Magnetic Resonance in Medicine 000:000000 (2011)

Mechanisms of Proton Spin Dephasing in a System of

Magnetic Particles
Hendrick W. de Haan*
For protons diffusing among a system of magnetic particles,
the process by which initial phase coherence is lost depends
substantially on particle size. In this article, evidence for three
dephasing mechanisms is presented: an incremental process
at small particle sizes (motional averaging regime), a discrete
process at intermediate particle sizes (visit limited regime), and
a continuous process at large particle sizes (static dephasing
regime). While motional averaging regime and static dephas-
ing regime are well known, the distinct dynamics in visit limited
regime are often overlooked. Revisiting earlier analytic treat-
ments for the dynamics in this regime, Monte Carlo simulations
are performed to extract the details of dephasing and to test
the concept of an inner zone of rapid dephasing herein named
the full dephasing zone. It is shown that the emergence of a
full dephasing zone marks the transition from motional aver-
aging regime to visit limited regime since protons can be fully
dephased in a single encounter. Moving from the visit limited
regime to the static dephasing regime, a crossover between a
purely discrete process anda purely continuous process occurs.
Developing a simple model of the dephasing process, the aver-
age dephasing time is demonstrated to be relatively constant
thus giving insight into the long lasting plateau in the relaxation
rate. Magn Reson Med 000:000000, 2011. 2011 Wiley-Liss,
Inc.
Key words: dephasing mechanisms; MRI constrast agent; mag-
netic particles; superparamagnetic nanoparticles; T
2
shorten-
ing; relaxivity
INTRODUCTION
Given their efcacy as contrast agents, the use of magnetic
particles in MRI measurements is increasing in prevalence
(15). Further, more elaborate applications such as selec-
tive binding show great promise for the rapid detection of
specic tissues (6,7). To achieve optimal contrast, a clear
picture of the dynamics leading to the loss of phase cor-
relation among the proton spins is benecial to aid in the
design of the particles.
In the absence of a refocusing pulse, the rate of dephas-
ing can be roughly broken into two regimes: the motional
averaging regime (MAR) in which proton diffusion is the
dominant factor and the static dephasing regime (SDR) in
which the relaxation rate is independent of diffusion. At
Department of Physics, University of Ottawa, 150 Louis Pasteur, Ottawa,
Ontario, Canada
*Correspondence to: Hendrick W. de Haan, Ph.D., Department of Physics,
University of Ottawa, 150 Louis Pasteur, Ottawa, Ontario, Canada, K1N 6N5;
E-mail: hendrick.dehaan@gmail.com
Received 3 December 2010; revised 14 March 2011; accepted 22 March 2011.
DOI 10.1002/mrm.22966
Published online in Wiley Online Library (wileyonlinelibrary.com).
large particle sizes inSDR, the lack of diffusiondependence
has a clear interpretation: the distance traveled by diffusion
is negligible compared with the interparticle distance.
However, this diffusion independence is maintained down
to relatively small particle sizes where the distance trav-
eled by diffusion is greater than the interparticle distance.
The mechanism yielding rapid dephasing is not as obvious
at these particle sizes.
The dynamics at these intermediate sizes were examined
in 2002 by Brooks, who divided space around the parti-
cles into inner zones of rapid dephasing and outer zones of
relative tranquility. (8) From this picture, protons that
reach the inner zone are rapidly dephased while those
outside dephase only minimal amounts. Building from a
chemical exchange model, a prediction of the resulting
relaxation rate was found to be in good agreement with sim-
ulation results. This concept of an inner zone was also used
in a concurrently published manuscript with additional
authors where protons in the inner zone were considered
fully dephased before the application of a refocusing pulse
and hence lost from the signal (9). This picture of an inner
zone gave context to the features of the decay signal and
provided more accurate predictions for the relaxation rates.
In this article, the concept of an inner in which pro-
tons are rapidly dephased (herein referred to as the full
dephasing zone) is revisited to demonstrate the presence
of a distinct dephasing mechanism between the motional
averaging mechanismand the static dephasing mechanism.
Given the thorough analytic treatment contained in previ-
ous studies (8,9), the focus here is to examine the dynamics
of dephasing via simulations and thus present a physical
picture of the dephasing process for a wide range of particle
sizes.
First, results from simulations in which the full dephas-
ing zone is excluded are presented to directly test the
importance of an inner zone of rapid dephasing. As these
simulations provide an assessment of the impact of an
exclusion layer across a wide range of particle sizes, the
data unites previous results obtained at very small par-
ticles and very large particles and conrms an analytic
prediction for the overall trend. Second, the details of the
phase trajectories are examined to conrm the existence
of three distinct dephasing mechanisms: incremental, dis-
crete, and continuous. From this picture and the concept
of a full dephasing zone, a simple model for the dephasing
process is developed. Analyzing the trajectories according
to this model then allows for a mapping of the transi-
tion from a nearly purely discrete mechanism just above
MAR to a nearly purely continuous process at large parti-
cle sizes. The smooth cross-over between mechanisms that
is observed yields a high, nearly constant, relaxation rate
2011 Wiley-Liss, Inc. 1
2 de Haan
at any particle size and thus results in a long plateau in the
relaxation rate. Hence, although there are three underlying
dephasing mechanisms, the smooth cross-over between the
purely discrete and purely continuous mechanisms results
in only two dephasing rate regimes.
THEORY
Dephasing by Magnetic Particles
By introducing local inhomogenities into an otherwise uni-
form magnetic eld, magnetic nanoparticles can greatly
enhance the relaxation rate. Modeling the particles as
dipoles of radius R, the z component of the magnetic eld is
B =

