Conference PaperPDF Available
Non-invasive Neural Stimulation
William J. Tylera*, Joseph L. Sanguinettib,c, Maria Finia, Nicholas Hoola
aSchool of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ USA
85331; bDepartment of Psychology, University of New Mexico, Albuquerque, NM USA 87131;
cArmy Research Laboratory, Aberdeen, MD USA 21005
ABSTRACT
Neurotechnologies for non-invasively interfacing with neural circuits have been evolving from those capable of sensing
neural activity to those capable of restoring and enhancing human brain function. Generally referred to as non-invasive
neural stimulation (NINS) methods, these neuromodulation approaches rely on electrical, magnetic, photonic, and
acoustic or ultrasonic energy to influence nervous system activity, brain function, and behavior. Evidence that has been
surmounting for decades shows that advanced neural engineering of NINS technologies will indeed transform the way
humans treat diseases, interact with information, communicate, and learn. The physics underlying the ability of various
NINS methods to modulate nervous system activity can be quite different from one another depending on the energy
modality used as we briefly discuss. For members of commercial and defense industry sectors that have not traditionally
engaged in neuroscience research and development, the science, engineering and technology required to advance NINS
methods beyond the state-of-the-art presents tremendous opportunities. Within the past few years alone there have been
large increases in global investments made by federal agencies, foundations, private investors and multinational
corporations to develop advanced applications of NINS technologies. Driven by these efforts NINS methods and devices
have recently been introduced to mass markets via the consumer electronics industry. Further, NINS continues to be
explored in a growing number of defense applications focused on enhancing human dimensions. The present paper
provides a brief introduction to the field of non-invasive neural stimulation by highlighting some of the more common
methods in use or under current development today.
Keywords: Neuromodulation, Noninvasive Brain Stimulation, Neural Interface, Human Performance Enhancement
1. INTRODUCTION
Our ability to interface with the brain for purposes of regulating its activity is maturing. For centuries humans have
possessed the knowledge and chemical or surgical tools for regulating neural activity. Today, we posses the knowledge
and tools required for the precise modulation of neural activity using electrical, magnetic, optical, and ultrasonic
methods and devices. Advances in high-speed electronics, integrated circuits, and materials science have impacted so
many facets of the modern world including communication, transportation, commerce, and healthcare. From a human
dimensions perspective, these technological advances continue to enable the development of hardware, firmware, and
software for engineering wearable computers and connected network architectures bridging other sensors and devices
that track, analyze, map, and predict our behaviors (interactions with and responses to the environment). Many of the
same advances have enabled neuroscience to discover and develop a broad set of tools for safely stimulating or
modulating brain activity to produce changes in human behavior. It does not take a stretch of imagination for one to
begin to appreciate how non-invasive neural stimulation (NINS) is about to transform the human experience. To
encourage broader commercial and defense industry participation in this evolution, our brief review provides a technical
summary of NINS methods and applications focused on restoring and enhancing human performance.
2. METHODS OF NON-INVASIVE NEUROMODULATION
AND NEURAL STIMULATION
It should be widely known that the nervous system, including the brain, receives, transmits, processes, integrates, stores,
recalls, and synthesizes information via neurons. Action potentials are electrochemical, thermal, mechanical, and optical
phenomenon, which occur in axons during transmission of information from one neuron to another or a target
organ/tissue. In addition to the electrical conductance changes that occur in nerves during action potential firing, there
are propagating optical and thermal impulses or waves that can be simultaneously recorded or visualized. Electrical
Invited Paper
Micro- and Nanotechnology Sensors, Systems, and Applications IX, edited by Thomas George,
Achyut K. Dutta, M. Saif Islam, Proc. of SPIE Vol. 10194, 101941L · © 2017 SPIE
CCC code: 0277-786X/17/$18 · doi: 10.1117/12.2263175
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action potentials can also be detected and recorded as propagating optomechanical waves in axons due, in part, to
membrane displacement or contraction as reviewed in detail elsewhere1, 2. These same physicochemical properties that
enable us to sense or record action potentials also enable us to stimulate or modulate them. Neurostimulation or
neuormodulation methods are broadly classified as invasive or non-invasive3, 4. Invasive neurostimulation or
neuromodulation refers to the implementation of a surgically implanted electrode(s) to exert an effect on neural activity.
Non-invasive neuromodulation or NINS methods do not require surgically implanted electrodes, but rather deliver
energy across the skin to directly influence peripheral nerves and across bone, such as vertebrae or skull to exert direct
actions on central nervous system activity. Below, we briefly highlight and discuss the most common NINS methods in
use today.
2.1 Transcranial Magnetic and Electrical Stimulation
More than a century ago Fritsch and Hitzig first observed that direct electrical stimulation of exposed cortex (skull
removed) can trigger changes in neural activity that produce behaviors5. Until TMS was discovered by Barker and
colleagues in the mid 1980’s however, it was difficult to stimulate the brain without removing the skull6. Today, TMS is
widely recognized as an effective tool that can safely modulate human brain activity and behavior3, 7. TMS modulates
brain activity when a brief, time-varying magnetic field generates an electrical field across the scalp, skull, dura,
cerebrospinal fluid, and cortex3. The spatial distribution of the electric field generated by TMS pulses is typically
restricted to superficial cortex influencing several cm2. The shape of the electric field is influenced in an individualized
manner as a function of specific tissue anisotropies and brain geometry, which can be simulated to predict
neurophysiological outcomes8. TMS gained FDA approval to treat depression in 2008 and more recently it was approved
for the treatment of headaches. Further, TMS has been successfully used to enhance human cognitive performance in
numerous studies reviewed elsewhere7, 9. In a recent proof-of-concept study, TMS was used in conjunction with EEG
sensors in a closed-loop system that enabled direct brain-to-brain communication between two humans 10. While TMS
may never provide the precision or fine spatial resolution required to encode detailed information directly to the cortex,
it does remain possible that personal TMS units could augment human cognitive performance based on the literature7, 9.
