausanne (EPFL)
A literature review report submitted to

Prof. Rolf Gruetter
[email protected]
Laboratory for Functional and Metabolic Imaging (LIFMET)
Centre d’Imagerie Biomédical (CIBM)
Advanced Biomedical Imaging Methods and Instrumentation

Doctoral School of Neuroscience (EDNE)
Frbruary 2015
35 pages
Computational Models and Simulators of fMRI
Acknowledgments
I would like to acknowledge and express my deepest gratitude to Prof. Gruetter, his team, all
the presenters and the researchers who have contributed to this outstanding course.
Marwan Abdellah
February 2nd , 2015
1
Contents
1 Introduction 6
1.1 fMRI Modeling and Simulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.2 Report Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2 The Biophysical Basis of BOLD fMRI 7
3 Data Generation Models for BOLD fMRI 8

3.1 Baseline Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.2 BOLD Activation Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.3 Noise Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4 BOLD Activation Models 11

4.1 Models for the Estimated HRF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4.2 Biophysically-plausible Models of the BOLD HR . . . . . . . . . . . . . . . . . . . 13
4.2.1 Models for Neural Basis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.2.2 Models for Energy Consumption and Metabolism . . . . . . . . . . . . . . 15
4.2.3 Models for Blood Flow (CBF) . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.2.4 Models for Vasculature Dynamics (CBV) . . . . . . . . . . . . . . . . . . . 16
4.2.5 Models for Oxygen Extraction . . . . . . . . . . . . . . . . . . . . . . . . . 16
4.2.6 BOLD Signal Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.3 Other BOLD HR Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
5 fMRI Simulation Studies 19

5.1 Single Voxel fMRI Simulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
5.2 Multi-Voxel fMRI Simulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.3 Multi-resolution BOLD Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5.4 fMRI artifacts Simulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
6 Simulation Software Applications 23

6.1 fMRI Simulation Toolbox (SimTB) . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
6.2 neuRosim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
7 Conclusion 26
List of Figures
1 The structural content of a unit volume (voxel) in the visual cortex of a monkey.
The stained image to the left shows a Nissl slice extracted from the cortex.
The central image depicts the relative density of the blood vessels in the same
area of the cortex. The vessel diameter is color coded. The three-dimensional
reconstructions demonstrate the difference in the diameters of the blood vessels
and the spatial distribution of a group of neurons between the blood vessels.
Image courtesy of Nikos K. Logothetis (Macmillan Publishers) [Log08]. . . . . . 9
2 A simplified block diagram of the underlying principle of fMRI within a sin-
gle voxel starting from the stimulation activity and until the generation of the
BOLD signal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3 Estimated models of the BOLD HRF . . . . . . . . . . . . . . . . . . . . . . . . . . 13
4 The underlying physiological processes that account for the generation of the
BOLD response. Image source: [Den06] . . . . . . . . . . . . . . . . . . . . . . . . 14
5 The two-stage fMRI computational model of Chen and Calhoun. The neuro-
physiology model simulates the neurovascular coupling process and the fMRI
technology model simulates the acquisition of the BOLD fMRI signal. . . . . . . 21
6 A description of the multi-resolution computational BOLD fMRI model pre-
sented by Chen and Calhoun. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
7 Data generation sequence of synthetic fMRI datasets in SimTB. Image courtesy
of Allen et al. [AEW∗ 11b] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
8 The simulated BOLD signals based on the three convolution functions imple-
mented in neuRosim for a 20-seconds ON/OFF block design. Image courtesy
of Welvaert et al. [WDM∗ 11] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
9 A block diagram summarizing the data generation models for fMRI simulations. 28
3
List of Acronyms
BOLD Blood Oxygenation-level Dependent
CBF Cerebral Blood Flow
CBM Cerebral Blood Magnetism
CBV Cerebral Blood Volume
CMRGL Cerebral Metabolic Rate of Glucose
CMRO2 Cerebral Metabolic Rate of Oxygen
DCM Dynamic Causal Modelling
deoxyHb Deoxygenated Hemoglobin
FPM Finite Perturber Method
fMRI functional Magnetic Resonance Imaging
GLM General Linear Model
GRE Gradient-recalled Echo
GUI Graphical User Interface
HR Hemodynamic Response
HRF Hemodynamic Response Function
ICA Independent Component Analysis
iEEG intra-cranial Electroencephalography
LFP Local Field Potential
MR Magnetic Resonance
MRI Magnetic Resonance Imaging
oxyHb Oxygenated Hemoglobin
pixel Picture Element
voxel Volume Element
4
Abstract
The introduction of functional Magnetic Resonance Imaging (fMRI) has pioneered the
neuroscience research to address the mapping of the functional aspects of the brain. Since
its inception about twenty years ago, several models and simulation studies for blood
oxygen-level dependent (BOLD) fMRI have been proposed and extensively discussed. Most
of these research studies have been focused on understanding the underlying mechanisms
of the technique. The complexity of fMRI data has challenged the development of com-
mon, precise and physiologically-plausible fMRI simulators, and consequently the data
generation models in the majority of the current simulators are ad hoc. This report reviews
the modelling work and numerical simulation studies of BOLD fMRI that have been covered
in the literature to date. Also, the review lists multiple software simulation packages that
have been developed recently to meet the increasing demands of the fMRI community.
Keywords fMRI, BOLD contrast, fMRI simulation, fMRI models, numerical simulations.
5
1 Introduction
There is no doubt that the inception of the functional magnetic resonance imaging (fMRI)
20 years ago was a significant scientific breakthrough for brain research and neuroimag-
ing [Ban12]. During this period, fMRI was growing exponentially until it became a standard
tool for cognitive studies. The impact of this advanced technology was associated with the
emergence of new scientific fields such as social neuroscience, neuroeconomics and neuro-
marketing [Ashss].
The main advantage of fMRI is its capability of mapping brain activity noninvasively. It
measures the blood oxygen-level dependent (BOLD) perturbations that arise in response to a
neuronal activity that follows a change in brain state [Jez99, Gor03, HSM09]. The principle
idea of BOLD fMRI is based on the fact that a neuronal activity will incur perturbations in the
cerebral blood magnetism (CBM) that can be measured by a T2∗ -weighted MRI sequence. By
and large, this process can be characterized by a neurovascular coupling model. This model ex-
presses the vascular response to a neuronal activity in terms of the cerebral blood flow (CBF),
cerebral blood volume (CBV) and the cerebral metabolic rate of oxygen (CMRO2 ) [CC12].
Despite its importance and the wide acceptance the technique has gained since its in-
troduction, the underlying mechanisms of BOLD fMRI in general and the complicated neu-
rovascular process in particular are not fully understood [HB99, MFPK07, MB08, HGCDB12].
This limitation makes the generated datasets with fMRI have no ground truth that can be
exploited to validate the statistical techniques being developed to analyse the measured sig-
nals and assess their properties quantitatively. Moreover, fMRI signals are contaminated by
different sources of noise mainly due to electronic and physiological artifacts, chemical shift
and the magnetic susceptibility induced by magnetic field inhomogeneities [Dro07]. Several
methods have been developed to establish the missing ground truth such as intra-cranial
electroencephalography(iEEG). Nevertheless, most of theses iEEG studies were not feasible
to reconstruct a precise ground truth [DGS∗ 08]. Additionally, various artifact-correction tech-
niques have been developed to suppress or at least minimize the artifacts that contaminate the
fMRI signal, but these techniques were based on the analysis of empirically measured fMRI
data, which fail to identify a valid ground truth.
6
1.1 fMRI Modeling and Simulation
Ultimately, the modeling and simulation of fMRI can be used to facilitate the understanding
the complex dynamics and the different mechanisms involved in the generation of the BOLD
effect quantitatively. Though, the realistic simulation of fMRI data is known to be an extremely
challenging mission due to the complexity that characterize the data itself. This simulation re-
quires very accurate computational models for the neurovascular responses, different sources
of noise and artifacts, a complete MR acquisition system and above all geometric definition of
the anatomy of the brain at different scales. Even if detailed models for each item in this list
were available, combining these features into a single simulation system is still an inspiring
task that require the collaborations of interdisciplinary research teams.
1.2 Report Objectives
In this report, the different modeling and simulation contributions of fMRI that have been
presented and discussed in the literature are reviewed. We also refer and highlight the features
of different fMRI simulation packages that have been developed recently to meet the demands
of the community for flexible and standard simulation software applications.
2 The Biophysical Basis of BOLD fMRI