0
M
3
_
R
r
_
3
(3 cos
2
() 1) [1]
where
0
is the permeability of free space (410
7
H/m),
M is the magnetization of the particle, r is the distance
from the particle center, and is the angle with respect to
the z direction. The corresponding phase shift for a proton
experiencing a net magnetic eld B from the particles for a
time t is given by
= Bt [2]
where is the gyromagnetic ratio (2.67 10
8
for water
protons). Protons near the particle will thus experience
rapid dephasing yielding a high relaxation rate R
*
2
. By
this mechanism, magnetic particles act as effective contrast
agents.
For the form of the magnetic eld given by Eq. 1, a 2D
plot of the eld is shown in Fig. 1. Interestingly, although
the eld was calculated for a particle of radius R = 50nm,
it scales for a particle of any size when the volume frac-
tion f of the system is kept xed (f = Nv/V with N being
the number of particles, v the volume per particle, and V
the total volume of the system). Although the simulations
will be conducted on a disordered system, a characteristic
separation between particles l can be dened by
l =
_
V
N
_
1/3
=
_
v
f
_
1/3
[3]
=
_
4
3

f
_
1/3
R. [4]
Since l R, the ratio of the particle size to the characteristic
separation between particles is a xed value for constant
f . Similarly, for the magnetic eld, B(r) (R/r)
3
. Thus,
on rescaling the system by the particle size, the magnetic
eld at a given position is independent of particle size; e.g.,
neither B(r = R) or B(r = l) are dependent on R.
Relaxation Rate Regimes
Three relaxation rate regimes are typically discussed: SDR,
MAR, and the slow motion regime (SMR) which arises
on application of a refocusing pulse (e.g., (913)). In this
manuscript, relaxation is simulated in the absence of a
refocusing pulse and hence MAR and SDR are focused on.
However, SMR is introduced for completeness. The stan-
dard picture of these regimes is presented following the
introduction of the static limit.
FIG. 1. z-component of the magnetic eld generated by a single
nanoparticle calculated for the average volume occupied by a sin-
gle nanoparticle at a volume fraction of f = 3.14 10
6
. The center
white dot is the nanoparticle to scale. The three zones of eld inten-
sity indicate the rapid decrease in the eld with distance from the
particle. In the inner-most region (dark blue for positive regions, red
for negative), the eld magnitude is greater than 1%of the maximum.
In the second region (navy blue-dark orange), the eld magnitude is
greater than 0.01% of the maximum. In the outer-most region (light
blue-light orange), the eld magnitude is greater than 0.0001% of
the maximum. Field values less than 0.0001% of the maximum are
black. For all regions, a brighter luminosity indicates a stronger eld
magnitude.
Static Limit
As the simplest starting point, consider the protons as xed
in place such that the magnetic eld felt by each pro-
ton is independent of time. An analytic solution for the
dephasing rate is then possible and is given by (14,15):
R
*
2
= 1.21f
0
[5]
where the star indicates the absence of a refocusing pulse
and the subscript 2 indicates it is the relaxation rate corre-
sponding to the T
*
2
relaxation time. Here,
0
is the Larmor
shift at the equator on the surface of the particle

0
=

0
M
3
[6]
where M is the magnetization of the nanoparticle. In this
study, the parameters are chosen as M = 2.58 10
5
T/m
3
and f = 3.14 10
6
to yield a static limit of R
*
2
= 109s
1
and a relaxation time of
SL
= 0.009s. Note that these val-
ues are chosen for M and f as being experimentally relevant
values and are very similar to values used in previous stud-
ies (e.g. (10)). As the protons are exactly conned, the static
limit is considered an absolute upper limit on the R
*
2
value.
Mechanisms of Proton Spin Dephasing in a System of Magnetic Particles 3
FIG. 2. Sketch of the dephasing regimes. The upper labels present
the standard delineation of regimes. For the bottom labels, labeling
based on the mechanism explored in this manuscript is given. Note
that the SMR sketches shown in light grey correspond to R
2
where
the absence of the * superscript indicates the presence of a refocus-
ing pulse. While the trends are consistent for any set of parameters,
the numbers provided here correspond to the values used in this
study: f = 3.14 10
6
and M = 2.588 10
5
T/m
3
.
Static Dephasing Regime
For the upper end of the SDR, consider the protons not as
xed in place, but diffusing minimal distances. The charac-
teristic distance traveled by diffusion in the
SL
relaxation
time is given by:
R
D
=
_
6D
SL
[7]
where D is the diffusion coefcient taken to be 2.5
10
9
m
2
/s corresponding to bulk water. Using
SL
as the
time interval ensures a conservative estimate for R
D
as
this time represents the fastest possible relaxation time.
If the particles are large enough that diffusion of protons
is small compared to the interparticle distance R
D
/l 1,
then the majority of the protons each experience a single
magnetic environment. Consequently, the relaxation rate
is unaffected by the diffusion of the protons and the rate
remains at (or near to) the value given by the static limit.
In practice, the SDR is taken to extend to small parti-
cle sizes since R
*
2
remains near the static limit over a wide
range yielding a relatively constant relaxation rate that is
independent of the value of the diffusion coefcient. It
is thus tempting to regard the dephasing mechanism at
the lower end of the SDR to be the same as that of the
upper end corresponding to the static limitparticularly
given the description static dephasing in the name. How-
ever, although the relaxation rate is relatively constant, the
dephasing mechanisms vary signicantly from the lower
end of the SDR to the upper. One of primary goals of
this manuscript is to gain insight into the long plateau
observed in the relaxation rate despite changes in the
underlying dephasing mechanisms. The range of the SDR
and corresponding high R
*
2
values are shown in Fig. 2.
Slow Motion Regime
The SMR (or echo limited regime) occupies a portion of
the SDR when a refocusing pulse is applied to the sample.
For a refocusing pulse, a second RF is applied at 180