Advances in TMS power management, magnetic coil/transducer designs, and multiple channel TMS will further open
this possibility.
Transcranial direct current stimulation (tDCS) is a specific form of transcranial electrical stimulation (TES) that has
become popular due to its simplicity. The tDCS method uses surface electrodes placed on the head and passes a direct
current (< 2 mA) through the skin, skull, dura, and cerebrospinal fluid into cortex to diffusely affect brain activity11.
Numerous studies have reported that tDCS enhances and perturbs cognitive processes, such as working memory or
creative problem solving when targeted to different brain regions12, 13. These findings have been grossly inconsistent
and/or have produced marginal effects14, 15. Due to these variable outcomes and lack of cohesive hypotheses, many have
begun to question the dogma that tDCS exerts its actions directly on cortex. Further supporting these challenges, it has
recently been shown that 1 mA TES produces a maximal electric field (Efield) strength of 0.5 mV/mm in humans16.
While it seems TES can produce a nonzero Efield strength, it remains questionable whether or not such low field
strengths can exert consistent and reliable effects on brain activity that are sufficient to alter human behavior, emotion,
or cognition.
To modulate brain oscillations related to cognitive functions, another embodiment of TES called transcranial alternating
current stimulation (tACS) has also been gaining in popularity. This method is similar to tDCS except that an AC instead
of DC stimulus is used. As with tDCS there have been numerous studies published about its effectiveness to treat
diseases or modulate certain brain functions. In many cases it is indeed apparent that tACS can functionally modulate
brain oscillations. For example, it has been shown that tACS can enhance endogenous 10 Hz brain oscillations, which
are thought to play a role in vision, after stimulation17. Indeed, pairing visual stimulation with 10 Hz tACS improves
visual motion adaptation18. In other examples voluntary movement has been slowed down with 20 Hz tACS while 70 Hz
tACS to motor cortex increased performance19. Numerous other studies have demonstrated the functional ability of tACS
to modulate brain activity as described elsewhere20. Despite many studies showing tACS can modulate oscillatory brain
activity however, it is not clear whether its entrainment of oscillations is actually achieved via direct actions on cortex or
whether they are encoded through some other bottom-up mechanisms. Further studies will be required to determine its
mechanisms of action and potential for future applications.
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2.2 Transdermal Electrical Neuromodulation of Cranial Nerves
The greatest variety of NINS methods are embodiments of transcutaneous electrical neurostimulation or TENS. There
are a tremendous number of acronyms and naming derivations to describe the basic procedure, which involves passing
static or dynamic electrical current patterns from surface electrodes across the skin to nerves. The electrical currents in
turn modulate or stimulate neuronal activity or action potentials. Transdermal neuromodulation can be achieved using
direct currents and pulsed or alternating currents spanning low (< 1 Hz) to high (kHz) frequency ranges. For use in the
periphery, electrical methods can be designed as devices or systems taking on a variety of different industrial designs
including gloves or other wearable forms using surface mounted electrodes or transducers. Although it is difficult to
regulate which neural pathways or fibers (sensory, pain, motor, or proprioceptive, for example) are activated using
transdermal methods, they can be powerful as further described below.
Given the safety of TENS and similar transdermal neurostimulation devices, there are many over-the-counter devices
cleared by the FDA as indicated for a variety of medical, cosmetic (aesthetic), and recreational purposes. These basic
methods also serve the foundation for modulation of a specific class of peripheral nerves called cranial nerves (CN’s).
There are twelve pairs of cranial nerves, which can provide powerful conduits to central regulators of brain activity.
Afferent fibers of the trigeminal (CN V), facial (CN VII), vagal (CN X), accessory (CN XI), and hypoglossal (CN XII)
nerves, as well as afferents of cervical nerves, like cervical spinal nerves and the phrenic nerve, project directly to
sensory nuclei of the brain stem. These nerves are readily accessible using surface electrodes placed on the head, face,
and neck. Sensory information relayed by these nerves is transmitted to cortical areas via thalamocortical pathways.
Prior to, during, and after signal propagation to cortex however, the incoming peripheral signals undergo extensive local
processing in a series of highly inter-connected structures including the ascending reticular activating system (RAS)
located in the brainstem. This first station of information integration in the brain is where higher consciousness is
thought to originate in brain stem circuits filtering, integrating, and processing incoming sensory information21. It is also
here that cranial and spinal nerves modulate the activity of RAS nuclei like the locus coeruleus (LC), raphe nuclei (RN),
and pedunculopontine nuclei (PPN), which in turn regulate cortical processing22-24.
