Magnetic Strategies for Nervous System Control (Chistiansen, M.G., et al., 2019)

Magnetic Strategies for Nervous System Control

Annu Rev Neuroscience 2019 July 08; 42: 271–293. doi:10.1146/annurev-neuro-070918-050241.

Michael G. Christiansen1 , Alexander W. Senko2, and Polina Anikeeva2

1 Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zurich, Switzerland
2 Department of Materials Science and Engineering, Research Laboratory of Electronics, and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA

Abstract

Owing to the low conductivity and negligible magnetic susceptibility of organic matter, magnetic
fields can pass through tissue undiminished and without producing harmful effects. Their resulting
ability to deliver stimuli wirelessly to targets of arbitrary depth in the body has motivated their use
as a minimally invasive means to control neural activity. Here, we review mechanisms and
techniques that couple magnetic fields to changes in electrochemical potentials across neuronal
membranes. Biological magnetoreception, the underlying mechanisms of which remain an active
area of study, is discussed as a potential source of inspiration for artificial magnetic
neuromodulation schemes. The emergence of magnetic properties in materials is briefly reviewed
to clarify the distinction between biomolecules containing iron or other transition metals and
ferrite nanoparticles that exhibit significant net moments. We then describe recent developments in
the use of magnetic nanomaterials as transducers that convert magnetic stimuli to forms more
readily perceived by neuronal signaling machinery, and discuss opportunities for multiplexed and
bi-directional control, as well as the challenges posed by delivery to the brain. The broad palette of
magnetic field conditions and the array of mechanisms by which they can be coupled to neuronal
signaling cascades serves to highlight the desirability of interchange between magnetism physics
and neurobiology, and the necessity of continued dialogue between the engineering and
neuroscience communities.

INTRODUCTION

Systems neuroscience and nearly all physiologically based interventions in psychiatric
patients rely on the upregulation or downregulation of the activity of specific neural circuits
or neuronal subtypes. Historically, this has been accomplished via pharmacology or surgical
lesions. In the past several decades, however, a variety of neuromodulation approaches have
emerged, some of which have found wide clinical use. For example, deep brain stimulation
(DBS) with chronically implanted electrodes is an approved therapy for Parkinson’s disease
(Obeso et al. 2001) and is being investigated as a treatment for psychiatric disorders. Other
methods, such as optogenetics, are mainly employed in basic neuroscience research (Deisseroth 2015). This review focuses on a class of neuromodulation approaches that rely on magnetic fields as stimuli.

As compared to other signals such electric fields, light, or ultrasound that may be used to
deliver stimuli to the brain, magnetic fields are appealing due to their limited coupling to
biological tissue (Young et al. 1980). A notable exception are the magnetic fields with large
time-derivatives, which are used for transcranial magnetic stimulation and discussed in
Inductive Methods section. The ability of magnetic fields to pass through the body
undiminished and without deleterious effects suggests their use in wireless delivery of
stimuli to deep targets. For many organisms, though not all, magnetic stimuli should be
imperceptible, a desirable feature for behavioral experiments in which the subject’s ability to
sense the application of a stimulus may compromise the results. An example is optogenetics,
in which visible light scattered by waveguides or tissue may be seen peripherally by the
subjects. Medical interventions would also benefit from completely remote stimulation
methods, and indeed one of the goals of magnetic neuromodulation strategies is to offer a
means of DBS with a system that does not rely on a physical connection to sites of
stimulation. This would reduce the invasiveness of DBS therapy and the tissue damage
associated with implanted hardware.

Some organisms exhibit magnetoreception, the ability to perceive magnetic fields (Ritz et al.
2000, Wiltschko & Wiltschko 2005). Though the biophysical mechanisms underlying
magnetoreception remain poorly understood (Johnsen et al. 2005), its existence suggests that
reverse engineering could be an intriguing approach to developing tools for magnetic control
over neural activity, especially if the necessary genetic machinery could be transferred to
specific neural circuits to permit selective activation with magnetic stimuli.
Alternatively, magnetic fields can be used as an intermediary for almost every type of
stimulus to which neurons have evolved to respond. Because all neurons are capable of
communicating electrically and chemically, it is natural to consider coopting these
mechanisms for external modulation of their activity. One approach to do this using
magnetic fields entails inducing electric currents in the brain that can either elicit or suppress
action potentials, as in transcranial magnetic stimulation (TMS). Alternatively, localized
actuation of voltage gated ion channels by magnetic fields may be made possible by the
introduction of nanoscale magnetoelectric composite materials (Guduru et al. 2015).
Other routes are suggested by specialized neurons that exhibit sensitivity to physical cues by
incorporating ion transporting proteins that respond to a specific stimulus, such as light,
mechanical forces, or temperature changes. Such channel proteins can be transgenically
introduced where they would otherwise be absent, as is done in optogenetics with opsins,
microbial optically-sensitive ion channels and pumps, to sensitize neurons to light. By
analogy, proteins native to mammalian sensory neurons can be artificially expressed in
neurons deep in the brain to sensitize them to mechanical force or heat. Using magnetic
materials as transducers, the magnetic field energy can be locally converted to heat (Chen et
al. 2015, Munshi et al. 2017, Munshi et al. 2018) or force (Tseng et al. 2012, Mannix et al.
2008, Lee et al. 2014).

It is worth noting that magnetic approaches represent a subset of a broader effort to identify
wireless means of stimulating neurons, such as transcranial focused ultrasound (Legon et al.
2014), temporally interfering high frequency electric fields (Grossman et al. 2017), near
infrared (NIR) light illumination, and NIR coupled to upconverting nanoparticles that allow
for transcranial light delivery for optogenetic stimulation of deep brain structures (Chen et
al. 2018). None of these approaches, however, match the combined resolution and
penetration depth afforded by magnetic fields.