to
the original pulse at a time
CP
after the initial time. Being
antiparallel to the initial pulse, the refocusing pulse inverts
the phases of the protons and subsequent dephasing will
then refocus the protons back toward being in phase. Hence
while there is a rapid decay between t = 0 and t =
CP
,
the signal after
CP
increases and culminates in a peak or
echo of the original signal at T
E
= 2
CP
. Fitting the decay
over these peaks yields a decay much slower than the decay
between peaks and the resulting R
2
is signicantly lower
than the static limit.
The strength of the echo depends on the degree of refo-
cusing: the more the protons are localized to a consistent
magnetic eld, the more effective the refocusing. Hence,
shorter pulse intervals yield lower R
2
rates than longer
pulses. Likewise, at any given
CP
, the refocusing is more
effective at large particles than at small particles where
the proton diffuses to a new magnetic environment more
easily. These facets have been explored in previous stud-
ies (e.g., (9,10,13)). While this study does not explore the
SMR regime, an introduction of the physical process of
refocusing is useful for further discussions.
Motional Averaging Regime
At the opposite extreme, the MARoccurs for small particles
where the distance traveled by diffusion is large compared
with l: R
D
/l 1. In Fig. 3, a comparison between this
regime (a) and the SDR (d) is shown. For small particles,
the inter-particle distance is much less than the distance
the proton is able to diffuse in the T
*
2
relaxation time. If
we consider a proton initially in a relatively large positive
B region, it will experience an initial positive dephasing.
However, as the rate of diffusion is large compared with l,
the proton will quickly leave its initial location and enter
a different magnetic environment. If B is negative in the
new location, the subsequent phase changes will partially
undo the previous dephasing. Analogous to the spin echo
refocusing of the SMR, the net effect is a diffusion induced
refocusing which yields R
*
2
values greatly diminished from
the static limit. This rate can be calculated to be (16):
R
*
2
=
16
45
f
2
0

D
[8]
where
D
is a characteristic diffusion time given by the ratio
of the particle size to diffusion coefcient of water:

D
= R
2
/D. [9]
From this estimation,
D
represents the approximate time
for a proton to diffuse a distance on the order of the
diameter of the particle.
THE VISIT LIMITED MECHANISM
The above discussion outlines two dephasing mechanisms.
In the upper end of the SDR, the particles are large enough
4 de Haan
FIG. 3. Schematic of the dephasing regimes. a: shows the MAR regime; b: the SDR regime; c; the VLR; and d: a mix of VLR and SDR. In all
images, the radius of the green circle corresponds to the average distance traveled by diffusion R
D
as dened by Eq. 7, the magenta circle
indicates the full dephasing zone R
FD
as dened by Eq. 15, and the eld of the nanoparticles are shown as in Fig. 1. Note that (a) and (b)
are shown at the same scale demonstrating that while the R
D
is a constant, R
D
/l increases with decreasing R. [Color gure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
that protons are fully dephased before reaching a signi-
cantly different magnetic environment. R
*
2
remains at the
static limit independent of the interparticle distance l (and
correspondingly independent of R). Conversely, in MAR,
the proton visits many nanoparticles before being fully
dephased. During this process, it undergoes refocusing and
R
*
2
drops dramatically with decreasing R (and l).
If we consider a particle at a size between these two
regimes, neither mechanism is appropriate. At R = 30nm,
the characteristic separation between particles is l =
3.3m. To compare, the average distance traveled by a pro-
ton by diffusion is R
D
= 11.7m and hence R
D
/l 3.5.
The proton certainly experiences a great variety of mag-
netic environmentsincluding diffusing between positive
and negative polarities. Correspondingly, it is unlikely that
a proton will be fully dephased while within its initial
magnetic environment as in static dephasing. However, the
measured R
*
2
value is still near the static limit indicating
that the dephasing mechanism is not that of the MAR: dif-
fusion induced refocusing is not a factor. It seems evident
that there must be another dephasing mechanism at this
particle size.
The Full Dephasing Zone
In comparing motional averaging with static dephasing,
the presence of two characteristic time scales in the sys-
tem becomes apparent: the time for the proton to diffuse
to a new magnetic environment
D
and the time for the
spin of the proton to fully dephase
R
. With the denition
given in Eq. 9, diffusion to a region of opposite polarity is
a likely event in the time
D
. Note that this scenario repre-
sents the most dramatic example of a thoroughly different
magnetic environment. By the symmetry of the magnetic
eld, this denition can be extended to any distance r from
the particle:

D
=
r
2
D
. [10]
To estimate
R
, a criteria for considering the proton
fully dephased must be assumed. When measuring the
correlation of the proton spins, the signal S is calculated
from
S(t) =
1
N
p
Np

i
cos(
i
(t)) [11]
Mechanisms of Proton Spin Dephasing in a System of Magnetic Particles 5
where N
p
is the number of protons simulated. Correspond-
ingly, the contribution of a particular proton to S decays
from one at = 0 to zero at || = /2. A reasonable con-
dition is thus to consider a proton fully dephased when
|| /2. To estimate the associated relaxation time, using
= /2 in Eq. 2 yields:

2
= B
R
. [12]
The magnetic eld varies greatly with , but a representa-
tive value can be dened by averaging the magnitude of B
over a shell at a xed r to obtain
|B|
0.4
0
M
3
_
R
r
_
3
. [13]
Using this result in Eq. 12, the resulting estimate of the
relaxation time
R
at a distance r from the particle is