Through bottom-up pathways the LC, RN, and PPN influence brain activity and behavior by controlling arousal,
attention, sleep/wake cycles, and higher cognitive functions including learning and memory by regulating levels of
norepinephrine (NE), serotonin (5-HT), and acetylcholine (ACh) respectively. To those not skilled in the art of
neuroscience it may not be obvious, but these signaling pathways and molecules are the classical targets of many potent
classes of drugs, such as beta-blockers, SSRI’s, MAOI’s, and amphetamine derivatives used to treat diseases or to
enhance human performance including cognition. Pharmacological methods swamp systems usually in an unspecific
manner resulting in complications or off-target side effects. Due to its targeting abilities, peripheral NINS may offer a
controlled method of achieving drug-like outcomes with fewer side effects. Further, since these pathways represent some
of the most powerful endogenous neuromodulators known to exist in the brain, learning to harness their signaling
abilities with pulsed transdermal electrical stimulation (pTES) of cranial nerves will be imperative to the success of
future NINS methods intended to augment human performance and cognition. This is true especially given the ease of
access of CN’s and the robust ability of pTES and similar transcutaneous electrical methods to modulate brain activity.
With respect to the safety, there exists a wealth of primary data and clinical endpoints demonstrating broad safety
margins for electrical stimulation of peripheral nerves including the vagus25, 26. Stimulation of the cervical and auricular
branch of the vagus has been repeatedly demonstrated to induce short-term and long-term brain plasticity25. It has also
been shown to modulate brain circuits and trigger signaling consequences supporting mechanisms of action for the
observed plasticity27-30. These methods have shown also been shown effective for treating depression, ADHD, anxiety,
epilepsy, and PTSD. Interestingly, transdermal auricular vagal nerve stimulation (taVNS) can be achieved using an ear-
bud headphone style electrode, which opens some interesting possibilities for the industrial design of future NINS
devices. In fact, a consumer version taVNS device integrated with an audio headphone is commercially available. Given
repeated demonstrations that transdermal VNS has been shown to be as effective as surgically implanted cervical VNS
electrodes, there is a shift towards favoring this non-invasive approach. Whether or not VNS can be advanced to harness
plasticity in a useful manner for real world gains remains to be determined. The introduction of VNS devices to
consumer mass markets will, no doubt, help shed light on this open question.
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The types of electrical NINS waveforms and anatomical targets that have been shown capable of exerting effects through
CN modulation have been diverse. Several electrophysiological and neuroanatomical studies have provided definitive
evidence of functional synaptic connectivity between trigeminal afferents and the PPN and LC22, 31-33. Depending on
their firing rates, neurons of the PPN can differentially mediate REM sleep states34, 35 and neurons of the LC can trigger
sleep/wake transitions36, 37. Disrupted activity of ascending RAS networks underlies several neuropsychiatric conditions
and disorders, such as insomnia, anxiety, depression, post-traumatic stress disorder (PTSD), and attention deficit
hyperactivity disorder (ADHD)24, 34, 38, 39. Therefore, a neural interface capable of dynamically and electrically
modulating RAS networks should be able to provide a chemical-free approach to restoring poor daily function
attributable to sleep loss or attention and mood disorders. Such an interface would also support new approaches capable
of optimizing normal human performance.
Transcutaneous trigeminal nerve stimulation (TNS) has been shown to be effective for treating neuropsychiatric
conditions like depression40, PTSD41, generalized anxiety disorder (GAD)42, ADHD43, as well as neurological disorders
like epilepsy44, 45 and headache46, 47. Interestingly, acute TNS at a frequency of 120 Hz has been demonstrated to induce
sleepiness and sedative like effects in healthy adults while 2.5 Hz stimulation frequency did not48. The observations
made by Piquet and colleagues (2011) suggest that TNS may provide some benefit for some sleep disturbances and
insomnia. High-frequency (kHz) pTES of trigeminal and cervical afferents via a small, wearable device attached to the
side of the forehead and base of neck has been shown capable of significantly suppressing stress responses during fear
conditioning by decreasing sympathetic tone and biochemical markers of noradrenergic activity in humans49. These
effects are also thought to underlie the mechanisms of action responsible for the ability of high frequency trigeminal
pTES to improve sleep quality and enhance mood as indicated by physiological, biochemical and behavioral measures50.
Such an ability of trigeminal or cervical nerve stimulation to modulate sleep raises interesting possibilities. Certainly
being able to modulate sleep/wake cycles or trigger restorative micro-naps on-demand would have profound
implications on human cognitive performance. Based on our preliminary findings it appears the modulation of the
cervical plexus and trigeminal-vagal circuits using NINS may provide a path to achieving such milestones50.
One of the major hurdles for developing CN modulation methods and systems intended to optimize human performance
and cognition will be to identify the optimal stimulation parameters required to drive neural plasticity. Systematic studies
have not been conducted to identify the best NINS parameters for optimizing neuromodulator signaling or plasticity in
the healthy adult brain. Many of the parameters that have been used to date were originally identified and adopted for
their ability to desynchronize or interfere with aberrant neural activity, like that which occurs in diseased brain states,
such as epilepsy, tinnitus, and depression. In fact, the VNS studies that have shown effects on plasticity have largely
borrowed their stimulation devices and parameters from the clinical designs and practices28, 51-55. This may pose
somewhat of an issue when developing systems for enhancing normal plasticity. It is simply not known whether
clinically identified and validated neurostimulation parameters are ideally suited for NINS applications where optimizing
normal brain function is the desired outcome. Therefore, future studies should continue to identify optimal targets and
parameter sets.
2.3 Photonic Methods and Neuromodulation by Longer Electromagnetic Waves
In addition to electrical and magnetic methods, several photonic-based NINS methods have been described. In particular,
near infrared (NIR) photons have been repeatedly shown to be capable of modulating peripheral nerve activity56-58.