Obviously, the signaling mechanisms involved in this process cannot be extensively discussed
in this sequel. Thus, this section is just a brief review of the basic physiological basis of the
underlying mechanisms of fMRI. It is though to be very helpful to identify and highlight the
different parameters that are required to model and simulate the BOLD response. For further
details, this set of references will be very helpful in this regard [FM10, Gor03, Bux02, Duy05,
UDB05].
Moreover, since the majority of fMRI experiments uses BOLD contrast to measure the
brain activity [Ashss], our coverage for the biophysical principles of fMRI will be limited to
BOLD-contrast fMRI only.
BOLD fMRI does not measure the neural activity itself. Instead, it provides an indirect way
to address the functional activity of certain brain region by measuring the changes in blood
7
oxygenation levels that happen in response to the local activation of certain functional network
of neurons in this brain region. The BOLD signal emerges within the vasculature as a result of
the concentration changes of the de-oxygenated hemoglobin (deoxyHb) that depends directly
on the CBF, CBV, and CMRO2 . During the neural activity, the CBF increases much more
than the CMRO2 . This results in more oxygenation of the venous blood that is accompanied
with susceptibility changes of the blood and creates magnetic field gradient around the vessel
(see Figure 1). This happens because the deoxyHb is more magnetic, i.e. paramagnetic, than
oxygenated hemoglobin (oxyHb), which is virtually resistant to magnetism, or diamagnetic.
This effect gradually changes the T2∗ relaxation time and finally causes changes in the detected
MRI signal over time. This improvement can be mapped to show which regions of the brain
are active at a time. Figure 2 summarizes the biophysical principles of BOLD fMRI in a
simplifying block diagram.
3 Data Generation Models for BOLD fMRI

There are two approaches to generate fMRI simulation data. The first and most common
one considers pure synthetic simulations and the other uses a hybrid simulation strategy. The first
approach relies completely on rigours or simplified mathematical models to reflect the charac-
teristics of the measured fMRI signals. In the hybrid approach, the generated fMRI combines
a realistic dataset acquired at resting state added to synthetic activation data. Although the
noise in this case is representative for real data, the parametrization or the manipulation of this
noise in the resulting simulated fMRI data is not applicable. This reason obviously accounts
for the widespread acceptance of the first approach in the literature [WR14].
Bellec et al. have discussed two simulation models for fMRI data and evaluated their per-
formance relying on the bootstrap framework in a completely controlled environment [BPE09].
The first model, Equation (1), adds a mixture of multiple components, mainly a baseline signal
b(t), the BOLD activation signal BAct (t) and random noise n(t) (for example [DMCPNM02,
MP04]).
BSim (t) = b(t) + BAct (t) + n(t) (1)
The second model adds a non-linear term to account for the motion artifacts either using
8
Figure 1: The structural content of a unit volume (voxel) in the visual cortex of a monkey.
The stained image to the left shows a Nissl slice extracted from the cortex. The central image
depicts the relative density of the blood vessels in the same area of the cortex. The vessel
diameter is color coded. The three-dimensional reconstructions demonstrate the difference in
the diameters of the blood vessels and the spatial distribution of a group of neurons between
the blood vessels. Image courtesy of Nikos K. Logothetis (Macmillan Publishers) [Log08].
spatial interpolation [ABH01, PLMD05] or a first principle model of MR physics [DGS∗ 06a,
XWR∗ 07, KYB08]. The advantage of the additive model is its flexibility that allows control
over the signal-to-noise ratio and the profile of the activated region. The majority of the
simulation studies have relied on the pure synthetic approach to generate the fMRI simulation
data [WR14].
9
Stimulation Activity
Neural
Neuronal Response
(Activity)
Vasculature
O2 Demande
Vasculature Response
CBF CBV CMRO2
Magnetic
Magnetization
Susceptibility Response
Magnetic Filed Changes
Signal
Single Voxel BOLD Response
Figure 2: A simplified block diagram of the underlying principle of fMRI within a single voxel
starting from the stimulation activity and until the generation of the BOLD signal.
10
3.1 Baseline Models
The modeling of the baseline signal was quite straightforward. It was assumed to be zero or
constant value in some cases, and time-varying in other cases to reflect the intensity varia-
tions of the signal. The time-varying case was used by Backfrieder et al. to model thermal
shifts [BBS∗ 96].
3.2 BOLD Activation Models
The classification of the BOLD activation models will be covered in depth in Section 4.
3.3 Noise Models
Roughly, the noise models were always involved in the generation of synthetic fMRI simula-
tion data. Gaussian noise was used in most of the models and other models have added to
it some drift. A little number of simulations have used experiment-specific noise models to
account for some artifacts of the BOLD signal such as physiological noise or motion-correlated
noise.
4 BOLD Activation Models