R
=
3.75

0
M
_
r
R
_
3
. [14]
Hence, the time required to fully dephase increases as r
3
in Eq. 14 while the time to reach a new magnetic environ-
ment goes as r
2
in Eq. 10. There will thus be a distance at
which protons closer to the particle will be fully dephased
before reaching a new environment while those further
away will diffuse to a new environment more quickly than
being dephased. Aborder dening this full dephasing zone
can be approximated by determining the distance, R
FD
, at
which
D
=
R
:
R
FD
=

0
M
3.75D
R
3
. [15]
Of course, as diffusion is a stochastic process, this is not
a sharp boundary but rather indicates a fuzzy region of
signicant probability of being fully dephased during the
encounter. However, to study how this approximate region
of full dephasing changes with particle size, it is useful to
dene a distinct region as given above.
As mentioned in the Introduction section, the con-
cept of an inner zone of rapid dephasing near the particle
was introduced by Brooks in 2002 (8). Considering sizes
above MAR, the dynamics of dephasing in this regime were
described as being fully dephased in a single encounter
and the regime was referred to as the visit limited regime
(VLR). The resulting physical picture of minimal phase
changes outside of this zone but rapid dephasing inside
corresponds to that presented here and the visit limited
description of the dynamics is adopted in accordance with
Brooks. Likewise, inFig. 2, the regionabove MARis labeled
VLR. Brooks considered this region terminated by either
SDR or SMR depending on the presence of a refocusing
pulse.
In a paper concurrently published by Gilles et al. (9), a
criteria for the lower bound of SDR is given:

D
= 1 [16]
where is dened differently than above. From this con-
dition, R
*
2
rates near the static limit are obtained if a proton
is dephased by at least 1 radian in a single encounter.
Again, although the numerical constants vary between
denitions, the concept is the same as that presented above.
Note that in both manuscripts, the wording single
encounter is used. In fact, a characterization of dephas-
ing by a single critical encounter is appropriate all the way
to the static limit where the protons are conned to a single
eld magnitude. Correspondingly, although by convention
static dephasing is used to describe the regime extend-
ing from large particle sizes all the way to MAR, a clearer
nomenclature would be to distinguish the multi-encounter
MAR from a single encounter regime. Then, within the sin-
gle encounter regime, the dynamics transition from pure
visit limited at relatively small particles to pure static
dephasing at large particles. This delineation is included in
the lower part of Fig. 2. As this article is concerned with the
details of the dephasing process, a discrimination between
the visit-limited and static dephasing mechanisms is neces-
sary. In an attempt to avoid confusing the static dephasing
mechanism with the SDR which is taken to encompass all
particles sizes where a single encounter dephasing pro-
cess occurs, discussion will revolve around the dephasing
mechanisms using the acronyms VL for visit-limited and
SD for static dephasing.
MAR Boundary
By the denition of R
FD
, there is a critical size at which the
border of the full dephasing zone equals the radius of the
particle. Setting R
FD
= R, this value R
SE
is solved to be
R
SE
=
_
3.75D

0
M
[17]
where the name R
SE
indicates that full dephasing in a sin-
gle encounter is possible at particles above this size. Using
the values cited previously, we nd R
SE
= 18.4nm. Hence,
for particle sizes less than 18.4 nm, R
FD
is inside the parti-
cle, and there is no full dephasing zone; even protons in
the strongest eld right at the particles surface will dif-
fuse to a new environment before being fully dephased. As
refocusing is then inevitable, this value denes the upper
boundary of the MAR.
Note that the upper boundary of MAR is often given
by nding the intersection between the R
*
2
curve of MAR
(Eq. 8) and the static limit (Eq. 5) and solving for the critical
size (12):
R
SE
=
_
3.4D

0
. [18]
This formulation yields R
SE
= 17nm in good agreement
with the derivation above.
VL and SD Crossover
At sizes just above R
SE
, the full dephasing zone extends
beyond the particle radius and protons are able to be fully
dephased in a single encounter. There is little change to the
phase of a proton until it wanders into this zone at which
point it is rapidly and fully dephased. These dynamics
dene the visit-limited mechanism.
6 de Haan
As the particle size increases, several compensatory
changes occur in the system. First, from Eq. 15, R
FD
increases rapidly with increasing particle size. For exam-
ple, comparing (b) with (c) in Fig. 3, note the dramatic
increase fromR = 50nmto R = 100nm. With respect to the
characteristic distance between particles l, the radius of the
full dephasing zone grows as the square of the particle size:
R
FD
/l R
2
. Conversely, the average distance traveled by
diffusion scaled by the characteristic interparticle distance
(R
D
/l) decreases as 1/R and the protons do not explore as
much relative space. Finally, while by the VL mechanism
protons are quickly dephased, the dephasing takes a longer
time at large particle sizes. To see this, note that at small par-
ticle sizes, R
FD
is small and protons in the full dephasing
zone are nearer to the particle in question. At large par-
ticle sizes, R
FD
is larger but recalling the simple scaling
implicit to the system, protons in the outer parts of the full
dephasing zone are inlower eldregions anddephase more
slowly. Through these changes, there is a smooth transition
from pure visit-limited dephasing to pure static dephasing.
The details of this long crossover which will be explored
in the results section.
For an estimate of the upper limit of the visit-limited
mechanism, at R = 200nm, we nd l = 22m and R
FD
=
23.4m (see Fig. 3d). Hence, the full dephasing zone lls
almost all of space. Even at this large particle size, the dif-
fusion distance (R
D
= 11.7m) still covers an appreciable
degree of l. However, diffusion will only minimally impact
the relaxation rate as protons are generally fully dephased
by the time they reach a magnetic environment of opposite
polarity.
SIMULATION SETUP
To investigate the details of the dephasing mechnaisms,
Monte Carlo simulations of protons moving through a
systemof magnetic nanoparticles were conducted. The pro-
cedure used in this article is based on that of previous
studies (9,10,13,1719) and has been shown to yield results
in excellent agreement with theoretical predictions of R
*
2
in
both MAR and SDR. These results have also been experi-
mentally veried for large, micron sized particles (13,17).
Recent experimental work examining nanometer sized par-
ticles has foundthat while the theoretical andexperimental
results are in reasonable agreement, there can be discrepan-
cies due to effects such as polydispersity in the particle size
distribution (11,12,20). As this article is concerned with
a theoretical investigation of the dephasing mechanisms,
such complications are neglected and left for further work.
Simulation Procedure
For each system realization, N = 100 nanoparticles are
placed within a cubic simulation cell whose length, L, is
determined by the volume fraction and particle size by
L = N
1/3
l =
_
N
4
3