Several mechanisms of action have been proposed and represent a source of some debate still in the field. Under many
conditions it is obvious that thermal effects can mediate neurostimulation by IR pulses altering local heat exchange
between water and lipid molecules and that this would alter membrane capacitance59. Adiabatic membrane deformations
produced by brief, low energy laser pulses could also underlie the ability of IR and visible photons to modulate neural
activity. Multiple mechanisms remain possible. For example, a leading candidate mechanism is that IR pulses generate
acoustic shockwaves and membrane nanopores, which lead to changes in capacitance and activation of voltage-gated ion
channels60. Visible wavelengths and mid-infrared (MIR) have also been shown to non-invasively stimulate neural
activity by producing optoacoustic effects, which could enhance cochlear implant technology61, 62. Future investigations
will be required to unravel the mechanisms, but this will not impede continued development and application of IR
neurostimulation technologies.
In other embodiments NIR light is also used for photobiomodulation (PBM), which involves lower energy levels for the
modulation versus stimulation of neurons. NIR photons can penetrate the cortex up to few centimeters to produce
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functional effects on brain activity63, 64. Applications of transcranial PBM (tPBM) using light emitting diodes (LEDs) for
transmitting NIR photons to the cortex have been shown to enhance cognitive function in patents suffering from several
neurological and psychiatric disorders65, 66. Interestingly, intranasal PBM has also been reported in a few cases to provide
cognitive benefits to patients suffering from mild to moderate dementia67. Transcranial NIR laser therapy has also been
shown to safely modulate emotional and cognitive function in healthy humans68. Despite the early promise of PBM,
tPBM and LLLT, these viable options of modulating brain activity have been understudied to date. Further studies into
the potential of tPBM for cognitive enhancement are certainly warranted. This is true especially when considering the
preliminary findings of safety and efficacy coupled with the fact that numerous off-the-shelf components can be used to
engineer relatively simple tPBM optical neural interfaces that may be effective.
Far infrared (FIR) and even longer electromagnetic wavelengths extending into the millimeter wave (MMW) range have
been shown capable of modulating neural activity. It has been suggested that nonthermal and microthermal effects of
GHz and THz waves on cellular activity and signaling may occur through the coherent vibration/activation of molecules
or linear/nonlinear resonance effects on molecules69, 70. Regardless of the mechanisms, there is clear evidence that THz
or GHz radiation can produce both nonthermal and thermal effects on the activity of cells including neurons. The
exposure of embryonic cells to 94 GHz radiation can trigger neuron-like calcium spiking mediated by N-type calcium
channels without producing significant heating effects71. Further, exposure of organotypic hippocampal cultures to low-
power MMW (60 GHz; < 0.5 mW/cm2) has been shown to induce hyperpolarization, a narrowing of action potential
width, and a bimodal effect on neuronal firing through non-thermal mechanisms72. Similarly, brief exposure of the leech
midbody ganglion to 60 GHz (1 – 5 mW/cm2) has also been shown to produce hyperpolarization effects upon neurons,
as well as to modulating neuronal firing through non-thermal actions73. Exposure to THz (0.7. 2.49, and 3.69 THz) laser
radiation at intensities as low as 1 mW/cm2 has been shown to modulate the growth dynamics of neurons without
affecting the abilities of neurons to maintain membrane potentials indicating that THz rays can affect neuronal structure-
function relationships74, 75. Whether or not these basic observations can be translated into practical applications remains
to be seen.
We hypothesize that recent breakthroughs in technologies that make the THz gap more readily penetrable by scientists
and engineers will shape the way we interface with the brain in the future. More specifically we believe that optical and
mechanical signals can be extracted from the nervous system using THz imaging and spectroscopy techniques. We also
believe that the non-thermal bioeffects of non-ionizing THz radiation may open new paths to modulating or regulating
neuronal activity and neural circuit dynamics. Certainly many technical challenges, such as water absorption and tissue
penetration must be considered but these are problems that can be addressed given sufficient time and resources.
2.4 Ultrasonic Neuromodulation
The idea of using ultrasound (US) to modulate biological activity can be traced back to the early part of the 20th Century
when Harvey first demonstrated that US could influence the activity of frog and turtle neuromuscular activity76. Other
advancements on this concept demonstrated that US could differentially effect the amplitudes and durations of
compound action potentials and field potentials evoked by sensory or electrical stimulation77-81. In other words, these
studies showed US is capable of influencing electrically evoked activity, but not that it could directly stimulate neuronal
activity or trigger action potentials. About a decade ago it was first shown that pulsed ultrasound (US) could directly and
noninvasively stimulate action potentials and synaptic transmission in brain circuits by acting through nonthermal
(mechanical) mechanisms on voltage-gated ion channel activity82. Since then the field of ultrasonic neuromodulation
(UNMOD) has emerged through numerous demonstrations that US can be used to safely and focally modulate the
activity of brain circuits in different organisms including humans83. It has also been shown in numerous different
experimental preparations that US can modulate peripheral neural circuits83. Because US can be transmitted and focused
across bone including skull deep into soft tissues, it has a variety of potential applications as a NINS solution as
discussed below.