Due to the fact that the BOLD response detected in most of the fMRI studies is merely an
indirect measure of the neuronal activation, precise models of the BOLD response do not exist
so far. A clear understanding of the exact underlying biophysical principles of the neural
activation and the observable BOLD response requires a rigours mathematical model that can
link the two variables. Consequently, most of the modeling studies of fMRI do not attempt to
model the neuronal activation at such biophysical detail and only assume that the neuronal
activation can be addressed by an abstract latent variable [Ashss, Den06]. Their hypothe-
sis was set such that a linear time-invariant relationship governs the transformation of the
neuronal activation directly into the BOLD response. This model allows exploiting powerful
analysis tools such as linear regressions and statistical tests [FHW∗ 94].
Several studies have addressed the validity of this linear relationship. Some of them have
confirmed that its deviation from linearity is not severe as long as the triggering events
11
are separated by few seconds and the duration of the exposure is larger than a certain
threshold [Ashss, BEGH96, VN98]. The others studies which involved different measure-
ment modalities have accounted for this non-linearity mainly due to the hemodynamic ef-
fects [MLL∗ 01, OLM∗ 04].
These conditions were enough such that the BOLD response Bi (t) can be described by
a linear system in terms of the input neuronal activation Ni (t). The transfer function of this
model f TF represents all the complex mathematical transformations that potentially contribute
to the conversion of the neural activation Ni (t) into the BOLD response Bi (t) where
Bi (t) = f TF [ Ni (t)] (2)
Relying on the superposition principle of linear systems, the BOLD response Bi (t) can be
obtained if the neural activation can be represented by an impulse function. In this case, the
BOLD response is called the hemodynamic response function (HRF) h(t). This is called the
general linear model (GLM), where the HRF is seen to be a hypothetical BOLD response to an
impulse neuronal activation. This means that the BOLD response Bi (t) to any complex neu-
ronal activation Ni (t) can be computed from the convolution integral described by Equation
(3) if the HRF is known a priori.
Z t
B(t) = N (τ )h(t − τ )dτ (3)
0
It is obvious from this previous integral in Equation (3) that the HRF can be simply ob-
tained if the input activation was an impulse. Nevertheless, such experiment is not practically
feasible because we do not have a direct control over the input neuronal activation.
4.1 Models for the Estimated HRF
Specific estimated models for the HRF can be used based on experimental observations and
previous knowledge characteristics of the function. There are two basic and famous models
that have been used to estimate the HRF: the gamma function [BEGH96, Coh97] and the dif-
ference of two gamma functions1 [FFJ∗ 98, Glo99]. The two models are depicted in Figures 3(a)
and 3(b).
1 Also known by the canonical HRF.
12
(a) The Gamma function model of the HRF (b) The canonical model of the HRF
Figure 3: Estimated models of the BOLD HRF
4.2 Biophysically-plausible Models of the BOLD HR
The standard convolution models and the BOLD HR estimations presented in the previous
section are blind to any physiological processes that result in the BOLD signal. They can only
reflect a simplification of a chain of physiological effects and complex mechanisms that extend
between the neuronal activation and the generated BOLD response. A more realistic approach
is to investigate the causal models of how BOLD responses are generated. These causal models
require deep and crystal-clear understanding of the different biophysical mechanisms that
translate the neuronal activation into a detected BOLD signal, as seen in Figure 4.
Following a neuronal activation, these physiological mechanisms can be briefly summa-
rized in the following points:
1. The demands of each activated neuron for the oxygen and glucose increase.
2. The cerebral metabolic rate of consumption of the glucose (CMRGL) and the oxygen
CMRO2 increase.
3. The extraction rate of glucose and the oxygen molecules from the blood stream increases.
4. The higher supply of glucose and oxygen causes the CBF to increase.
5. The increased CBF cause the venous vessels to dilate according to their visco-elastic
properties.
6. The CBF effect dominates over those of the CMRO2 and CBV, and consequently, blood
becomes more oxygenated.
13
7. The susceptibility is changed and the MR signal increases.
Figure 4: The underlying physiological processes that account for the generation of the BOLD
response. Image source: [Den06]
.
Each of the previous points requires a complex physiological model in order to be able to
formulate an accurate and complete biophysically-plausible model of the BOLD HR. During
the last decade, there have been sustained efforts to model each individual mechanism that
is suspected to contribute to this chain of effects. According to the classification proposed
by Buxton et al. [BUDL04] and Deneux and Faugeras [Den06], the biophysical models of the
BOLD response can be divided into the following categories:
1. Models for neural basis.
2. Models for energy consumption and metabolism.
3. Models for blood flow (CBF).
4. Models for vasculature dynamics (CBV).
14
5. Models for oxygen extraction.
6. BOLD signal models.
4.2.1 Models for Neural Basis
A neural basis model would be valuable to identify the main neuronal activity that affects
the BOLD response. Mathiesen et al. have discussed a sigmoid dependence of the CBF on
LFP [MCAL98]. Logothetis et al. have concluded that the BOLD response is proportional
to intra-cortical processing of a given brain area and not due to its spiking activity [Log02].
Kim et al. have shown a high correlation between the LFP and the amplitude of the BOLD
response measured in the same region [KRO∗ 04]. Friston et al. have presented the dynamic
causal modeling (DCM) that was considered the first step to present comprehensive forward
models that take into account parameters at the neuronal level to model the causal chain
starting from the external stimulus to the BOLD response [FHP03].
4.2.2 Models for Energy Consumption and Metabolism
Aubert and Costalat have presented a relatively sophisticated mathematical model that ac-
counts for the different mechanisms involved in the oxygen metabolism for a given neural
activity [AC02]. This model was used to simulate the BOLD responses for several patterns of
neuronal activities and different assumptions for the changes of the CMRO2 signal. Davis et
al. have presented another model that only accounts for the CMRO2 response using a step
function [DWK∗ 94]. Buxton et al. have proposed a more relaxed model by convolving the
neuronal activity with a gamma-variate function [BUDL04].
4.2.3 Models for Blood Flow (CBF)
Four neurovascular coupling models were discussed extensively in the literature [Blo07, Den06].
Based on an empirical approach, Miller et al. have considered a non-linear relation between
the CBF and the BOLD signal [MLL∗ 01]. Friston et al. have proposed a damped oscillator
model that relates the CBF to a flow-inducing signaling mechanism [Blo07]. Their model ac-
counts for the CBF in terms of the neuronal activity, blood flow value at resting state, neural
efficacy and auto-regulatory feedback time constant. Behzadi et al. have extended Friston’s
model to account for the changes in the muscular compliance of the cerebral arteriole [BL05].
15
The previous models provide a more realistic reflection of the blood flow that that pre-
sented by Buxton et al. that convolve the neuronal activity with a gamma-variate func-
tion [BWF98].
4.2.4 Models for Vasculature Dynamics (CBV)
Vasculature models have to account for the density of blood in a fixed volume, or the perfu-
sion (CBV). In general, the dynamics of CBV and CBF depend on each others according to the
visco-elastic properties of the vasculature. Grubb has proposed a very simplified model to link
the two variables relying on a power law V = F α . The Grubb’s constant α was estimated be-
tween 0.25 and 0.4 [Den06]. This model is only valid in steady state and thus, a dynamic model
is necessary to precisely reflect the vasculature response. Mainly, two reference dynamic mod-
els exist. The first one is the Balloon model presented by Buxton et al. [BWF98] and the other
one was proposed by Mandeville et al. and is called the Windkessel model [MMA∗ 99]. The Bal-
loon model has expressed the output flow as the sum of a linear component and a power law
to determine the volume dynamics. The Windkessel model has discussed an analogy between
the blood pressions and the CBF. Kong et al. have improved the Windkessel model to account
for the delayed compliance by modelling it using an additional state variable [KZJ∗ 04].
4.2.5 Models for Oxygen Extraction
Since deoxyHb molecules cause the paramagnetism responsible for the BOLD signal, there
should be some biophysical models for describing the oxygen extraction from the hemoglobin
molecules in the blood stream. Buxton and Frank have proposed a model of the dynamics of
oxygen delivery to the tissue within the context of the Balloon model [BF97, BWF98]. It was
called the Oxygen limitation model. This model has assumed no capillary recruitment, negligi-
ble arteriolar contribution to the volume, zero oxygen concentration in the tissue and finally
the presence of the all the deoxyhemoglobin in the venous vasculature. As a consequence of
the simplification of this model, due to the previous assumptions, the oxygen extraction rate
was found to depend only on the CBF. A more elaborated model was presented by Zheng et al.
called Oxygen tissue transport model [ZMJ∗ 02]. This model has discarded several assumptions
from Buxton’s model. It incorporated non-zero concentration of the oxygen into the tissue
and established a direct relation between tissue oxygenation and the metabolic demand.
16
4.2.6 BOLD Signal Models
The BOLD signal is generated due to the paramagnetic properties of deoxyHb. This affects the
T2∗ relaxation time of the MR signal as a consequence of the increased inhomogeneity of the
induced magnetic field. Ogawa et al. have presented a first model to this effect in [OMT∗ 93].
Afterwards, several studies have been developed to introduce improved models of this effect,
but the first attempt of proposing a precise model for the BOLD signal was taken by Davis
et al. [DKWR98, UDB05]. Their model have introduced the relationship between the BOLD
signal changes and the underlying physiological variables of the neurovascular coupling pro-
cess and few other parameters that characterize the local tissue. This simplified model was
based on several reasonable approximations and previous outcomes of different numerical
simulations [DKWR98]. Due to the simplicity of this model, it was proven to be a very sig-
nificant step towards the understanding of the BOLD effect in a quantitative manner. In that
regard, Buxton et al. have presented another simplified model of the MR signal acquisition
that links the solution of the Balloon model to an approximation of the measured BOLD
signal [BWF98]. This model computes the changes in the BOLD signal as a function of the
changes in the deoxyHb content in the blood and the blood volume. The formalism of this
model is discussed below.
The basic MR signal in Buxton’s model was represented with the following decaying ex-
ponential function in terms of the echo time TE
∗
S = S0 · e−TE· R2 (4)
where S0 is the effective spin density2 and R2∗ is the transverse relaxation rate constant.
This constant is expressed in terms of the T2∗ relaxation time by the following formula
1
R2∗ = = R0 + R (5)
T2∗
R2∗ can be also expressed by the sum of the two terms R0 and R which represent the
value of R2∗ if no deoxyHb is present and the additional relaxation produced by the deoxyHb
respectively.
Few years later, Buxton’s model was updated by Obata et al. to account for the difference in
2 Signal measured at TE = 0
17
the intra-vascular and extra-vascular signal contributions to the final BOLD signal [OLM∗ 04].
In this model, the signal measured from a single voxel at resting state S0 is approximated by
a volume weighted sum of the intra-vascular signal SI and the extra-vascular one SE (Equa-
tion 6). One of the critical assumptions of this model was the random and isotropic distribu-
tion of the blood vessels in the tissue. Based on this assumption, the intra-vascular signal has
neglected the effect of the arterial blood and it was only assumed to reflect a venous volume
fraction V0 merged with the contribution of the capillaries. The intra- and extra-vascular sig-
nals were represented by a decaying exponential function in terms of R2∗ of each component
(Equation 7).
S0 = (1 − V0 ) · SE + V0 · S I (6)
− TE· R2∗ − TE· R2∗