NATURAL MAGNETORECEPTION AS A MODEL

Behavioral studies suggest the ability of a variety of animals to perceive the Earth’s
magnetic field, including insects, amphibians, reptiles, fish, and birds. Migratory birds, for
instance, have been suggested to not only orient themselves by sensing the inclination of the
field (Wiltschko & Wiltschko 1972) but also may deduce location by discerning minute local
variations in the geomagnetic field (Kishkinev et al. 2015). By analogy to other sensory
input such as light or sound, the existence of specialized receptor cells has been thought to
enable the detection of magnetic field direction and intensity. The biophysical mechanisms
that underlie magnetoreception in nature would be an appealing source from which to draw
inspiration for the development of effective technologies to enable magnetic control of the
nervous system. One can imagine either emulating these mechanisms indirectly, or perhaps
manipulating cells of interest to artificially produce the requisite biomolecules for magnetic
sensitivity. Though it has its merits, this line of reasoning has thus far encountered practical
difficulties for two likely reasons: 1) it fails to account for the dissimilarity between natural
magnetic cues and the magnetic stimuli available in the laboratory, and 2) unequivocal
mechanisms for natural magnetoreception remain elusive despite decades of research and
debate.

The geomagnetic field is relatively weak (50 to 60 μT) and can be regarded as uniform at the
scale of an organism and constant at the timescale of animal behavior. Aside from a rare
transient magnetic field pulse associated with lightning strikes at very close range (Fuchset
et al. 1998) or weak electromagnetic signals linked to human technology or solar wind
(LaBelle & Treumann 2002, Engels et al. 2014), the geomagnetic field seems to be the
principal magnetic stimulus of evolutionary significance to animals in their natural habitat.
In contrast, the types of magnetic fields available in the laboratory are orders of magnitude
stronger in field strength (e.g. ~1 T for TMS), can exhibit dramatic gradients (e.g. >100
T/m), and can act dynamically, for instance by rotating or alternating (Figure 1). While
examining biological magnetoreception presents an exciting research avenue, leveraging the
full palette of magnetic fields accessible in the laboratory may offer a more expedient and
robust route to controlling the nervous system than direct emulation of magnetically
sensitive molecular and cellular machinery.

Figure 1.

A palette of artificial magnetic stimuli, categorized according to spatial and temporal
characteristics. (a ) Nearly uniform fields can be created, for example, using a Helmholtz coil
(two current carrying rings separated by a distance equal to their radius). (b ) A conical
permanent magnet magnetized along its azimuthal axis produces a field at the tip that decays
rapidly with distance, resulting in a high magnetic field gradient. Fields with various spatial
distributions can also be categorized by how they vary in time. (c ) Magnetic fields can
remain constant over the timescale of interest. (d ) Rotating fields maintain a constant
magnitude while changing direction, revolving around some axis. A simple, planar rotation
is shown. (e ) Alternating magnetic fields sinusoidally change polarity, and are typically
generated by applying AC current to a solenoid. If the linear dimensions of the solenoid are
much less than the corresponding wavelength of electromagnetic radiation, the field is
quasimagnetostatic. (f ) Pulsed fields, which exhibit high dB/dt, can be generated by
discharging a momentary burst of current through a coil. This approach is often used in TMS
pulses.

Despite many decades of scientific search for biophysical mechanism underlying
magnetoreception, consensus has not been forthcoming and key questions remain
unanswered (Mouritsen 2018). There are two main hypotheses for mechanisms of
magnetoreception in terrestrial animals (Figure 2): 1) magnetically influenced radical pair chemistry, typically thought to involve cryptochrome (Hore & Mouritsen 2016), and 2) the use of biomineralized magnetic nanoparticles or assemblies formed from them to actuate mechanotransduction (Kirschvink et al. 2001). A third hypothesis suggests that elasmobranch fishes such as sharks may perceive magnetic fields via sensitive detection of induced electric potentials (Kalmijn 1981, Paulin 1995).

Figure 2.

Lessons offered by hypothesized mechanisms of magnetoreception. (a ) Pigeons are an
example of organisms that sense the inclination of the Earth’s magnetic field and also
possess a “map sense.” They are thought to to detect minute local variations in the magnetic
field and remember those variations to help navigate. (b ) In the radical pair hypothesis,
cryptochrome generates radical pairs when exposed to ultraviolet or blue light, and weak
magnetic fields bias the proportion of radical pairs in the triplet or singlet state, altering the
generation of downstream products detectable by neurons. (c ) Magnetite nanoparticles have
been reportedly found in many animals and could perhaps interact with the Earth’s magnetic
field strongly enough to produce forces detectable by neurons. A 50 nm magnetite particle is
contrasted with the mineralized core of ferritin in terms of interaction energy with the
Earth’s magnetic field (50 μT). Thermal energy at room temperature is marked as kBT,
where kB is the Boltzmann constant and T is temperature.

Many regard radical pair formation as a likely explanation of “compass sense” in at least
some organisms, and a growing body of biophysical, genetic, and behavioral evidence is
consistent with this hypothesis and with the notion that cryptochrome is necessary for
magnetoreception (Gegear et al. 2008, Muheim et al. 2016). Cryptochrome is thought to
mediate the formation of metastable radical pairs upon exposure to photons of ultraviolet or
visible light with suitable energy and polarization, a nonequilibrium state that soon proceeds
along reaction paths toward one of two possible sets of products (Muller & Ahmad 2011).
Because radicals contain unpaired electrons, they exhibit a net magnetic moment, and the
presence and orientation of the geomagnetic field can plausibly influence the fraction of
these radical pairs existing in either singlet or triplet states. This, in turn, biases the products
resulting from their reaction, and a currently unknown mechanism downstream is imagined
to use this shifting balance of products to transduce neural activity. One compelling form of
evidence based on a magnetic stimulus is the use of alternating magnetic fields varied over a
wide frequency band in the low MHz to induce transitions between the singlet and triplet
states that apparently interfere with magnetosensation (Ritz et al. 2004, Wiltschko et al.
2015). The full radical pair hypothesis is conceptually richer and is discussed in detail in a
recent comprehensive review by Hore and Mouritsen (Hore & Mouritsen 2016). For the
present discussion, the most intriguing aspect of this theory is the elegant way in which it
plausibly circumvents the intrinsic energetic weakness of magnetic interactions with
individual spin moments, merely requiring it to bias the path of a metastable state toward
possible equilibria.