f
_
1/3
R. [19]
Note that the system length scales directly with R. The
nanoparticles are placed at random but not allowed to
overlap. A proton is then placed at a random location
within this system (not overlapping with a nanoparticle).
The trajectory of the proton is evolved in time steps of
t = 1ns where at each time step, the proton jumps a
distance given by
dr =

6Dt [20]
in a random direction. In the case of a collision with the
nanoparticle, the jump is rejected and the proton is left in
place. Periodic boundary conditions are used to wrap the
proton back into the central cell when the proton jumps
out of the system.
At each step of the trajectory, the net magnetic eld
from the nearby nanoparticles is calculated using Eq. 1.
Periodic boundary conditions are used to replicate the sys-
tem in x, y, and z to avoid artefacts at the simulation cell
edges. The associated change in phase during the step is
approximated by
= Bt [21]
with the accumulated phase producing the phase trajec-
tory (t) for the proton. This process was repeated across
four independent nanoparticle setups with 2000 protons
simulated for each setup. The decay signal corresponding
to the dephasing among the protons is then calculated for
each setup fromEq. 11, and the nal R
*
2
value is the average
among the four setups.
In calculating the net magnetic eld due to nearby
nanoparticles, only particles within l of the proton are con-
sidered. Using B(r) =
0M
3
(
R
r
)
3
as a representative magnetic
eld at a distance r, we nd B(l) = 8.126 10
8
T for any
particle size. If the proton remains at this eld for the relax-
ation time given by the static limit, the net phase change
is
T
= 0.199rad. The associated drift from the initial
coherence is then 1cos(
T
) 2%. Hence, a proton in this
low eld will not signicantly contribute to the decay sig-
nal and, on this basis, the eld from particles even further
away is neglected.
This cutoff was tested against simulations in which the
eld due to all 100 nanoparticles was considered. Not only
was the resulting decay rate the same well within error
but also the features of the curves themselves showed only
minimal deviations. That neglecting particles further than
l away has only a trivial impact is a direct result of the rapid
decrease in B with r given by B 1/r
3
.
RESULTS
Excluding the Full Dephasing Zone
To directly test the role of an inner or full dephasing
zone, simulations were conducted with an exclusion layer
around the particles. Experimentally, an exclusion layer
may arise from dense polymer coatings that exclude water
or other material which attaches to the surface of the mag-
netic core of the particle (12,2023). Three exclusion layer
thicknesses were simulated: equal to the radius of the par-
ticle (1), three times the radius of the particle (3), and 10
times the radius of the particle (10). The layer thickness
is chosen to scale with the particle size to maintain a con-
stant volume fraction of excluded region. The resulting R
*
2
vs. R curves as well as the data for bare particles is shown
in Fig. 4.
Mechanisms of Proton Spin Dephasing in a System of Magnetic Particles 7
FIG. 4. Relaxation rate curves vs. particle size for bare particles (red
circles), an exclusion layer equal to the radius (green squares), three
time the radius (blue diamonds), and 10 times the radius (brown
crosses in circles). The estimated cross over at which the total par-
ticle size R
T
equals the radius of the full dephasing zone R
FD
is
indicated for each curve by a solid purple dot. [Color gure can be
viewed in the online issue, which is available at wileyonlinelibrary.
com.]
The bare curve displays a result in agreement with the
picture discussed earlier: a sharp increase in R
*
2
with
increasing particle size in MAR followed by a long plateau.
On implementation of an exclusion layer, the rates in MAR
drop signicantly: the dephasing per encounter has been
further reduced. This result is in agreement with the results
of LaConte et al. (19) who found a rapid drop at R = 3nmas
the thickness of the exclusionlayer grew. At sizes just above
R
SE
, the rate has also decreased. Note that if the dephas-
ing mechanism at these sizes corresponded to that of the
SDR, no signicant change would be expected. The exclu-
sion layer removes only a small fraction of protons and for
those outside, if diffusion is negligible, the presence of an
exclusion layer should have little effect since the magnetic
eld is the same value at their location regardless.
However, with the physical picture of the VLR, the pres-
ence of the exclusion layer blocks access to the full dephas-
ing zone. Hence, protons are no longer able to be fully
dephased in a single encounter; refocusing is inevitable
and R
*
2
drops. The range of this degradation can be esti-
mated by recalling that the full dephasing zone grows as
R
3
. With a constant scaling of the layer thickness, the total
particle size scales as R. Hence, the full dephasing zone
grows much more rapidly than the particle size and will
quickly extend outside of the particle to facilitate single
encounter full dephasing once again. This cross-over point
can be calculated by solving for the particle size at which
the total radius of the particle R
T
given by the sum of R
and the exclusion layerequals R
FD
given by Eq. 15. This
point is shownFig. 4 for the bare curve andeachlayer thick-
ness. Note that each point lies consistently at the cross-over
between the increasing R
*
2
of MAR and the onset of the
VL/SD plateau.
Comparing between the curves, the exclusion layer effec-
tively shifts the bare curve to the right to a degree that
depends on the layer thickness. As shown by Chen et al.
(12), this behavior can be derived by considering that a
particle with an exclusion layer is equivalent to a larger
particle (at a higher volume fraction) of a lower magnetiza-
tion (but same magnetic moment). Rescaling the equations
by this transformation, the upper bound of MAR shifts to
the right, but the saturation value remains the same. This