S0 = (1 − V0 ) · SE0 · e E + V0 · S I0 · e I (7)
The final BOLD signal that corresponds a neuronal activation was given by
− TE· R2∗ − TE· R2∗

S = (1 − V ) · S E · e E + V · SI · e I (8)
and the fractional signal changes is given by
δS 1 h
− TE· R2∗ − TE· R2∗
i
= (1 − V ) · e E + es · V · e I − (1 − V0 ) − es · V0 ) (9)
S0 1 − V0 + eS V0
where es = S I /SE represents the ratio of the blood to tissue signal, and the venous volume
fraction V0 was changed to V for generalization.
Assuming a first-order linear approximation, this model was simplified to
δS
≈ − TE · δR2∗E − eS V · TE · δR2∗I + (V0 − V )(1 − eS ) (10)
S0
where by δR2∗I and δR2∗E represent an increment in the R2∗ of both signal components.
The modelling of these two terms was based on the numerical simulations of Ogawa et
al. [OMT∗ 93].
18
4.3 Other BOLD HR Models
According to [WR14], there are many fMRI simulations that have not used any of the previous
models for representing the BOLD activation in the synthetic fMRI data. Some of them have
ignored the simulation of the BOLD activation component3 BAct (t) entirely and others have
selected a boxcar function Π(t) to reflect it.
5 fMRI Simulation Studies
5.1 Single Voxel fMRI Simulations
Boxerman et al. have presented an fMRI model to evaluate the intra- and extra-vascular
contributions of a single voxel to the fMRI signal at 1.5 Tesla using Monte Carlo simulation
for modelling the susceptibility-based contrast and physiological model for the neurovascular
coupling process [BBK∗ 95]. The results of their model have shown good agreements with the
experimental designs, and therefore they have confirmed that the intra-vascular components
have major contributions to the fMRI signal changes.
In 2008, Pathak et al. have developed a novel modelling technique called the Finite Perturber
Method (FPM) to model the different susceptibility-based contrast mechanisms for arbitrary
vasculature morphologies at the micro-scale [PWS08]. FPM has shown excellent agreement
with the theory and the extant susceptibility modelling data. Later the same year, Marques
and Bowtell have applied a three-dimensional finite element method to a realistic model of the
cortical vasculature to evaluate the reliability of the infinite cylinder model used previously in
the literature [MB08]. They have used the realistic model to highlight the relative importance
of intra- and extra-vascular contributions to the BOLD signal.
Martindale et al. have developed a generalization of the Monte Carlo models presented
by Boxernamn et al. [BBK∗ 95] that can accurately model the intra- and extra-vascular signals
for an arbitrary tissue with various imaging parameters [MKJ∗ 08]. This model was verified
against combined measurements of fMRI and optical imaging.
3 Refer to Equation (1)
19
5.2 Multi-Voxel fMRI Simulations
The majority of fMRI simulations were performed to compute the BOLD signal in a single
voxel and others have considered only a few number of voxels in their simulations. This
limited approach was taken due to the computational complexity of the algorithm needed or
the memory requirements to express the BOLD effect for a four-dimensional fMRI volume.
Such approach cannot be useful if a complete simulation of three-dimensional spatial distri-
bution of the BOLD signal is required. In 2012, Chen and Calhoun have proposed an overall
multi-voxel BOLD fMRI simulation model. This model was decomposed into two cascaded
stages. The first stages reflects the neurophysiology of the neurovascular coupling process. It
characterizes the neurovascular coupling mechanism in terms of susceptibility perturbations
for MR signal detection, i.e. it generates a series of snapshots of three-dimensional suscep-
tibility distributions. The susceptibility change is expressed in terms of the susceptibility
difference between the oxyHb and deoxyHb χdo , CBV, CBF, CMRO2 and the neuronal activa-
tion NA ( x, y, z, t) as seen in Equation (11). This stage is based on previous models presented
in the literature [AB02, AI02, Bux10, BF97, ZLHC08]. The other stage simulates the MRI tech-
nology that is used to image the susceptibility changes based on similar ideas for single voxel
BOLD simulations [CC10, CCC11]. The field map due to the susceptibility map computed in
the first stage can be computed by the convolution operation in Equation (12), where h( x, y, z)
is represented by a point dipole filed three-dimensional kernel. The final BOLD signal is
generated based on the volume integral in Equation (13) in terms of the filed distribution δB,
the gyromagnetic ratio γ, and the echo time of the sequence TE. The block diagram of this
computational model is illustrated in Figure 5.
δχ( x, y, z, t) = χdo · f (CBV, CMRO2 ) · CBV ( x, y, z, t) · NA ( x, y, z, t) (11)
δB( x, y, z, t) = conv(δχ( x, y, z, t), h( x, y, z)) (12)
Z Z Z
SBOLD ( xi , yi , zi ) = exp(i · γ · δB · TE)dxdydz (13)
20
Figure 5: The two-stage fMRI computational model of Chen and Calhoun. The neurophys-
iology model simulates the neurovascular coupling process and the fMRI technology model
simulates the acquisition of the BOLD fMRI signal.
21
5.3 Multi-resolution BOLD Models
Chen and Calhoun have presented a computational multi-resolution (four levels of resolution)
model for BOLD fMRI [CC11]. They were motivated to use this model in a numerical sim-
ulation in order to capture and understand several aspects of the BOLD signal formation at
different scales. This model has considered multiple spatial scales that range from the atomic
scale (10−6 m) and up to the millimeter scale (10−6 m) based on a spin packet model presented
in their previous study [CC10]. Their model has involved bulk nuclear spin precession in a
BOLD-induced inhomogeneous magnetic field with a millimeter-resolution voxel. The model
has considered the partitioning of the nuclear spin pool into spin packets at a macroscopic
scale and calculating the multi-resolution voxel signal by grouping the spin packets at a meso-
scopic scale (Figure 6). Based on this multi-resolution model, and assuming a small-angle
approximation, they have concluded that the BOLD signal intensity is related to its phase
counterpart by a two-resolution-level relationship.
5.4 fMRI artifacts Simulations
According to Drobnjak, early fMRI simulators have used naïve techniques to generate the
synthetic fMRI data [Dro07]. These techniques were based on using existing MRI data and
artificially integrate into this data an activation time-series to reflect the behaviour of the
activated brain regions in response to an external stimulus. The spatial distributions of the
assigned activations were pre-defined to certain voxels in the brain image. In some studies,
these voxels were determined relying on the results of previous experiments [EFS∗ 02] and in
others they were manually selected based on the region of interest [FM01, GSS∗ 02, LWS02,
WEM∗ 92]. The objective of these simulators was only dedicated to generate synthetic fMRI
data for static objects without considering any motion artifacts.
Drobnjak and his colleagues have presented an advanced computational model for the
fMRI acquisition process that takes into account different sources of artifacts in the fMRI sig-
nal. This model was used later in the development of an extensive software toolbox that can
simulate these artifacts including rigid-body motion, magnetic field inhomogeneities, chem-
ical shift and eddy currents [DGS∗ 06b, DGS∗ 06a]. Their simulator was dependent on three
main components: (1) a mathematical model of the BOLD activation, (2) a three-dimensional
22
FOV
Sproton
10
10 m Spin Pool
S✏
6
10 m Spin Packet
5 3 Sj=i
10 10 m
Multi-resolution
Voxel Tree
4 3
10 10 m Voxel
S0
3 1
10 10 m Image Array
Figure 6: A description of the multi-resolution computational BOLD fMRI model presented