The second hypothesis of magnetoreception circumvents the energetic weakness of biomolecular interactions with magnetic fields by instead supposing that biomineralized
magnetic materials could play a role. The magnetic moments of these particles, which are
orders of magnitude larger than the moment of an unpaired electron, are capable of
interacting with the geomagnetic field at energies significantly exceeding the ambient
thermal noise. This principle is illustrated by magnetotactic bacteria, which contain
magnetosomes, cellular membrane invaginations filled with chains of magnetite (Fe3O4)
nanoparticles, which align with the local geomagnetic field. While magnetite of suspected
biogenic origin has also been identified in other organisms (Gould et al. 1978, Walcott et al.
1979, Kirschvink et al. 1985), including humans (Kirschvink et al. 1992, Gilder et al. 2018),
it likely serves a metabolic rather than a sensory function, and evidence of magnetite-
dependent cell signaling remains elusive (Treiber et al. 2012, Edelman et al. 2015). Perhaps
the most compelling evidence for this hypothesis comes from the reversal of the magnetic
compass sense in a variety of organisms upon application of a millisecond magnetic pulse, a
phenomenon that could be straightforwardly explained by remanence magnetization in
magnetic particles or their assemblies and not by any of the other theories (Holland 2010).
In an effort to draw useful lessons from the progress in the field, it is worth considering the
implications each hypothesis could have for informing magnetic stimulation technology if it
were true. Note that the hypotheses discussed above are not mutually exclusive, and that
additional unanticipated mechanisms are likely at work. The cryptochrome-dependent
radical pair mechanism requires the formation of metastable chemical intermediates via
optical excitation at wavelengths absorbed and scattered by tissue. An approach requiring
both illumination and magnetic field to stimulate cell populations in the central nervous
system does not offer clear advantages over existing optogenetic methods. If the hypothesis
of magnetoreception via cellular interaction with nanoscale biogenic magnetite crystals
holds true in some instances, then natural magnetoreception could share an underlying
mechanistic similarity with the methods reliant on synthetic magnetic nanoparticles
discussed at length in a later section.

MAGNETOGENETICS

The desire for facile “magnetogenetics” methods has drawn significant interest in recent
years. In concept, these techniques would be analogous to optogenetics (Deisseroth 2015) or
chemogenetics (Rogan & Roth 2011), relying solely upon expression of a single protein
responsive to magnetic field. This vision is appealing because such methods would be
readily adoptable by the neuroscience community, allowing for the retention of many of the
established methodologies used in optogenetics, while eliminating the need for the
implanted optical waveguides or light-emitting devices that deliver stimuli in behavioral
experiments.

This goal has been pursued by fusing the iron-binding protein ferritin to ion channels from
the transient receptor potential vanilloid (TRPV) family. The earliest published example
fused ferritin to the capsaicin receptor, TRPV1, and showed that exposure to a weak (5 mT)
rapidly alternating (465 kHz) magnetic field triggered intracellular calcium ion (Ca2+) influx
(Stanley et al. 2012). Because the TRPV1 is a heat-responsive, Ca2+ permeable cation
channel (Caterina et al. 1997), hysteretic heating of the ferritin was suggested as a putative
mechanism for actuating the channel (Stanley et al. 2012). In a follow-up study the same
ferritin-fused TRPV1 appeared to be actuated by applying comparatively large (~0.5 T)
static magnetic fields (Stanley et al. 2014). An independent study presented evidence that a
similar fusion of ferritin to another TRPV channel, TRPV4, was sufficient to produce a
similar effect at ten times lower applied field magnitudes (50 mT) (Wheeler et al. 2016). The
ability of TRPV1 and TRPV4 to respond to mechanical stimuli has led to a hypothesis that
the mechanism underlying the observed effects of magnetic fields on cellular signaling and
rodent behavior was mechanical (Stanley et al. 2014, Wheeler et al. 2016). A single amino
acid substitution in the pore of the modified TRPV1 was subsequently reported to convert
this protein to a chloride-selective channel activated by similar magnetic stimuli to produce
inhibitory effects (Stanley et al. 2016).

The energy scale of interaction between ferritin and the magnetic fields with magnitudes
employed in these studies was, however, shown to be 4–10 orders of magnitude below the
ambient thermal fluctuations (Meister 2016) (Figure 2c), which is far too weak to directly
generate mechanically induced conformational changes in a protein. While these articles
appear careful in their experimental execution, the attempts to identify mechanisms should
be regarded as tentative. For instance, the functional equivalence of the ferrihydrite core of
ferritin and magnetite nanoparticles implicitly posited by this work is not substantiated by
the body of literature characterizing ferritin (Chasteen & Harrison 1999). Magnetic fields
generated at length scales of centimeters, and alternating at frequencies corresponding to
electromagnetic radiation with a wavelength of more than half a kilometer are referred to as
“radio waves”, which is imprecise given their quasimagnetostatic nature (Stanley et al. 2012,
Stanley et al. 2014, Stanley et al. 2016). For these methods to be properly understood and
disseminated, additional experimental and theoretical studies are necessary to uncover the
biophysical principles at the core of the observed physiological effects.

Another strategy for developing magnetogenetics has been to attempt to identify a
previously unknown magnetic receptor. If valid, such a discovery would simultaneously
enhance understanding of magnetoreception and offer a valuable technology for genetically
targeted magnetic stimulation. It was recently claimed that iron-sulfur cluster assembly 1
(IscA1) protein isolated through a genome-wide screening of Drosophila and renamed as
MagR interacts with cryptochrome to generate torque in magnetic fields and act as a
“magnetic protein biocompass” (Qin et al. 2015). Concerns have been raised over the
underlying mechanisms of magnetoreception reported in this work, especially since data
displayed in the same article showed the magnetization of MagR to be about a thousand
times lower than that of ferritin (Meister 2016, Winklhofer & Mouritsen 2016). Independent
efforts to reproduce the key findings from this work have not yet succeeded (Panget et al.
2017).

These studies highlight the strong the impetus that exists to offer magnetogenetics as a tool
for the neuroscience community (Long et al. 2015) and the discussions they have sparked
highlight the need for refinement or revision of our understanding of the basic physics of
these systems.

INDUCTIVE METHODS

Electromagnetic induction is a phenomenon described by Faraday’s law, in which a time-
varying magnetic flux induces electric fields in a conductive medium. Transcranial magnetic
stimulation (TMS) is based on this effect, but electromagnetic induction also plays a central
role in several other types of wireless brain stimulation techniques.