prediction is in excellent agreement with the displayed
results.
Finally, note that for the case of a very thick exclu-
sion layer (10), the data converges to the bare result by
R = 100nm. Hence, even for such a large exclusion layer,
it has no impact already by R = 100nm. This result again
indicates how quickly the full dephasing zone grows. Fur-
ther, it is in agreement with several studies where it was
found that for larger particles, very large exclusion layers
were required to have any impact on the R
*
2
rate (9,12). At
these sizes, the dynamics are crossing over to that of the
static limit: diffusion is becoming negligible and thus an
exclusion layereven a very large onehas no impact.
Dephasing Mechanisms
With the above validation of the concept of a full dephasing
zone, the details of the dephasing mechanisms across the
range of particle sizes are examined in this section. To this
end, a simple model of the dephasing process is developed
and tested with simulation data.
(t) Curves
To give a direct picture of the dephasing mechanisms
discussed in the section Theory, the raw data for the
accumulated phase for sample proton trajectories is shown
in Fig. 5. Two sample trajectories for three particle sizes
are displayed: R = 5nm (MAR), R = 30nm (VL), and
R = 200nm (SD).
In MAR (R = 5nm), the trajectory can approximately
be broken up into sections of long, slowly varying plateaus
and discrete jumps. The jumps correspond to an encounter:
the proton diffuses to high eld region in the vicinity of
the particle. While these jumps primarily determine the
shape of the trajectory, the time spent in such a region is
too short lived to fully dephase the proton. Instead, the
phase slowly builds up by small amounts and it is not until
late in both trajectories that a net phase of |/2| is reached.
The resulting picture of dephasing in the MAR is a slow,
often backtracking, incremental dephasing mechanism, the
inefciency of which yields low R
*
2
values.
For the VL (R = 30nm) data, evolves in a similar fash-
ion to the MAR example. However, the jumps in phase are
much larger and are now clear discontinuties. In the rst
trajectory, the rst sizeable jump is just short of full dephas-
ing, while for the second it is over full dephasing. For both
cases, the proton has diffused into a high eld region and
is effectively fully dephased in a single encounter. The
dephasing mechanism is thus a discrete process: little hap-
pens to the protonuntil it reaches aninner or full dephasing
zone at which point rapid and full dephasing is achieved.
This picture agrees with that developed by Brooks and
outlined above.
8 de Haan
FIG. 5. Accumulated phase for two proton trajectories at three par-
ticle sizes: R = 5nm (MAR), R = 30nm (VL), and R = 200nm (SD).
[Color gure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Finally, for the SD (R = 200nm) trajectory, changes
smoothly with time. This slow variation corresponds with
the picture of static dephasing: diffusion of the proton is
negligible. However, even at R = 200nm, the effects of
diffusion can be seen as the rate of dephasing gradually
changes. Most noticeably, for the rst trajectory, there is a
distinct peak where the proton initially diffuses to a high
positive eld region yielding a steep increase and then to a
high negative eld region with a sharp decreases. But given
the excessive dephasing occurring before, this decline is far
from constituting refocusing.
Simple Model of Dephasing
Given the difference between the visit-limited and static
dephasing mechanisms, it is interesting that very similar
R
*
2
rates are obtained at R = 30nm and R = 200nm, let
alone all the points in between. For the VL mechanism,
dephasing is essentially a discrete process: the proton wan-
ders around with minimal phase changes until it comes
close to a particle and, in this single encounter, becomes
fully dephased. From this picture, the resulting relaxation
rate corresponds to the frequency of these full dephasing
events. In the SD mechanism, the distance traveled by dif-
fusion is small compared with the interparticle distance
and hence the proton undergoes continuous dephasing.
Here, the relaxation rate corresponds to protons in lower
and lower eld regions becoming fully dephased.
To explore the dephasing mechanisms at these extremes
as well as intermediate values, a simple form for the relax-
ation rate can be developed. Taking an all-or-nothing
view of dephasing, the decay in S corresponds to the
number of fully dephased protons
N
FD
(t) 1 S(t). [22]
To test this model, the number of fully dephased protons
(|| /2) as a function of time is shown in Fig. 6.
From Fig. 4, a relaxation rate near the static limit is
obtained at both R = 30nm and R = 200nm. Correspond-
ingly, the R = 30nm and R = 200nm curves in Fig. 6
are in relatively good agreement with each other. Both
curves show a steep increase and subsequent saturation.
The vertical line at t = 0.009s indicates the relaxation
time corresponding to the static limit (
SL
= 1/109s). Note
that both curves reach about 0.5 at
SL
indicating that in
this model, about 50% of the protons are fully dephased in
the relaxation time determined from the full analysis. For
the R = 5nm data, the time to fully dephase a proton is
comparatively long and the curve displays a much slower
accumulation of fully dephased protons. Correspondingly,
a lower R
*
2
value of 9.14s
1
about 1/10 that of the other
curvesis obtained.
Note that in this all or nothing view of dephasing, the
VL curve yields a higher rate than the SD curve. For
the VL data, partial refocusing after /2 is reached is
neglected thus overestimating the rate while in SD, the par-
tial dephasing of protons whose phase has not yet reached
/2 is neglected thus underestimating R
*
2
. Despite these
approximations, modeling the loss of phase correlations
among protons in the system simply by measuring the rate
at which || /2 is achieved is relatively accurate.
Building on this picture, the instantaneous dephasing
rate is given by the time derivative of the number of fully
dephased protons:

N
FD
(t) =
dN
FD
(t)
dt
[23]
FIG. 6. Number of fully dephased protons as function of time for
three particle sizes: R = 5nm(red dashed line), R = 30nm(blue dark
shading), and R = 200nm (green light shading). [Color gure can be
viewed in the online issue, which is available at wileyonlinelibrary.
com.]
Mechanisms of Proton Spin Dephasing in a System of Magnetic Particles 9
The right hand side of Eq. 23 thus denes the frequency of
full dephasing events:

N
FD
(t) = f
FD
[24]
Although f
FD
changes signicantly with time, a character-
istic rate can then be dened by the average f
FD
:

N
FD
= f
FD
[25]
This approximation allows for a simple model of dephas-
ing, but it will underestimate the decay rate compared with
the full analysis where the rate is determined from tting
the exponential decay. However, in this all or nothing pic-
ture, most events occur near the beginning of the relaxation
process (see Fig. 6), where an approximation by a linear
decay would give a reasonable, albeit rough, estimate. Con-
sequently, as will be shown, this simple model yields low
but physically reasonable rates.
Taking an encounter based picture of dephasing, f
FD
is
equal to the frequency of particle encounters, f
enc
, mul-
tiplied by the average gain toward being fully dephased
achieved in an encounter. In MAR, even though the proton
experiences only partial dephasing, there will some aver-
age net dephasing
net
which is not refocused. From this,
a denition for the average net dephasing gained towards
eventual full dephasing can be represented by:
P

=
_

net

FD
_
[26]
where
FD
= /2 by the denition of full dephasing used
here. Using this in Eq. 23,

N
FD
= f
enc
P

. [27]
Finally, the frequency of encounters is the inverse of the
time between encounters: f
enc
=
1
tenc
. The time between
encounters is the sum of the time required to nd the par-
ticle t
nd
and the time of the encounter itself t
dephase
during
which dephasing occurs. This yields:

N
FD
=
P

t
nd
+t
dephase

[28]
From Eq. 28, all three dephasing mechanisms can be
demonstrated. In the MAR, a proton is only partially
dephasedinanencounter: P

< 1. As Rincreases, the rela-

tive distance traveled by diffusion, R
D
/l, decreases and cor-
respondingly there are fewer encounters, more dephasing
per encounter, but a longer time betweenencounters. While
these competing factors would tend to balance out, the
reducedamount of refocusing resulting fromfewer encoun-
ters overwhelms these considerations to yieldanincreasing
P

. Consequently, the rate

N
FD
increases dramatically
with increasing particle size in MAR.
At R = R
SE
, P

saturates at 1. While a proton can

be dephased more than /2 in an encounter, additional
dephasing beyond full dephasing does not contribute any
more to the decay but rather constitutes over-dephasing.
Hence, the sharp increase in R
*
2
in the MAR is halted and
the dynamics crossover fromMARto SER: protons are fully
dephased in a single encounter. Eq. 28 then reduces to

N
FD
=
1
t
nd
+t
dephase

. [29]
As demonstrated in Fig. 5, there are two dephasing mech-
anisms above MAR: pure visit-limited just above R
SE
and
pure static dephasing at large R. For pure visit-limited, the
full dephasing zone is small, but the relative diffusion dis-
tance is large and dephasing is rapid. Hence, full dephasing
occurs as essentially discrete events when protons diffuse
to r < R
FD
. In this limit, t
dephase
0 and the rate reduces
to:

N
FD
=
1
t
nd

[30]
This result was formally derived by Brooks where the relax-
ation rate was found to be the inverse of the time required
to go from state A (outer zone) to state B (inner zone) in
the limit of a large eld difference between the two (8). It
is from this rate limiting mechanism that the name VLR
arises.
At large particle sizes, dephasing occurs by the static
dephasing mechanism. Here, the full dephasing zone lls
all of space and the protons need not diffuse to nd it:
t
nd
= 0. However, the dephasing events are no longer
instantaneous. Rather, relaxation occurs by the sequential
dephasing of protons in regions of lower and lower mag-
netic eld magnitudes. In this limit, the rate is the inverse
of the average time required to dephase a proton:

N
FD
=
1
t
dephase

[31]
This formulation agrees in essence with the methods used
to calculate the static limit where the dephasing rate of
stationary protons is averaged over all space (14).
To calculate these times from simulation data, t
nd
can
be dened as the time required for the proton to nd the
full dephasing zone and t
dephase
to be the subsequent time
until || /2 is reached. However, a slight modication
to the denition of the full dephasing zone is required. Pre-
viously, variations in the magnetic eld with have been
neglected to present a simple picture of a full dephasing
zone as a sphere. However, there are regions of low eld
magnitude even close to the particle and a trajectory in
which the proton passes through the full dephasing zone
but experiences little dephasing is possibleparticularly
at small particle sizes. Hence, while r R
FD
is a neces-
sary condition, it is not a sufcient one. Rather, a more
precise denition of the full dephasing zone(s) is given by
the regions of high eld magnitude within R
FD
: a lobe at
each polar region and a ring around the equator. To dene
these regions, the maximum eld at a distance r is given
by
20M
3
(
R
r
)
3
and using this as the minimum eld criteria
ensures that all regions are all inside of R
FD
. A drawing
of these full dephasing zones as encompassed by R
FD
at
R = 50nm is included in Fig. 7, where t
nd
and t
dephase

are plotted against particle size.