Following our initial observations that low-intensity US could directly stimulate action potentials, synaptic transmission,
and brain circuit activity in vitro, we aimed at developing ultrasonic methods for conducting non-invasive, transcranial
stimulation of brain circuits. To this end we developed methods demonstrating non-invasive in vivo stimulation of motor
cortex and hippocampus84, as well as the rapid attenuation (within seconds) of kainic acid induced electrographic seizure
activity in mice85. It has also been shown by a number of different groups that the mechanical bioeffects of focused
ultrasound (FUS) can stimulate the activity of intact cortical, thalamic, and hippocampal circuits in rodents86-89, rabbits90,
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sheep91, and behaving, non-human primates92. In most cases the acoustic intensities that have been used in these studies
to stimulate brain circuits are below the recommended upper limits (< 190 W/cm2) deemed safe for imaging
applications.
Depending on the particular application, US for NINS can yield high spatial resolutions approaching the single cell level.
For example it has been elegantly shown that FUS can precisely stimulate retinal circuits at speeds faster than photic
transduction by circumventing slow photochemical reactions required during natural visual processing93. The spatial
resolution of retinal stimulation in these studies was 90 μm using 43 MHz FUS93. High frequency US can be used in
such peripheral applications to interface with neural circuits since transmission across bone is not required. As discussed
throughout the literature, the optimal US frequency for transcranial transmission and focusing tends to be < 0.7 MHz,
which does currently limit the spatial resolution to a degree. Using a pulsed US waveform having a fundamental acoustic
frequency of 0.5 MHz at peak intensities < 50 W/cm2, we first demonstrated that transcranial FUS (tFUS) can
physiologically and functionally modulate sensory-driven activity of primary sensory cortex (S1)94. The spatial
resolution of the acoustic field produced in cortex by tFUS was an ellipsoid having a minor axis length (lateral spatial
resolution) of about five millimeters and a major axis length (axial resolution) of about 18 millimeters in healthy human
volunteers94. With similar spatial resolutions studies have more recently shown that 0.35 MHz tFUS targeted to S1 can
directly stimulate and evoke somatosensory potentials and thermal/mechanical/pain sensations in the hand and fingers of
human volunteers95. Most recently Lee and reported that tFUS targeted to primary visual cortex can elicit visual
sensations and evoke sensory potentials in humans96. Although the evidence to date has demonstrated convincingly that
UNMOD is safe, appropriate safety precautions should always be taken when modulating brain or neural function with
FUS since the full spectrum of safe and effective parameters are still being identified, optimized and refined.
It is important to realize that the past decade has seen a flurry of activity demonstrating US can stimulate and modulate
activity. However, we are just at the beginning of an effort that will require decades in order to unravel how mechanical
energy influences the electrical activity of brain circuits. In many cases, the basic observations that US can stimulate
brain circuit activity simply do not fit with our conventional models of electrochemical neural activity2. Therefore the
generation of new frameworks, such as the bilayer sonophore and NICE models that elegantly consider how mechanical
forces can interact with conventional models of neuronal excitability are required97, 98. It has taken several decades to
understand how electrical currents or pulsed electromagnetic fields influence brain activity and these tools already fit
within our existing working models of neuroscience. Despite more than a century of use, we are still grappling with how
electrical neuromodulation effects brain function and behavior. Thus, one can be certain that understanding the
biophysical mechanisms of UNMOD poses a particularly difficult challenge that will require research by numerous
multidisciplinary groups to solve. Large cross-disciplinary efforts aimed at solving these issues should be justified
however since they will reveal some completely novel information about how mechanical forces act to regulate brain
activity and plasticity.
Advances in acoustic metamaterials and acoustic hyperlenses have enabled super-resolution acoustic imaging over the
past decade by producing sub-diffraction US99, 100. Whether such advances in acoustic metamaterials99, hyperlenses100,
sound bullets101, or propagation invariant acoustic field needle beams102 can enable super-resolution UNMOD by tFUS is
not yet known, but most certainly worth exploring since such methods could enable totally unprecedented spatial control
of both superficial and deep-brain circuit activity in a manner that is non-invasive. More interestingly, the use of
holographic US makes it feasible to modulate multiple sites within a neural circuit simultaneously. This can be achieved
in a manner such that the multifocal US neurostimulation patterns can be spatiotemporally modulated rapidly to convey
complex sensory information103, 104. Forward looking applications of such a technology are being developed as an
acoustic retinal prosthetic103, 104. Similarly US can be used in different ways to deliver haptic inputs (ultrahaptics), as
well as for generating virtually interactive 3D objects in free space105, 106. Such contact-free or touch-less neural
interfaces implementing US and UNMOD pose a world of intriguing possibilities especially for entertainment and
communications purposes106.
Optical holograms can be superimposed with ultrasonic holograms to create virtual multisensory stimuli that can be seen
and felt. The potential for enhancing learning, communication, strategic planning, and entertainment with multiplexed
optical and acoustic holograms is staggering. Another enticing prospects is an embodiment, which incorporates the
neuromodulation capabilities of US with ultrasound imaging abilities in an integrated, wearable form factor to both
stimulate and image brain activity in freely behaving humans. There are active and ongoing efforts to develop both of
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these types of technologies by multiple research groups around the world. Thus, it can be anticipated that the next decade
of UNMOD development will bring several new breakthroughs.
3. FUTURE OF NON-INVASIVE NEURAL STIMULATION
There is no doubt that the future of non-invasive neural stimulation will exert great impacts on society. In the past we
have seen cutting-edge neuroscience technologies be developed through confined, clinical research studies or shielded
by academic labs. Chatter about neuromodulation and brain stimulation used to be the talk of science fiction or fantasy.