by Chen and Calhoun.
geometric representation to model the brain and (3) a model to solve Bloch equations. Further
details on the development of the different models for the simulator, its numerical implemen-
tation and its validation procedures are present in [Dro07].
6 Simulation Software Applications

The main obstacle that have blocked the generalization and sharing the simulation results
of fMRI to the community was the absence of flexible software architectures that could be
used to unify and standardize the simulation procedures. Major contributions and research
studies have created their synthetic fMRI datasets mainly relying on their in-house fMRI
simulators that would not fit for other studies [MBM14, WR14]. Fortunately, during the last
four years, the introduction of several open software packages have reduced this gap and
23
met the demands of the community. This section highlights the features of two software
applications that are continuously developed and released to the community on a regular
basis.
6.1 fMRI Simulation Toolbox (SimTB)
Allen et al. have developed a flexible MATLAB-based fMRI simulation environment called
SimTB for generating synthetic fMRI datasets and verifying a huge variety of statistical an-
alytic methods [AEW∗ 11b, EOW∗ 12]. The underlying structure of this toolbox is based on
spatio-temporal separability assumptions of independent component analysis (ICA) such that
the resulting data can be expressed by the product of time courses and spatial maps. This
package is capable of systematically capturing the characteristics of realistic fMRI data. The
flexibility of this software package comes due to the full parametrization and user control-
lability of the data generation model employed to generate the synthetic datasets. SimTB is
designed to allow MATLAB beginners to easily design and execute different types of sim-
ulations. For this reason, it was provided with friendly graphical user interface (GUI) and
also comes with batch scripting support to automate and customize the simulation process.
Figure 7 illustrates a flowchart for the data generation model in SimTB. The software package
is freely downloadable at [AEW∗ 11a] and its documentation is available online at [AEW∗ 13] .
6.2 neuRosim
Welvaert et al. have developed an R-based software package for simulating fMRI data called
neuRosim [WDM∗ 11]. They aimed to provide an open tool for fMRI simulation that can spark
the researchers to focus their studies on further validated simulation methods for fMRI data
to generalize the results of the simulation studies. The application of neuRosim can be of
importance for two kinds of researchers. On one hand, it can be used to evaluate the perfor-
mance of fMRI designs for particular research question. On the other hand, it is a very useful
tool for theoretical modelling scientists and statisticians to validate existing and new fMRI
interpretation methods based on the analysis of the generated data.
Currently, there are three different response functions (Figure 8) that can be simulated in
neuRosim:
24
Figure 7: Data generation sequence of synthetic fMRI datasets in SimTB. Image courtesy of
Allen et al. [AEW∗ 11b]
1. A gamma-variate HRF based on the model presented by Buxton et al. [BUDL04]. This
function is implemented in the procedure gammaHRF.
2. A double-gamma HRF based on the model presented by Friston et al. [FFJ∗ 98]. This
function is implemented in the procedure canonicalHRF.
3. The Balloon model presented by Buxton et al. [BUDL04] is implemented in the balloon
procedure.
Moreover, neuRosim supports several various functions to model different types of noise
in fMRI signals.
1. Drift signals based due to system noise can be simulated with the lowfreqdrift func-
tion.
2. Physiological noise due to the cardiac and respiratory artifacts is implemented in the
physnoise function.
25
Figure 8: The simulated BOLD signals based on the three convolution functions imple-
mented in neuRosim for a 20-seconds ON/OFF block design. Image courtesy of Welvaert
et al. [WDM∗ 11]
3. Task-related noise due to the spontaneous neuronal activity is implemented in the tasknoise
function.
7 Conclusion
The modelling and simulation of fMRI is known to be an extremely challenging research
topic due to the complexity of the data and its underlying causal mechanisms. Realistic,
or biophysically-plausible, simulations of fMRI are subject to the development of sophisticated
models that can capture and reflect the potential signalling mechanisms that account for the
generated BOLD response. This review has summarized the different modelling work, nu-
merical simulation studies and software simulation packages of BOLD fMRI that have been
26
reported in the literature to date. The categories of the underlying models are highlighted in
Figure 9.
27
fMRI Data Generation Models for Simulations
Hybrid
Data Generation Models
Pure Synthetic
Data Generation Models
Baseline Models
Constant
Time Varying
Neural Basis Models
BOLD Activation Models

Energy Consumption and
Metabolism Models
Estimated HRF Models
Physiologically-Plausible Blood Flow (CBF) Models

Models
Vasculature Dynamics
(CBV) Models
Noise Models
Vasculature Geometric
Random Models
Experiment Oxygen Extraction Models