TMS, transcranial direct current stimulation (tDCS), and electroconvulsive therapy (ECT) all
rely on passing current through the brain to alter neural firing patterns. It is hypothesized
that this gives rise to neuroplasticity (Nitshe et al. 2008, Lefaucheur et al. 2017), though the
exact mechanism by which long-term behavioral changes are manifested is still unclear.
Understanding the effects of TMS is further complicated by inhomogeneity in the induced
current, the likely significance of the orientation of the axons being stimulated, the influence
of pulse duration (which can either potentiate or depress activity), and the indirect activation
of other brain regions (Yasuo 2002, Ruff et al. 2009). Some efforts to elucidate the
mechanisms involve combining TMS with fMRI to correlate behavioral changes to
hemodynamic signals as a proxy for neural activation (Bergmann et al. 2016). TMS has
shown promise for treating depression (Brunoni et al. 2017, McClintock et al. 2018) and
neuropathic pain, while emerging applications such as the treatment of stroke and
Alzheimer’s disease require further investigation (Lefaucheur et al. 2014).
TMS involves placing a magnetic field coil close to the scalp and applying millisecond
pulses of current through the coil to produce time derivatives of magnetic field (dB/dt ≈
3×104 T/s, peak field amplitude ~2 T) that induce currents in the brain (Wagner et al. 2007)
(Figure 3a). Only the top 1 – 2 cm of cortex directly below the coil will be stimulated, and by engineering the coil shape the field can be concentrated to spot sizes smaller than the coil
diameter. A common coil geometry is the figure-eight or butterfly coil, which has two
slightly overlapping coils wound in opposite directions (Figure 3b). This geometry produces a concentrated field at the point of overlap between the coils. Regardless of the TMS coil
shape, magnetic field decreases with distance from the center of coil, which implies that
superficial brain structures will consistently receive a stronger stimulus than deeper brain
structures (Wagner et al. 2007).

Figure 3.

Electromagnetic induction can be used to control neural activity. (a ) Schematic of the
electromagnetic induction in the context of TMS. A butterfly coil is held over the head of a
human and a pulsed current is applied, resulting in a rapidly increasing magnetic field that
induces a current in the brain (from Wagner et al. 2007). (b ) Examples of TMS coils, single
and butterfly (from magstim.com). (c ) Electromagnetic induction could be used to stimulate
deep brain structures via implanted millimeter-scale solenoids (from Bonmassar et al. 2012).
(d ) Implanted devices may be powered using electromagnetic induction. This device may be
implanted into an animal and rectifies the induced voltage from an externally applied
alternating magnetic field into a DC current that can stimulate neural activity (from Freeman
et al. 2017).

While TMS cannot reach deep brain structures without stimulating cortical tissue with
greater intensity, the implantation of miniature magnetic coils has been suggested as an
alternative to DBS electrodes. An example of such a device consisted of a ~1 mm solenoid
connected by wires to a battery pack, and generated a magnetic field that caused
electromagnetic induction in neighboring neural tissue (Figure 3c).
This device is thought to be potentially immune to eventual failure caused by glial scarring that plagues implanted electrodes, due to the fact that the induced fields extend for several hundred microns
(Bonmassar et al. 2012). This would also mitigate safety concerns associated with
electrochemical reactions at direct interfaces between electrodes and neural tissue (Park et
al. 2013, Lee et al 2016).

Related alternatives to DBS electrodes include inductively powered implanted devices. Such
devices use a pickup coil to couple to an external primary coil through mutual inductance,
and power is transferred via an alternating magnetic field in a manner analogous to a
transformer. One example of a miniaturized implantable device has been demonstrated to
work 7.5 cm away from the power coil in a rat model (Figure 3d). It has approximate
dimensions of 2×0.5×0.5 mm, and operates by rectifying induced voltages at a
predetermined resonance frequency (e.g. 10 MHz) to produce a DC electric field capable of
depolarizing adjacent neurons (Freeman et al. 2017). Like TMS, this device relies on
external application of magnetic fields, but in this case the field is used solely as a source of
wireless power for an electrical device. Other types of miniature implanted inductively
powered electrical devices have also been designed, for example to drive microscale LEDs
(μLEDs) for optogenetics (Kwon et al. 2015).

MAGNETIC MATERIALS

Basis for the Utility of Magnetic Particles

Techniques employing magnetic materials to stimulate the central nervous system tend to
rely on coupling magnetic fields to other stimuli that are more readily detected by neuronal
biochemical machinery. The role of the magnetic material in this approach is to provide an
energetically plausible handle upon which a magnetic field can act. The dissimilarity in
magnetic properties between the magnetic material and the tissue surrounding it serves as
the basis for selective influence of the field. To appreciate why the interaction of a magnetic
field with such materials differs from its interaction with biomolecules or clusters of atoms,
it is helpful to consider the origins of their magnetism (Figure 4).

While certain elements such as iron or rare earth metals exhibit higher magnetic moments
than other atoms, their presence in a system alone does not constitute a magnet. A magnetic
field applied to a population of such atoms, responding in effective isolation from one
another, results in paramagnetic behavior (Cullity & Graham 2009) (Figure 4a). This is
observed at room temperature in FeO (wüstite), which contains iron and oxygen atoms in a
rock-salt crystal arrangement. The competition of thermal fluctuations with the energetic
influence of an applied magnetic field determines the extent to which such a population of
moments aligns with the field. For a paramagnetic material, the energies of interaction
between the field and individual atoms are so small that even an applied field as strong as 1T
will typically produce a magnetization value <1% of saturation (complete alignment). Because paramagnetism is an inherently weak effect, such materials are suboptimal handles for magnetic actuation (Figure 4a).

Figure 4.