Today, hackers, enthusiasts, small companies, larger corporations, and private enterprises are rapidly developing
neurotechnologies. The same is true for neuromodulation, which is similarly supported by numerous online support
forums dedicated to openly sharing recipes, protocols, hardware insights, PCB layouts, firmware mods, software hacks,
as well as other information about NINS. This proliferation of neuromodulation resources in the public domain
combined with the presently ongoing early adoption of non-invasive neuromodulation devices by consumers will bring
about rapid growth in the field over the coming decade. State-of–the-art devices will eventually evolve into multimodal
NINS systems incorporating optical, electrical, magnetic, and ultrasonic modalities to simultaneously read and write
human brain activity.
Academic and clinical neuroscience efforts will benefit from NINS growth since it will greatly scale our real world
insights into human brain behavior relationships. Medicine will be able to develop better NINS-based therapies using
these insights. Closed-loop architectures enabling NINS treatment protocols or stimulation paradigms to be delivered in
response to physiological triggers or environmental cues will become the norm. Further, activities like the ongoing
development of NINS technologies for accelerating learning will change education and skill training. The ongoing
development of NINS technologies to improve sleep can improve the general mental health and well-being of hundreds
of millions of individuals. Modulation of sleep/wake cycles by NINS could also save industries billions of dollars by
reducing work related accidents due to fatigue. Similarly, the modulation of attention and vigilance using NINS could
maximize efficiency by streamlining workflows or improving mental efforts during long tasks. While there are
numerous possibilities grounded by the literature referenced in our short review, seeing these possibilities become
realities will always depend on the advancement of transparent science and the engineering of high quality NINS devices
for safety and reliability purposes.
4. CONCLUSION
The major goal of the present paper was to provide a brief overview of non-invasive neural stimulation for the general
defense and commercial sensing community. Brain stimulation and neuromodulation have been relatively obscure fields
until recently. There are major unmet needs and gaps in the field of neuromodulation that can be filled by engineers and
scientists who are experts at developing advanced sensor and transducers intended for other industrial or defense
applications. Therefore, the rise of NINS and neuromodulation present unique opportunities for developing next
generation neurotechnologies that will become an integral part of our future communications, entertainment, defense,
and medical industries.
REFERENCES
[1] W. J. Tyler, “The mechanobiology of brain function,” Nat Rev Neurosci, 13(12), 867-78 (2012).
[2] J. K. Mueller, and W. J. Tyler, “A quantitative overview of biophysical forces impinging on neural function,”
Phys Biol, 11(5), 051001 (2014).
[3] T. Wagner, A. Valero-Cabre, and A. Pascual-Leone, “Noninvasive human brain stimulation,” Annu Rev Biomed
Eng, 9, 527-565 (2007).
[4] S. Luan, I. Williams, K. Nikolic et al., “Neuromodulation: present and emerging methods,” Frontiers in
Neuroengineering, 7, (2014).
[5] G. Fritsch, and E. Hitzig, “Über die elektrische Erregbarkeit des Grosshirns,” Arch. Anat. Physiol., 37, 300–332
(1870).
Proc. of SPIE Vol. 10194 101941L-7
Downloaded From: http://proceedings.spiedigitallibrary.org/pdfaccess.ashx?url=/data/conferences/spiep/92914/ on 05/23/2017 Terms of Use: http://spiedigitallibrary.org/ss/termsofuse.aspx
[6] A. T. Barker, R. Jalinous, and I. L. Freeston, “Non-invasive magnetic stimulation of human motor cortex,”
Lancet, 1(8437), 1106-7 (1985).
[7] B. L. Parkin, H. Ekhtiari, and V. F. Walsh, “Non-invasive human brain stimulation in cognitive neuroscience: A
primer,” Neuron, 87(5), 932-45 (2015).
[8] A. Opitz, N. Zafar, V. Bockermann et al., “Validating computationally predicted TMS stimulation areas using
direct electrical stimulation in patients with brain tumors near precentral regions,” Neuroimage Clin, 4, 500-7
(2014).
[9] B. Luber, and S. H. Lisanby, “Enhancement of human cognitive performance using transcranial magnetic
stimulation (TMS),” Neuroimage, 85, 961-70 (2014).
[10] R. P. Rao, A. Stocco, M. Bryan et al., “A direct brain-to-brain interface in humans,” PLoS One, 9(11), e111332
(2014).
[11] A. V. Peterchev, T. A. Wagner, P. C. Miranda et al., “Fundamentals of transcranial electric and magnetic
stimulation dose: definition, selection, and reporting practices,” Brain Stimul, 5(4), 435-53 (2012).
[12] V. Dubljevic, V. Saigle, and E. Racine, “The rising tide of tDCS in the media and academic literature,” Neuron,
82(4), 731-6 (2014).
[13] A. Floel, “tDCS-enhanced motor and cognitive function in neurological diseases,” Neuroimage, 85, 934-47
(2014).
[14] J. C. Horvath, J. D. Forte, and O. Carter, “Evidence that transcranial direct current stimulation (tDCS) generates
little-to-no reliable neurophysiologic effect beyond MEP amplitude modulation in healthy human subjects: A
systematic review,” Neuropsychologia, 66, 213-236 (2015).
[15] J. C. Horvath, J. D. Forte, and O. Carter, “Quantitative review finds no evidence of cognitive effects in healthy
populations from single-session transcranial direct current stimulation (tDCS),” Brain Stimulation: Basic,
Translational, and Clinical Research in Neuromodulation, (2015).