Specific
BOLD Signal Models
Figure 9: A block diagram summarizing the data generation models for fMRI simulations.
28
References
[AB02] Arthurs O. J., Boniface S.: How well do we understand the neural origins of
the fMRI BOLD signal? Trends in Neurosciences 25, 1 (2002), 27 – 31. URL: http:
//www.sciencedirect.com/science/article/pii/S0166223600019950, doi:
http://dx.doi.org/10.1016/S0166-2236(00)01995-0.
[ABH01] Ardekani B. A., Bachman A. H., Helpern J. A.: A quantitative comparison of

motion detection algorithms in fMRI. Magnetic resonance imaging 19, 7 (2001),
959–963.
[AC02] Aubert A., Costalat R.: A model of the coupling between brain electrical
activity, metabolism, and hemodynamics: Application to the interpretation of
functional neuroimaging. NeuroImage 17, 3 (2002), 1162 – 1181. URL: http:
//www.sciencedirect.com/science/article/pii/S1053811902912243, doi:
http://dx.doi.org/10.1006/nimg.2002.1224.
[AEW∗ 11a] Allen E. A., Erhardt E. B., Wei Y., Eichele T., Calhoun V. D.: SimTB
software repository, 2011. URL: http://mialab.mrn.org/software.
[AEW∗ 11b] Allen E. A., Erhardt E. B., Wei Y., Eichele T., Calhoun V. D.: A simulation
toolbox for fMRI data: SimTB . Tech. rep., The Mind Research Network, Albu-
querque, New Mexico, USA and University of New Mexico, Albuquerque,
New Mexico, USA and University of Bergen, Bergen, Norway, East Lansing,
Michigan, June 2011. 96 pages. URL: http://mialab.mrn.org.
[AEW∗ 13] Allen E. A., Erhardt E. B., Wei Y., Eichele T., Calhoun V. D.: SimTB
online documentation, 2013. URL: http://mialab.mrn.org/software/simtb/
docs/htmldoc/index.html.
[AI02] Attwell D., Iadecola C.: The neural basis of functional brain imaging sig-
nals. Trends in neurosciences 25, 12 (2002), 621–625.
[Ashss] Ashby F. G.: An introduction to fMRI. An introduction to Model-based Cognitive

Neuroscience (in press). URL: https://labs.psych.ucsb.edu/ashby/gregory/
{fMRI}_SS.pdf.
[Ban12] Bandettini P. A.: Twenty years of functional MRI: The science and the sto-
ries. NeuroImage 62, 2 (2012), 575 – 588. URL: http://www.sciencedirect.
com/science/article/pii/S1053811912004223, doi:http://dx.doi.org/10.
1016/j.neuroimage.2012.04.026.
[BBK∗ 95] Boxerman J. L., Bandettini P. A., Kwong K. K., Baker J. R., Davis T. L.,
Rosen B. R., Weisskoff R. M.: The intravascular contribution to fMRI signal
change: monte carlo modeling and diffusion-weighted studies in vivo. Mag-
netic resonance in medicine 34, 1 (1995), 4–10.
[BBS∗ 96] Backfrieder W., Baumgartner R., Samal M., Moser E., Bergmann H.:
Quantification of intensity variations in functional MR images using rotated
principal components. Physics in Medicine and Biology 41, 8 (1996), 1425.
29
[BEGH96] Boynton G. M., Engel S. A., Glover G. H., Heeger D. J.: Linear systems
analysis of functional magnetic resonance imaging in human v1. The journal of
neuroscience 16, 13 (1996), 4207–4221.
[BF97] Buxton R. B., Frank L. R.: A model for the coupling between cerebral blood
flow and oxygen metabolism during neural stimulation. J Cereb Blood Flow
Metab 17, 1 (Jan. 1997), 64–72. URL: http://view.ncbi.nlm.nih.gov/pubmed/
8978388.
[BL05] Behzadi Y., Liu T. T.: An arteriolar compliance model of the cerebral blood
flow response to neural stimulus. Neuroimage 25, 4 (2005), 1100–1111.
[Blo07] Blockley N. P.: Investigating the BOLD haemodynamic response. PhD thesis,
University of Nottingham, 2007. URL: http://eprints.nottingham.ac.uk/
10473/.
[BPE09] Bellec P., Perlbarg V., Evans A. C.: Bootstrap generation and evaluation of
an fMRI simulation database. Magnetic resonance imaging 27, 10 (2009), 1382–
1396.
[BUDL04] Buxton R. B., Uludağ K., Dubowitz D. J., Liu T. T.: Modeling the hemody-
namic response to brain activation. NeuroImage 23, Supplement 1, 0 (2004), S220
– S233. Mathematics in Brain Imaging. URL: http://www.sciencedirect.
com/science/article/pii/S1053811904003787, doi:http://dx.doi.org/10.
1016/j.neuroimage.2004.07.013.
[Bux02] Buxton R.: Introduction to Functional Magnetic Resonance Imaging: Principles and
Techniques. Cambridge University Press, 2002. URL: http://books.google.
ch/books?id=pi3ogRUXxgYC.
[Bux10] Buxton R. B.: Interpreting oxygenation-based neuroimaging signals: the im-