Forms of magnetic ordering. (a ) Paramagnetism: uncoupled spins are randomly oriented in
the absence of applied field, but they asymptotically approach complete alignment with the
application of large magnetic fields. (b ) In ferromagnetic materials, magnetic moments
spontaneously align to give the material a net magnetic moment. In anti-ferromagnetic
materials, adjacent magnetic moments align anti-parallel to perfectly cancel, resulting in
zero net magnetization. In ferrimagnetic materials, adjacent magnetic moments align anti-
parallel but have unequal magnitude, resulting in a net magnetic moment for the material. (c )
Single and multi-domain particles: below a critical size determined by the material
properties, all moments within a ferromagnetic particle are aligned. At larger sizes, particles
develop multiple domains to minimize their magnetostatic energy. For simplicity, the
domain wall is illustrated as if it were abrupt; in reality, there would be spins of intermediate
orientation between the two opposing domains. (d ) Superparamagnetism: an ensemble of
singledomain particles of ferromagnetic or ferrimagnetic material has zero net magnetization
at zero applied field, but upon the application of moderate magnetic fields, the particle
moments align with the applied field.

When atoms are arranged in close proximity, for example in a crystal, the possibility for
spontaneous ordering of their magnetic moments sometimes arises (Figure 4b). Magnetic
moments of atoms can interact with one another through “exchange interaction,” a quantum
mechanical phenomenon that can occur either between nearest neighbors or can be mediated
via neighboring nonmagnetic atoms (Cullity & Graham 2009). Because it requires
overlapping wave functions, exchange interactions between atoms are appreciable only
when they are separated by sub-nanometer distances. If this interaction causes neighboring
magnetic moments in a crystal to align in parallel, for instance as in a body centered cubic
crystal of metallic Fe, the material is referred to as “ferromagnetic” (Figure 4b). If, instead,
the exchange interaction drives antiparallel alignment and their moments cancel, the material
is referred to as “antiferromagnetic,” (Figure 4b) such as FeO at temperatures below −80°C
(Fischer et al. 2009). Intermediate “ferrimagnetic” cases are possible, with antiparallel
alignment of dissimilar moments or antiparallel alignment of unequal subpopulations of
moments so that an overall net magnetization remains (Figure 4b). Biomineralized crystals
of Fe3O4 (magnetite) and gregite (Fe3S4) fall into this category (Roberts et al. 2011). Crystal
defects and surface effects in sufficiently small nanoscale crystals can play a significant role
in determining properties. While the protein shell of ferritin has been used as a nucleation
site for the growth of a variety of synthetic nanomaterials (Jutz et al 2015), in humans and
other mammals its mineralized 5.5-6.0 nm core consists of ferrihydrite (5Fe2O3 9H2O)
(Chasteen & Harrison 1999). The Fe3+ ions in the ferrihydrite crystal are
antiferromagnetically ordered, but defects and surface states lead to incomplete cancellation,
leaving a weak residual moment of approximately 300 bohr magnetons (Jutz et al 2015).
Magnetic ordering is an effect that emerges from structure and cannot be reduced to the
presence or absence of certain elemental constituents. The above examples of paramagnetic,
ferromagnetic, antiferromagnetic, and ferrimagnetic materials all derive their magnetic
properties from iron, and yet the behavior of these materials differs markedly.

In a macroscopic object, the presence of magnetic ordering at the scale of the crystal often
does not result in an overall net magnetization. This is because, in the absence of an applied
field, magnetostatic energy can be reduced through the spontaneous formation of opposing
domains (Figure 4c). These domains are separated by domain walls, where the local
magnetization turns gradually from one direction to another. These walls have a
characteristic width that depends on the strength of the exchange interaction and other
material properties. In particles much smaller than this width, the energy cost associated
with forming a domain wall outweighs the resulting reduction in magnetostatic energy, so
multiple domains do not form. For magnetite, the approximate cutoff for single domain
behavior is approximately 80 nm (Moskowitz & Banerjee 1979). Notably, in structures with
linear dimensions within this range, behaviors intermediate between single and multidomain
states can emerge, including the possibility for vortex states (Liu et al. 2015, Yang et al.
2014).

Simply because a particle is uniformly magnetized does not imply that its moment maintains
a fixed direction. Indeed, the moments of sufficiently small particles fluctuate rapidly with
respect to their crystal axes at a rate that decreases exponentially with increasing particle
volume for a given temperature (Neél 1949). When a magnetic field is applied, if the
timescale is longer than the characteristic rate of fluctuation, a population of these particles
will show behavior similar to paramagnetism, with the important distinction that saturation
occurs at field magnitudes thousands or tens of thousands of times smaller (millitesla to tens
of millitesla), depending on their volume and the magnetization of the material (Figure 4d).
This behavior is known as “superparamagnetism,” because the population of single domain
magnetic nanoparticles acts as a collection of magnetic moments that are individually many
thousands of times larger than those of individual atoms (Bean & Livingston 1959).
It is these large effective moments, made possible by ferro- or ferrimagnetic ordering in the
crystals, that make these particles so useful for external magnetic manipulation. This is
reflected in the chains of high quality, biomineralized magnetite or gregite nanoparticles that
natural selection has favored in magnetotactic bacteria (Moskowitz et al. 1993, Schüler &
Frankel 1999, Faivre & Schüler 2008).

Synthesis of Magnetic Nanoparticles

The observation that high quality magnetic nanoparticles can be generated by cells led to the
hope that the requisite genes could be transferred to mammalian cells to artificially induce
magnetoreception. This vision has not yet been realized, but some progress has been made,
including the induction of iron oxide nanoparticle synthesis in human mesenchymal stem
cells (Elfick et al. 2017). One barrier to transfecting brain cells with magnetosome genes in
vivo is their large size, which presents a challenge to their packaging into viral vectors.
An alternative to genetically engineering cells to produce magnetite is to introduce synthetic
magnetite into an organism, such as by injecting a solution of magnetite nanoparticles
directly into the target brain area (Chen et al. 2015, Munshi et al. 2017). Magnetite
nanoparticles can be synthesized via a variety of means, each offering certain advantages.
For instance, co-precipitation cheaply produces large quantities of magnetite and
hydrothermal methods can create interesting morphologies, such as hollow structures (Wu et
al. 2015). To achieve a high degree of size uniformity and a high saturation magnetization (a
measure of the particles’ magnetic moments) high-temperature thermal decomposition
methods are often preferred (Kim et al. 2009, Park et al. 2004). During thermal
decomposition synthesis, a solution of high-boiling point organic solvents and
organometallic precursor (such as iron oleate or iron acetylacetonate) is heated until the
decomposition of the organometallic precursor leads to the nucleation and growth of iron
oxide nanoparticles (van Embden et al. 2015). By choosing solvents that undergo radical
decomposition to favor an oxidative environment, the production of phase pure Fe3O4 can be
promoted (Chen at al. 2016, Hufschmid et al. 2015). The magnetic properties of
nanoparticles can be influenced not only by altering their shape and dimensions but also by
introducing other transition metal atoms including Co, Mn, and Zn. While partial
substitution of Fe2+ by Zn2+ allows for increased saturation magnetization as compared to
magnetite (Jang et al. 2009, Noh et al. 2012), the other two atoms are typically used to
modify magnetic anisotropy, a property that is discussed in greater detail below in the
context of nanoparticle heating. Akin to pure magnetite, tertiary ferrite nanoparticles doped
with these atoms (MexFe3-xO4, Me = Mn, Co, Zn) are readily produced via thermal
decomposition at similarly high uniformity and crystallinity (Sun et al. 2004, Chen et al
2013).