[16] A. Opitz, A. Falchier, C.-G. Yan et al., “Spatiotemporal structure of intracranial electric fields induced by
transcranial electric stimulation in humans and nonhuman primates,” Scientific Reports, 6, 31236 (2016).
[17] T. Zaehle, S. Rach, and C. S. Herrmann, “Transcranial alternating current stimulation enhances individual alpha
activity in human EEG,” PLOS ONE, 5(11), e13766 (2010).
[18] K. Kar, and B. Krekelberg, “Transcranial alternating current stimulation attenuates visual motion adaptation,” J
Neurosci, 34(21), 7334-40 (2014).
[19] S. D. Muthukumaraswamy, “Functional properties of human primary motor cortex gamma oscillations,” J
Neurophysiol, 104(5), 2873-85 (2010).
[20] C. Herrmann, S. Rach, T. Neuling et al., “Transcranial alternating current stimulation: a review of the underlying
mechanisms and modulation of cognitive processes,” Frontiers in Human Neuroscience, 7(279), (2013).
[21] J. Parvizi, and A. Damasio, “Consciousness and the brainstem,” Cognition, 79(1-2), 135-60 (2001).
[22] L. B. Couto, C. R. Moroni, C. M. dos Reis Ferreira et al., “Descriptive and functional neuroanatomy of locus
coeruleus-noradrenaline-containing neurons involvement in bradykinin-induced antinociception on principal
sensory trigeminal nucleus,” J Chem Neuroanat, 32(1), 28-45 (2006).
[23] C. W. Berridge, and B. D. Waterhouse, “The locus coeruleus-noradrenergic system: modulation of behavioral
state and state-dependent cognitive processes,” Brain Res Brain Res Rev, 42(1), 33-84 (2003).
[24] S. J. Sara, “The locus coeruleus and noradrenergic modulation of cognition,” Nat Rev Neurosci, 10(3), 211-23
(2009).
[25] E. Ben-Menachem, D. Revesz, B. J. Simon et al., “Surgically implanted and non-invasive vagus nerve
stimulation: a review of efficacy, safety and tolerability,” Eur J Neurol, 22(9), 1260-8 (2015).
[26] D. B. McCreery, W. F. Agnew, T. G. H. Yuen et al., “Charge density and charge per phase as cofactors in neural
injury induced by electrical stimulation,” IEEE Transactions on Biomedical Engineering, 37(10), 996-1001
(1990).
[27] J. Fang, P. Rong, Y. Hong et al., “Transcutaneous vagus nerve stimulation modulates default mode network in
major depressive disorder,” Biol Psychiatry, 79(4), 266-73 (2016).
[28] E. Frangos, J. Ellrich, and B. R. Komisaruk, “Non-invasive access to the vagus nerve central projections via
electrical stimulation of the external ear: fMRI evidence in humans,” Brain Stimulation: Basic, Translational, and
Clinical Research in Neuromodulation, 8(3), 624-636 (2015).
[29] S. E. Krahl, and K. B. Clark, “Vagus nerve stimulation for epilepsy: A review of central mechanisms,” Surgical
Neurology International, 3(Suppl 4), S255-S259 (2012).
Proc. of SPIE Vol. 10194 101941L-8
Downloaded From: http://proceedings.spiedigitallibrary.org/pdfaccess.ashx?url=/data/conferences/spiep/92914/ on 05/23/2017 Terms of Use: http://spiedigitallibrary.org/ss/termsofuse.aspx
[30] T. Kraus, K. Hösl, O. Kiess et al., “BOLD fMRI deactivation of limbic and temporal brain structures and mood
enhancing effect by transcutaneous vagus nerve stimulation,” Journal of Neural Transmission, 114(11), 1485-
1493 (2007).
[31] B. S. Grunwerg, H. Krein, and G. M. Krauthamer, “Somatosensory input and thalamic projection of
pedunculopontine tegmental neurons,” NeuroReport, 3(8), 673-675 (1992).
[32] J. K. Harting, and D. P. Van Lieshout, “Spatial relationships of axons arising from the substantia nigra, spinal
trigeminal nucleus, and pedunculopontine tegmental nucleus within the intermediate gray of the cat superior
colliculus,” The Journal of Comparative Neurology, 305(4), 543-558 (1991).
[33] D. L. Voisin, N. Guy, M. Chalus et al., “Nociceptive stimulation activates locus coeruleus neurones projecting to
the somatosensory thalamus in the rat,” J Physiol, 566, 929-37 (2005).
[34] E. Garcia-Rill, B. Luster, S. Mahaffey et al., “Pedunculopontine arousal system physiology – Implications for
insomnia,” Sleep Science, 8(2), 92-99 (2015).
[35] J. Lu, D. Sherman, M. Devor et al., “A putative flip–flop switch for control of REM sleep,” Nature, 441(7093),
589-594 (2006).
[36] K. I. Kaitin, D. L. Bliwise, C. Gleason et al., “Sleep disturbance produced by electrical stimulation of the locus
coeruleus in a human subject,” Biol Psychiatry, 21(8-9), 710-6 (1986).
[37] M. E. Carter, O. Yizhar, S. Chikahisa et al., “Tuning arousal with optogenetic modulation of locus coeruleus
neurons,” Nat Neurosci, 13(12), 1526-33 (2010).