In Fig. 7, the time to nd the full dephasing zones
decreases with increasing R: the majority of the time at
low R is spent nding a full dephasing zone; at large R,
t
nd
0 since the full dephasing zones ll almost all
of space. Conversely, the time to dephase increases with
increasing R: at low R, full dephasing occurs shortly after
nding a full dephasing zone; at large R, the entirety of the
10 de Haan
FIG. 7. Separation of times across the SER particle size range. The
time to nd the full dephasing zone decreases with increasing R
(green squares), the average dephasing time once in the full dephas-
ing zone increases with R (brown diamonds), and the total time is
conserved (black circles). [Color gure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
encounter is spent dephasing. These dynamics correspond
to the VL and SD mechanisms respectively.
In between these extremes, there is a smooth trade-
off between the times such that the total average time
per encounter remains relatively constant. The total time
decays from 0.015 to 0.014 and thus exhibits only
a small net deviation considering the large underlying
changes in t
nd
and t
dephase
. Further, the T
*
2
times given
by the inverse of R
*
2
from the full analysis decay over
this range: T
*
2
(R = 30) 0.011s compared with T
*
2
(R =
200) 0.01s and so a slight decline might be expected.
(Note that while the assumption of a constant rate does
underestimate the relaxation rates, the values are still rea-
sonable). This conservation means that the average time
per full dephasing event is essentially constant, regardless
of size, provided that full dephasing can occur in a single
encounter. The resulting rate, R
*
2
, is then R independent
and there is a long plateau that extends all the way from
the onset of VL after R
SE
up to the static limit of innitely
large particles.
DISCUSSION AND CONCLUSION
In this article, the details of proton spin dephasing mech-
anisms across a large range of particle sizes were studied.
In agreement with the pictures developed by Brooks and
Gilles et al., three distinct regimes were identied (in the
absence of a refocusing pulse). At small sizes, the dynamics
correspondto that of the MARwhere diffusionis dominant.
Protons are not fully dephased from an interaction with a
particle anda slow, incremental dephasing is observed. Due
to diffusion induced refocusing, the resulting R
*
2
rate is low.
After a critical size, the possibility of full dephasing in a
single encounter appears. At this point, the dynamics cor-
respond to the visit-limited mechanism where the protons
fully dephase in discrete events. The rate of these events is
sufcient to yield a high R
*
2
rate. For large particles, the
dynamics follow the continuous dephasing of the static
dephasing mechanism. Here, diffusion has little impact
and the protons experience only gradual changes in their
dephasing rates. As this mechanism corresponds to that of
the static limit, an R
*
2
rate near the maximum is obtained.
Although this manuscript does not present results for the
relaxation rate in the presence of a refocusing pulse, this
physical picture is readily extended to typical R
2
results
as sketched in Fig. 2. As discussed in the Introduction
section, a refocusing pulse can reverse previous dephasing
to yield anecho of the initial phase coherence and thus
reduce the relaxation rate. The effectiveness of the refocus-
ing depends strongly on the extent to which the protons
remainina consistent magnetic environment. If the protons
are exactly contained, the initial dephasing can be exactly
undone and no relaxation is observed. Conversely, if the
protons travel through many magnetic environments dur-
ing the initial dephasing interval, further dephasing over a
different trajectory during the refocusing interval will not
result in refocusing among protons. With this picture, it is
clear that the refocusing pulse has a large impact in SDR
but no effect in MAR. Likewise, in pure VLR where dephas-
ing is discrete event, a refocusing pulse does not affect
the relaxation rate. However, with increasing particle size,
there is a crossover from pure VL to pure SD; dephasing is
no longer instantaneously but takes a nite amount of time
(see Fig. 7). If
CP
is less than this full dephasing time, then
the pulse will at least partially refocus the protons yield-
ing echos and a decreased relaxation time. Furthermore,
the shorter that
CP
is, the further into the VLR regime the
refocusing will have an effect. This physical picture agrees
with the behavior sketched out in Fig. 2.
Finally, it was demonstrated that in going between VL
and SD, there is a gradual transition from discrete dephas-
ing dynamics to continuous dephasing dynamics as the
particle size increases. As the average total time for a
dephasing event is conserved anywhere between these
extremes, the relaxation rate is independent of particle size
resulting in the long plateau extending from VL to SD. In
fact, as there is little variation in R
*
2
between them, the dis-
tinction between these mechanisms/regimes is not often
made. However, the distinct dynamics of the VL mecha-
nismare key to understanding the results for certain system
setups. For example, at sizes just above R
SE
, contrary to the
SD picture, the presence of an exclusion layer can have a
signicant impact. Dynamics distinct fromSDalso provide
important insight when considering the impact of intro-
ducing a hydrophillic coating around the particles. These
topics will be explored in future manuscripts.
ACKNOWLEDGMENTS
The author is indebted to Chantal Paquet for many useful
discussions and assistance with the manuscript along with
David Sean and Tyler Shendruk. Simulations were per-
formed using the computational resources of SHARCNET
and HPCVL.
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