Magnetomechanical Methods

Magnetic nanoparticles in a uniform magnetic field experience a torque that pulls their
magnetization in the direction of the applied field, and magnetic nanoparticles in a magnetic
field gradient experience a translational force (as in magnetic tweezers) (Figure 5a). These two mechanisms of interaction of magnetic nanoparticles with magnetic fields allow
particles attached to biomolecules, organelles, and cells to exert forces on these structures
(Pankhurst et al. 2003, Monzel et al. 2017). Sensory neurons in the peripheral nervous
system express mechanosensitive ion channels that are responsible for our sense of touch,
balance (via neurons in the inner ear), and painful pressure (Delmas et al. 2011, Coste et al.
2010) (Figure 5d). Mechanosensitive ion channels open in response to tension in the
membrane or to directly applied mechanical force. In principle, akin to opsins in
optogenetics and designer receptors in chemogenetics, these channels could be transfected
into the central nervous system to allow for magnetic nanoparticle-mediated force-based
control of the nervous system.

Figure 5.

Strategies for using synthetic nanomaterials for neuronal stimulation with magnetic fields.
(a ) Forces may be applied to magnetic particles in highly nonuniform fields, and torques
may be generated if particles exhibit anisotropy. (b ) Magnetoelectric composite
nanoparticles couple the strain resulting from magnetostriction of their core to a
piezoelectric shell, producing a change in electric polarization. (c ) The lag in response of
magnetization to an applied alternating magnetic field, which can be graphically represented
by hysteresis loops, results in dissipated heat. (d ) Force or torque may be used to actuate
mechanosensitive ion channels. (e ) Magnetoelectric composite particles can, in principle, be
used to trigger the response of voltage gated ion channels. (f ) Temperature-sensitive channel
proteins may be actuated by the heat dissipated by magnetic nanoparticles, whether through
nanoscale or bulk effects. (g ) Heat may also be used to trigger the release of chemical
agonists or antagonists that actuate ion channels.

The use of magnetic nanoparticles to activate mechanosensitive ion channels has been
demonstrated in vitro via patch clamp studies (Hughes et al. 2007) and calcium imaging
(Lee et al. 2014, Tay et al. 2017). These studies have relied on devices similar to magnetic
tweezers (Seo et al. 2016) that generate high magnetic field gradients on the order of 100
T/m. This implies that the cells being stimulated have to be in close proximity to the
magnetic elements (within 10s to 100s of microns), and for this reason the high-magnetic
field gradient approach does not translate easily to studies in vivo.

In contrast, it is possible to create low-gradient magnetic fields over volumes large enough to
fit a human, for example those in an MRI magnet. As noted above, uniform magnetic fields
can exert torques on magnetic nanoparticles, especially anisotropic ones. This torque-based
approach has been used to trigger necrosis in cancer cells, using both anisotropic particles
such as discs (Kim et al. 2009, Shen et al. 2017) as well as chains of isotropic particles
(Cheng et al. 2017) in combination with low frequency uniform fields (<20 Hz) 10s of mT in amplitude. By analogy with magnetothermal neural stimulation, which was originally inspired by magnetic hyperthermia treatment of cancer, magnetomechanical neural stimulation may work most effectively by adapting this torque-based approach to tumor destruction and tuning down the applied forces to physiologically safe levels. Another interesting application of magnetic nanoparticles as force transducers is in neural regeneration scaffolds that can be wirelessly actuated. Neurons respond to mechanical cues (Lamoureux et al. 2002), and neural regeneration may be enhanced by mechanical actuation (Smith et al. 2001, Abraham et al. 2018). Prototype neural regeneration scaffolds actuated by magnetic nanoparticles have been developed that enhance the growth of cultured sensory neurons (Tay et al. 2018). These comprise hydrogels impregnated with magnetic nanoparticles that stretch periodically in response to periodic magnetic field application and removal, exerting forces on the neurons. In the future, it may be possible to implant such scaffolds to bridge nerve injuries, and then externally and non-invasively apply a slowly varying magnetic field to actuate the scaffold and promote growth. Such hydrogel scaffolds would be resorbable, and thus magnetic actuation would enable devices that are powered remotely and do not require explantation. Magnetoelectric Composites

Since all neurons express voltage-gated ion channels, which are necessary for propagating
an action potential, it could be advantageous to develop nanomaterials capable of
transducing externally applied magnetic fields into localized electric fields in the vicinity of
the membrane, at the scale of the relevant cellular machinery (Kargol et al. 2012, Yue et al.
2012) (Figure 5b,e). This method does not rely on electromagnetic induction, which is
fundamentally electrodynamic in character, instead finding its basis in quasi-electrostatic
and quasi-magnetostatic behavior. In intrinsically magnetoelectric materials, coupling is
typically weak and is manifested only at temperatures far lower than the physiological
environment (Brown et al. 1968). Magnetoelectric (multiferroic) composites offer a more
feasible approach, and combine a material in which strain and magnetization are coupled
(magnetostriction) to a material in which strain and electrical polarization are coupled
(piezoelectricity) (Nan et al. 2008). Strain within the composite structure then links
magnetization and electric polarization (Figure 5b). In practice, macroscopic versions of
such composites exhibiting high coupling coefficients are typically driven at mechanical
resonance in order to maximize the strain amplitude (Nan et al. 2008). In contrast, studies
aiming to apply magnetostrictive-piezoelectric nanoscale composites for neural stimulation
have driven these particles with slowly varying magnetic fields with frequencies from 0–20
Hz and amplitudes of 10mT (Guduru et al. 2015). Because the magnetoelectric response of a
composite can be limited by the materials properties of either component, it is important to
select constituents that are strongly magnetostrictive and piezoelectric. Unfortunately many
strongly piezoelectric materials contain lead, which poses toxicity concerns for deployment
in biological settings. Composite nanoparticles designed for neural stimulation at the stage
of exploratory experiments have incorporated CoFe2O4 as the magnetostrictive component
and BaTiO3 as the piezoelectric component (Guduru et al. 2015).