portance and the challenge of understanding brain oxygen metabolism. Fron-
tiers in neuroenergetics 2 (2010).
[BWF98] Buxton R. B., Wong E. C., Frank L. R.: Dynamics of blood flow and oxygena-
tion changes during brain activation: the balloon model. Magnetic resonance
in medicine 39, 6 (June 1998), 855–864. URL: http://view.ncbi.nlm.nih.gov/
pubmed/9621908.
[CC10] Chen Z., Calhoun V. D.: Magnitude and phase behavior of multiresolution
BOLD signal. Concepts in Magnetic Resonance Part B: Magnetic Resonance En-
gineering 37B, 3 (2010), 129–145. URL: http://dx.doi.org/10.1002/cmr.b.
20164, doi:10.1002/cmr.b.20164.
[CC11] Chen Z., Calhoun V.: A computational multiresolution BOLD fMRI model.
Biomedical Engineering, IEEE Transactions on 58, 10 (Oct 2011), 2995–2999.
[CC12] Chen Z., Calhoun V.: Volumetric BOLD fMRI simulation: from neurovascu-
lar coupling to multivoxel imaging. BMC medical imaging 12, 1 (2012), 8.
30
[CCC11] Chen Z., Chen Z., Calhoun V.: Multiresolution voxel decomposition of
complex-valued BOLD signals reveals phasor turbulence. Proc. SPIE 7961
(2011), 79613Y–79613Y–11. URL: http://dx.doi.org/10.1117/12.877295,
doi:10.1117/12.877295.
[Coh97] Cohen M. S.: Parametric analysis of fMRI data using linear systems methods.
Neuroimage 6, 2 (1997), 93–103.
[Den06] Deneux T.: Hemodynamic Models: Investigation and Application to Brain Imag-
ing Analysis. Theses, Ecole Polytechnique X, May 2006. URL: https://tel.
archives-ouvertes.fr/tel-00457464.
[DGS∗ 06a] Drobnjak I., Gavaghan D., Suli E., Francis P. J., Jenkinson M.: Develop-
ment of a FMRI simulator for modelling realistic rigid-body motion artifacts.
Magnetic Resonance in Medicine 56, 2 (2006), 364–380.
[DGS∗ 06b] Drobnjak I., Gavaghan D., Suli E., Pitt-Francis J., Jenkinson M.: Develop-
ment of a functional magnetic resonance imaging simulator for modeling re-
alistic rigid-body motion artifacts. Magnetic Resonance in Medicine 56, 2 (2006),
364–380.
[DGS∗ 08] David O., Guillemain I., Saillet S., Reyt S., Deransart C., Segebarth C.,
Depaulis A.: Identifying neural drivers with functional MRI: an electrophys-
iological validation. PLoS biology 6, 12 (2008), e315.
[DKWR98] Davis T. L., Kwong K. K., Weisskoff R. M., Rosen B. R.: Calibrated func-
tional MRI: Mapping the dynamics of oxidative metabolism. Proceedings of the
National Academy of Sciences 95, 4 (1998), 1834–1839.
[DMCPNM02] Della-Maggiore V., Chau W., Peres-Neto P. R., McIntosh A. R.: An em-
pirical comparison of spm preprocessing parameters to the analysis of fMRI
data. Neuroimage 17, 1 (2002), 19–28.
[Dro07] Drobnjak I.: FMRI Simulator: Development and Applications. PhD the-
sis, University of Oxford, 2007. URL: http://etd.lib.metu.edu.tr/upload/
12611465/index.pdf.
[Duy05] Duyn J. J. H.: Basic principles of fMRI. Alzheimer’s & Dementia 1, 1 (2005).
Alzheimer’s Association International Conference on Prevention of Demen-
tia: Early Diagnosis and Intervention. URL: http://www.sciencedirect.
com/science/article/pii/S155252600500378X, doi:http://dx.doi.org/10.
1016/j.jalz.2005.06.377.
[DWK∗ 94] Davis T., Weisskoff R., Kwong K., Boxerman J., Rosen B.: Temporal aspects
of fMRI task activation: dynamic modeling of oxygen delivery.
[EFS∗ 02] Esposito F., Formisano E., Seifritz E., Goebel R., Morrone R., Tedeschi G.,
Di Salle F.: Spatial independent component analysis of functional MRI time-
series: To what extent do results depend on the algorithm used? Human Brain
Mapping 16, 3 (2002), 146–157. URL: http://dx.doi.org/10.1002/hbm.10034,
doi:10.1002/hbm.10034.
31
[EOW∗ 12] Erhardt E., Object, Wei Y., Object, Calhoun V.: SimTB, a simulation tool-
box for fMRI data under a model of spatiotemporal separability. Neuroim-
age 59, 4 (2012), 4160–4167. URL: http://www.sciencedirect.com/science/
article/pii/S105381191101370X.
[FFJ∗ 98] Friston K. J., Fletcher P., Josephs O., Holmes A., Rugg M., Turner R.:
Event-related fMRI: characterizing differential responses. Neuroimage 7, 1
(1998), 30–40.
[FHP03] Friston K. J., Harrison L., Penny W.: Dynamic causal modelling. Neuroimage
19, 4 (2003), 1273–1302.
[FHW∗ 94] Friston K. J., Holmes A. P., Worsley K. J., Poline J.-P., Frith C. D., Frack-
owiak R. S. J.: Statistical parametric maps in functional imaging: A gen-
eral linear approach. Human Brain Mapping 2, 4 (1994), 189–210. URL:
http://dx.doi.org/10.1002/hbm.460020402, doi:10.1002/hbm.460020402.
[FM01] Freire L., Mangin J.-F.: Motion correction algorithms of the brain mapping
community create spurious functional activations. In Information Processing
in Medical Imaging, Insana M., Leahy R., (Eds.), vol. 2082 of Lecture Notes in
Computer Science. Springer Berlin Heidelberg, 2001, pp. 246–258. URL: http:
//dx.doi.org/10.1007/3-540-45729-1_27, doi:10.1007/3-540-45729-1_27.
[FM10] Faro S., Mohamed F.: BOLD fMRI: A Guide to Functional Imaging for Neurosci-
entists. Springer New York, 2010. URL: http://books.google.ch/books?id=
lYb8jwEACAAJ.
[Glo99] Glover G.: 3d z-shim method for reduction of susceptibility effects

in BOLD fMRI. Magnetic Resonance in Medicine 42, 2 (1999), 290–299.
cited By 102. URL: http://www.scopus.com/inward/record.url?eid=2-s2.
0-0032868199&partnerID=40&md5=e3a96cd004b90b4ccc6c43f55f91e558.
[Gor03] Gore J. C.: Principles and practice of functional MRI of the human brain.
Journal of Clinical Investigation 112, 1 (2003), 4.
[GSS∗ 02] Gavrilescu M., Shaw M. E., Stuart G. W., Eckersley P., Svalbe I. D.,
Egan G. F.: Simulation of the effects of global normalization procedures
in functional MRI. NeuroImage 17, 2 (2002), 532–542. URL: http://www.
sciencedirect.com/science/article/pii/S1053811902912267, doi:http://
dx.doi.org/10.1006/nimg.2002.1226.
[HB99] Howseman A. M., Bowtel R. W.: Functional magnetic resonance imaging:

imaging techniques and contrast mechanisms. Philosophical Transactions of the
Royal Society of London B: Biological Sciences 354, 1387 (1999), 1179–1194. doi:
10.1098/rstb.1999.0473.
[HGCDB12] Handwerker D. A., Gonzalez-Castillo J., D’Esposito M., Bandettini P. A.:

The continuing challenge of understanding and modeling hemodynamic vari-
ation in fMRI. Neuroimage 62, 2 (2012), 1017–1023.
32
[HSM09] Huettel S., Song A., McCarthy G.: Functional Magnetic Resonance Imaging.
Freeman, 2009. URL: http://books.google.ch/books?id=BNhMPgAACAAJ.
[Jez99] Jezzard P.: Basic physics of fMRI, 1999. URL: http://users.fmrib.ox.ac.

uk/~peterj/lectures/hbm_1/index.htm.
[KRO∗ 04] Kim D.-S., Ronen I., Olman C., Kim S.-G., Ugurbil K., Toth L. J.: Spatial
relationship between neuronal activity and bold functional mri. Neuroimage
21, 3 (2004), 876–885.
[KYB08] Kim B., Yeo D. T., Bhagalia R.: Comprehensive mathematical simulation of
functional magnetic resonance imaging time series including motion-related
image distortion and spin saturation effect. Magnetic resonance imaging 26, 2
(2008), 147–159.
[KZJ∗ 04] Kong Y., Zheng Y., Johnston D., Martindale J., Jones M., Billings S., May-
hew J.: A model of the dynamic relationship between blood flow and volume
changes during brain activation. Journal of Cerebral Blood Flow & Metabolism 24,
12 (2004), 1382–1392.
[Log02] Logothetis N. K.: The neural basis of the blood–oxygen–level–dependent

functional magnetic resonance imaging signal. Philosophical Transactions of the
Royal Society of London B: Biological Sciences 357, 1424 (2002), 1003–1037. doi:
10.1098/rstb.2002.1114.
[Log08] Logothetis N. K.: What we can do and what we cannot do with fMRI.
Nature 453, 1 (2008). URL: http://www.nature.com/nature/journal/v453/
n7197/suppinfo/nature06976_S1.html, doi:http://dx.doi.org/10.1016/j.
jalz.2005.06.377.
[LWS02] Lukic A. S., Wernick M. N., Strother S. C.: An evaluation of methods