Magnetothermal Methods

A number of minimally invasive neural stimulation strategies have recently emerged that
either directly or indirectly make use of heat dissipated by magnetic nanoparticles in
alternating magnetic fields with frequencies ranging from tens of kHz to the low MHz and
amplitudes in the 10s of mT. This heating arises from the work done by magnetic torque
against dissipative forces during the cyclic response of the magnetization (Figure 5c). These
dissipative forces can include either friction with the surrounding liquid medium when the
entire particle physically rotates with the magnetization vector or damping processes internal
to the crystal when the magnetization vector rotates independently of particle motion
(Rosensweig 2002). Whichever of these occurs more rapidly will dominate the behavior of
the system, but the latter tends to dominate when alternating magnetic field amplitudes are
sufficiently large. This is because nanoparticles exhibit preferred orientations of their
magnetic moment with respect to the crystal, a phenomenon called “anisotropy,” and applied
fields lower the energy barriers separating preferred axes (Neél 1949). The symmetry of
these these “easy axes” and the height of the energy barriers separating them can be
influenced by properties of the crystal, particle shape (Usov & Barandiaran 2012), strain
(Suzuki et al 1999), or surface effects (Peddis et al 2008). Among particles with similar
material properties and different size, the anisotropy barrier approximately scales with
volume (Neél 1949), a fact that helps explain the crucial importance of size control and
monodispersity for synthetically produced magnetic nanoparticles.

Viewing the magnetic nanoparticles from a macroscopic vantage point, the periodic lag in
response between their population-averaged magnetization and the rapidly alternating
magnetic field has a convenient graphical representation in the form of hysteresis loops,
which assume shapes that reflect the particular response of the magnetization. Despite their
differences, models describing the heat dissipation of magnetic nanoparticles predict
hysteresis loops and find their area, which corresponds to energy dissipated per cycle of the
field. Examples of common models with differing domains of validity include linear
response theory (valid at low field amplitudes compared to the Stoner-Wohlfarth coercive
field, the “anisotropy field”) (Rosensweig 2002), dynamic hysteresis (valid at frequencies
low compared to the precession of the particle moment) (Carrey et al. 2011), and stochastic
Landau-Lifshitz-Gilbert models (most general, but still containing simplifying assumptions)
(Usov 2010).

The suitability of ferrimagentic particles for heat dissipation compared to biomolecules and
weakly magnetic nanoparticles like the ferrihydrite core of ferritin can be anticipated by
considering the influence of their magnetic properties on hysteresis loops. A magnetite
nanoparticle 20 nm in diameter contains ~500,000 iron atoms in a ferrimagnetic inverse
spinel lattice. This ferrimagnetic ordering results in a higher magnetization compared to
other phases of iron oxide, stretching the scale of the vertical axis. The anisotropy energy
barrier increases with the volume of the particle and enables larger coercive fields at
sufficiently high applied amplitudes. Both of these influences tend to increase the hysteresis
loop area and result in greater dissipated power. In contrast, the ferrihydrite core of ferritin
that contains ~2500 iron atoms exhibits a low saturation magnetization that arises only
because of a small number of uncompensated spins in crystal defects of its otherwise
antiferromagnetic arrangement. Furthermore, its minute anisotropy barrier, evidenced by a
low blocking temperature of 40K, ensures that it should be expected to exhibit virtually no
hysteresis at physiological temperatures (Chasteen & Harrison 1999).

Local increases in temperature are capable of triggering the response of temperature
sensitive channel proteins such as TRPV1, and several studies have demonstrated
stimulation following injections of magnetic nanoparticles and viral delivery of trpv1
transgenes (Huang et al. 2010, Stanley et al. 2012, Chen et al. 2015). Applications making
use of hysteretic heat dissipation can be divided into two categories: those relying on bulk
heating effects and those relying on nanoscale heating effects (Figure 5f). The former
requires a highly concentrated and localized droplet of injected nanoparticles to heat itself
and the surrounding tissue, and, combined with TRPV1 expression, this has been
demonstrated as a viable approach for neuromodulation (Chen et al. 2015). On the other
hand, the possibility for nanoscale heating is less intuitive when considering the effect of
scaling relationships on the expected surface temperature of a heat-dissipating nanoscale
sphere. Indeed, an extrapolation of macroscopic heat transport equations to the nanoscale
suggests rapid equilibration on the timescale of hundreds of nanoseconds and an
infinitesimal temperature change that drops off inversely with distance (Keblinski et al.
2006, Meister 2016). Nevertheless, a growing and varied body of experimental evidence
contradicts this prediction, instead suggesting that temperatures at nanoscale interfaces reach
steady state far more slowly (seconds or even tens of seconds) and can achieve effective
temperature increases of 10s of °C in the nanometer vicinity of the nanoparticle surfaces
before dropping off rapidly in solution (Huang et al. 2010, Riedinger et al. 2013, Dong &
Zink 2014).

The use of nanoscale heating to wirelessly actuate the response of temperature sensitive
channel proteins for neuromodulation precedes not only the bulk heating approach for
neuromodulation, but also much of the work that has recently produced compelling evidence
of nanoscale heating in similar situations. In principle, the main advantage of systems based
on nanoscale heating is that they require lower quantities of magnetic material and avoid
bulk heating effects on surrounding tissue. This work often includes targeting moieties that
link the magnetic nanoparticles to the cell membranes or even the heat-sensitive channel, a
design feature consistent with the close proximity that seems to be a requisite for the
nanoscale heating effects to be relevant (Huang et al. 2010, Stanley et al. 2012). The
technique has been demonstrated to trigger TRPV1 and drive neural activity and behavioral
responses in awake, freely moving mice (Munshi et al. 2017). More recently, the concept
was extended to neural inhibition by actuating a temperature gated chloride channel,
TMEM16A (Munshi et al. 2018), offering a route to bi-directional neuromodulation
analogous to chloride channels leveraged for optogenetics (Deisseroth 2015).

Nanoscale effects of hysteretic heating have also been used as a means of triggering release
of chemical payloads from a variety of carriers, including temperature sensitive liposomes
(Amstad et al. 2011) (Figure 5g), mesoporous silica particles (Rühle et al 2016), and
individual magnetic nanoparticles functionalized with thermally labile bonds (Riedinger et
al. 2013). If the chemical species released can act as an agonist or an antagonist for a
channel protein, then it is possible to couple magnetic stimulus to chemical actuation or
downregulation of neuronal activity, mediated by heat. This concept has been demonstrated
for in vitro, when an agonist of TRPV1, allylisothiocyanate anchored to the surface of
magnetic nanoparticles via thermally sensitive azide bonds was used to stimulate neurons
expressing this cation channel (Romero et al. 2016). While conceptually promising, this
approach was restricted to payloads suited for chemical fusion to nanoparticle surfaces via
thermally labile bonds, and the quantity available for release was quickly exhausted. Future
work in this area could further develop the concept by making use of release schemes that
are less chemically restrictive and focus on receptor-agonist pairs that respond sensitively
and consistently to a wide range of concentrations.

In coming years, an appreciation of the physics underlying nanoparticle heat dissipation in
magnetic fields could offer opportunities to extend the functionality of these techniques. For
instance, dynamic hysteresis models have revealed the possibility for magnetothermal
multiplexing, the ability to selectively heat magnetic nanoparticles with distinct physical or
chemical properties using different alternating magnetic field conditions (Christiansen et al.
2014). This may enable bidirectional neural control, whether through actuating the separate
release of excitatory and inhibitory compounds from carriers or selectively actuating TRPV1
or TMEM16A.

The spatial selectivity of stimulation offered by magnetothermal methods is presently
limited by the localization of the injection, but foreseeable opportunities exist for more
precise targeting enabled by superimposed magnetostatic gradient fields. For such a
configuration, in regions with a large magnetostatic contribution, the net field would
oscillate with an offset and magnetic nanoparticles would remain saturated and largely
unresponsive to the superimposed alternating component of the field. At the point or line
where the magnetostatic field vanishes, the magnetic nanoparticles would be able to undergo
hysteretic heat dissipation. Precisely the same kind of superposition of alternating and static
magnetic fields is currently employed in magnetic particle imaging to isolate signal from
voxels (Knopp & Buzug 2014), though the amplitude and frequency of the alternating field
would need to be increased. While efficiently producing strong alternating magnetic fields at
frequencies in the hundreds of kHz in medically relevant working volumes is nontrivial,
there is no fundamental barrier to scaling (Christiansen et al. 2017), and these technical
opportunities for multiplexed and site specific neuromodulation techniques may spur on
further development of the necessary instrumentation.

CONCLUSION AND OUTLOOK

Magnetic fields offer unparalleled access to the signaling processes occurring at arbitrary
depths within the body because of the negligible magnetic permeability and low
conductivity of tissue. Harnessing magnetic field energy as a means to control neuronal
activity, however, requires transducing imperceptible magnetic fields into stimuli capable of
triggering endogenous or genetically engineered signaling cascades within these cells. The
enigmatic magnetoreception of migratory animals continues to inspire a vigorous search for
genetically encoded machinery that responds directly to magnetic fields. The cryptochrome-
dependent radical pair mechanism proposed to underlie the magnetic compass sense in birds
and insects appears to necessitate an optical stimulus, and thus cannot be implemented
within the body without implanted light sources. Magnetosomes produced by magnetotactic
bacteria, while suitable for transduction of weak magnetic fields into mechanical or thermal
stimuli, require the amount of genetic material too large to be delivered by a single viral
vector.

Paralleling the basic study of biological magnetoreception, the use of synthetic
nanomaterials is a promising and expanding means for controlling neuronal activity.
Magnetic nanoparticles can mediate interactions between magnetic fields and cellular
machinery equipped to respond to heat, forces, and chemical stimuli. Magnetic
neuromodulation methods can, in many cases, be implemented without transgenes, relying
solely on endogenously expressed ion channels in mammalian neurons. Furthermore,
nanomaterials composed of magnetite are considered biocompatible with notable examples
being used as approved MRI contrast agents (Wang 2011) and promising means to treat
brain tumors in a recent Phase II clinical trial (van Landeghem et al 2009). One outstanding
issue is that of delivering nanomaterial to targets in the brain, which at present requires
direct injection. While not a significant concern for experiments in animal models, the need
for direct injection into neural tissue may slow down the translation of otherwise promising
magnetic neuromodulation methods to clinical application. Challenges posed by delivery
across the blood brain barrier are a topic of active research, and a number of strategies
including monovalent antibodies (Niewoehner et al. 2014) and temporary permeabilization
of the barrier with focused ultrasound (Hynynen et al. 2001, Szablowski et al. 2018) or
chemical compounds (Cosolo et al. 1989) have recently emerged to aid transport of
molecules or viruses injected systemically. Such methods may require additional
engineering to account for the sizes of magnetic nanoparticles needed to effectively
transduce magnetic fields into thermal (tens of nm), electrical (tens to hundreds of nm), or
mechanical (hundreds of nm) stimuli.

The emerging interest in magnetic neuromodulation approaches demands close interactions
between physicists, chemists, engineers, and neurobiologists to appreciate the advantages
and overcome the challenges associated with these methods. Understanding of biophysical
mechanisms governing the transduction of magnetic stimuli into cellular responses is
essential not only for delivering robust and reliable magnetic neuromodulation tools for
basic neuroscience community, but is key to refining these tools as future means to
understand and treat diseases of the nervous system.

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