for detecting brain activations from functional neuroimages. Artificial Intelli-
gence in Medicine 25, 1 (2002), 69–88. Exploratory Data Analysis in Functional
Neuroimaging. URL: http://www.sciencedirect.com/science/article/
pii/S093336570200009X, doi:http://dx.doi.org/10.1016/S0933-3657(02)
00009-X.
[MB08] Marques J. P., Bowtell R. W.: Using forward calculations of the magnetic
field perturbation due to a realistic vascular model to explore the BOLD effect.
NMR in Biomedicine 21, 6 (2008), 553–565. URL: http://dx.doi.org/10.1002/
nbm.1224, doi:10.1002/nbm.1224.
[MBM14] Mikl M., Bartoň M., Mareček R.: Simulations of fMRI data with us-
age of estimated physiological artifacts. Clinical Neurophysiology 125, 5
(2014), e34 – e35. URL: http://www.sciencedirect.com/science/article/
pii/S1388245713013059, doi:http://dx.doi.org/10.1016/j.clinph.2013.
12.069.
33
[MCAL98] Mathiesen C., Caesar K., Akgören N., Lauritzen M.: Modification of
activity-dependent increases of cerebral blood flow by excitatory synaptic ac-
tivity and spikes in rat cerebellar cortex. The Journal of physiology 512, 2 (1998),
555–566.
[MFPK07] Moon C.-H., Fukuda M., Park S.-H., Kim S.-G.: Neural interpre-
tation of blood oxygenation level-dependent fMRI maps at submillime-
ter columnar resolution. Journal of Neuroscience 27, 26 (2007), 6892–6902.
cited By 41. URL: http://www.scopus.com/inward/record.url?eid=2-s2.
0-34347334618&partnerID=40&md5=46540dbe61d195aa80639f45f6d7601d.
[MKJ∗ 08] Martindale J., Kennerley A. J., Johnston D., Zheng Y., Mayhew J. E.: The-
ory and generalization of Monte Carlo models of the BOLD signal source.
Magnetic resonance in medicine 59, 3 (Mar. 2008), 607–618. URL: http://view.
ncbi.nlm.nih.gov/pubmed/18224696.
[MLL∗ 01] Miller K. L., Luh W.-M., Liu T. T., Martinez A., Obata T., Wong E. C.,
Frank L. R., Buxton R. B.: Nonlinear temporal dynamics of the cerebral
blood flow response. Human brain mapping 13, 1 (2001), 1–12.
[MMA∗ 99] Mandeville J. B., Marota J. J., Ayata C., Zaharchuk G., Moskowitz M. A.,
Rosen B. R., Weisskoff R. M.: Evidence of a cerebrovascular postarteri-
ole windkessel with delayed compliance. Journal of Cerebral Blood Flow &
Metabolism 19, 6 (1999), 679–689.
[MP04] Marchini J., Presanis A.: Comparing methods of analyzing fMRI statistical
parametric maps. Neuroimage 22, 3 (2004), 1203–1213.
[OLM∗ 04] Obata T., Liu T. T., Miller K. L., Luh W.-M., Wong E. C., Frank L. R., Buxton
R. B.: Discrepancies between BOLD and flow dynamics in primary and sup-
plementary motor areas: application of the balloon model to the interpretation
of {BOLD} transients. NeuroImage 21, 1 (2004), 144 – 153. URL: http://www.
dx.doi.org/10.1016/j.neuroimage.2003.08.040.
[OMT∗ 93] Ogawa S., Menon R., Tank D., Kim S., Merkle H., Ellermann J., Ugurbil
K.: Functional brain mapping by blood oxygenation level-dependent contrast
magnetic resonance imaging. a comparison of signal characteristics with a bio-
physical model. Biophysical Journal 64, 3 (1993), 803 – 812. URL: http://www.
dx.doi.org/10.1016/S0006-3495(93)81441-3.
[PLMD05] Pickens D. R., Li Y., Morgan V. L., Dawant B. M.: Development of computer-
generated phantoms for fMRI software evaluation. Magnetic resonance imaging
23, 5 (2005), 653–663.
[PWS08] Pathak A. P., Ward B. D., Schmainda K. M.: A novel technique for modeling
susceptibility-based contrast mechanisms for arbitrary microvascular geome-
tries: the finite perturber method. Neuroimage 40, 3 (2008), 1130–1143.
34
[UDB05] Uludag K., Dubowitz D. J., Buxton R. B.: Basic principles of functional MRI,
2005.
[VN98] Vazquez A. L., Noll D. C.: Nonlinear aspects of the BOLD response in
functional MRI. Neuroimage 7, 2 (1998), 108–118.
[WDM∗ 11] Welvaert M., Durnez J., Moerkerke B., Berdoolaege G., Rosseel Y.: neu-
rosim: An R package for generating fMRI data. Journal of Statistical Software
44, 10 (10 2011), 1–18. URL: http://www.jstatsoft.org/v44/i10.
[WEM∗ 92] Worsley K. J., Evans A. C., Marrett S., Neelin P., et al.: A three-
dimensional statistical analysis for cbf activation studies in human brain.
[WR14] Welvaert M., Rosseel Y.: A review of fMRI simulation studies. PLoS ONE
9, 7 (07 2014), e101953. URL: http://dx.doi.org/10.1371%2Fjournal.pone.
0101953, doi:10.1371/journal.pone.0101953.
[XWR∗ 07] Xu Y., Wu G., Rowe D. B., Ma Y., Zhang R., Xu G., Li S.-J.: Complex-model-
based estimation of thermal noise for fMRI data in the presence of artifacts.
Magnetic resonance imaging 25, 7 (2007), 1079–1088.
[ZLHC08] Zhang N., Liu Z., He B., Chen W.: Noninvasive study of neurovascular
coupling during graded neuronal suppression. Journal of Cerebral Blood Flow &
Metabolism 28, 2 (2008), 280–290.
[ZMJ∗ 02] Zheng Y., Martindale J., Johnston D., Jones M., Berwick J., Mayhew J.: A
model of the hemodynamic response and oxygen delivery to brain. Neuroimage
16, 3 (2002), 617–637.
35
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Computational Models and Simulators of functional MRI

Technical Report · February 2015

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A literature review report submitted to

Advanced Biomedical Imaging Methods and Instrumentation

2 The Biophysical Basis of BOLD fMRI 7

3 Data Generation Models for BOLD fMRI 8

4 BOLD Activation Models 11

5 fMRI Simulation Studies 19

6 Simulation Software Applications 23

CBF Cerebral Blood Flow

CBM Cerebral Blood Magnetism

CBV Cerebral Blood Volume

CMRGL Cerebral Metabolic Rate of Glucose

CMRO2 Cerebral Metabolic Rate of Oxygen

DCM Dynamic Causal Modelling

deoxyHb Deoxygenated Hemoglobin

FPM Finite Perturber Method

fMRI functional Magnetic Resonance Imaging

GLM General Linear Model

GRE Gradient-recalled Echo

GUI Graphical User Interface

HRF Hemodynamic Response Function

ICA Independent Component Analysis

iEEG intra-cranial Electroencephalography

LFP Local Field Potential

MRI Magnetic Resonance Imaging

oxyHb Oxygenated Hemoglobin

pixel Picture Element

voxel Volume Element

1.1 fMRI Modeling and Simulation

1.2 Report Objectives

2 The Biophysical Basis of BOLD fMRI

3 Data Generation Models for BOLD fMRI

BSim (t) = b(t) + BAct (t) + n(t) (1)

CBF CBV CMRO2

Magnetic Filed Changes

Single Voxel BOLD Response

3.1 Baseline Models

3.2 BOLD Activation Models

3.3 Noise Models

4 BOLD Activation Models

Bi (t) = f TF [ Ni (t)] (2)

4.1 Models for the Estimated HRF

Figure 3: Estimated models of the BOLD HRF

4.2 Biophysically-plausible Models of the BOLD HR

7. The susceptibility is changed and the MR signal increases.

1. Models for neural basis.

2. Models for energy consumption and metabolism.

3. Models for blood flow (CBF).

4. Models for vasculature dynamics (CBV).

5. Models for oxygen extraction.

6. BOLD signal models.

4.2.1 Models for Neural Basis

4.2.2 Models for Energy Consumption and Metabolism