[38] A. Gummadavelli, A. J. Kundishora, J. T. Willie et al., “Neurostimulation to improve level of consciousness in
patients with epilepsy,” Neurosurg Focus, 38(6), E10 (2015).
[39] J. J. Lemaire, A. Sontheimer, H. Nezzar et al., “Electrical modulation of neuronal networks in brain-injured
patients with disorders of consciousness: a systematic review,” Ann Fr Anesth Reanim, 33(2), 88-97 (2014).
[40] I. A. Cook, L. M. Schrader, C. M. Degiorgio et al., “Trigeminal nerve stimulation in major depressive disorder:
acute outcomes in an open pilot study,” Epilepsy Behav, 28(2), 221-6 (2013).
[41] A. P. Trevizol, P. Shiozawa, I. Albuquerque Sato et al., “Trigeminal nerve stimulation (TNS) for post-traumatic
stress disorder: A case study,” Brain Stimul, 8(3), 676-8 (2015).
[42] A. P. Trevizol, P. Shiozawa, I. A. Sato et al., “Trigeminal nerve stimulation (TNS) for generalized anxiety
disorder: A case study,” Brain Stimul, 8(3), 659-60 (2015).
[43] J. J. McGough, S. K. Loo, A. Sturm et al., “An eight-week, open-trial, pilot feasibility study of trigeminal nerve
stimulation in youth with attention-deficit/hyperactivity disorder,” Brain Stimul, 8(2), 299-304 (2015).
[44] C. M. DeGiorgio, D. Murray, D. Markovic et al., “Trigeminal nerve stimulation for epilepsy: long-term feasibility
and efficacy,” Neurology, 72(10), 936-8 (2009).
[45] C. M. DeGiorgio, J. Soss, I. A. Cook et al., “Randomized controlled trial of trigeminal nerve stimulation for drug-
resistant epilepsy,” Neurology, 80(9), 786-91 (2013).
[46] D. Magis, S. Sava, T. S. d'Elia et al., “Safety and patients' satisfaction of transcutaneous supraorbital
neurostimulation (tSNS) with the Cefaly(R) device in headache treatment: a survey of 2,313 headache sufferers in
the general population,” J Headache Pain, 14, 95 (2013).
[47] J. Schoenen, B. Vandersmissen, S. Jeangette et al., “Migraine prevention with a supraorbital transcutaneous
stimulator: a randomized controlled trial,” Neurology, 80(8), 697-704 (2013).
[48] M. Piquet, C. Balestra, S. L. Sava et al., “Supraorbital transcutaneous neurostimulation has sedative effects in
healthy subjects,” BMC Neurology, 11, 135-135 (2011).
[49] W. J. Tyler, A. M. Boasso, H. M. Mortimore et al., “Transdermal neuromodulation of noradrenergic activity
suppresses psychophysiological and biochemical stress responses in humans,” Sci Rep, 5, 13865 (2015).
[50] A. M. Boasso, H. Mortimore, R. Silva et al., “Transdermal electrical neuromodulation of the trigeminal sensory
nuclear complex improves sleep quality and mood,” bioRxiv, (2016).
[51] N. D. Engineer, J. R. Riley, J. D. Seale et al., “Reversing pathological neural activity using targeted plasticity,”
Nature, 470(7332), 101-4 (2011).
[52] M. S. Borland, W. A. Vrana, N. A. Moreno et al., “Cortical map plasticity as a function of vagus nerve
stimulation intensity,” Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 9(1),
117-123 (2016).
[53] H. I. L. Jacobs, J. M. Riphagen, C. M. Razat et al., “Transcutaneous vagus nerve stimulation boosts associative
memory in older individuals,” Neurobiology of Aging, 36(5), 1860-1867 (2015).
[54] R. Sellaro, J. W. van Leusden, K. D. Tona et al., “transcutaneous vagus nerve stimulation enhances post-error
slowing,” J Cogn Neurosci, 27(11), 2126-32 (2015).
Proc. of SPIE Vol. 10194 101941L-9
Downloaded From: http://proceedings.spiedigitallibrary.org/pdfaccess.ashx?url=/data/conferences/spiep/92914/ on 05/23/2017 Terms of Use: http://spiedigitallibrary.org/ss/termsofuse.aspx
[55] L. Steenbergen, R. Sellaro, A.-K. Stock et al., “Transcutaneous vagus nerve stimulation (tVNS) enhances
response selection during action cascading processes,” European Neuropsychopharmacology, 25(6), 773-778
(2015).
[56] J. Wells, C. Kao, E. D. Jansen et al., “Application of infrared light for in vivo neural stimulation,” Journal of
Biomedical Optics, 10(6), 064003-064003-12 (2005).
[57] C. P. Richter, and X. Tan, “Photons and neurons,” Hear Res, 311, 72-88 (2014).
[58] G. D. Baxter, D. M. Walsh, J. M. Allen et al., “Effects of low intensity infrared laser irradiation upon conduction
in the human median nerve in vivo,” Experimental Physiology, 79(2), 227-234 (1994).
[59] M. G. Shapiro, K. Homma, S. Villarreal et al., “Infrared light excites cells by changing their electrical
capacitance,” Nat Commun, 3, 736 (2012).
[60] T. B. Hope, P. T. Gleb, D. M. Joshua et al., “Plasma membrane nanoporation as a possible mechanism behind
infrared excitation of cells,” Journal of Neural Engineering, 11(6), 066006 (2014).
[61] A. D. Izzo, J. T. Walsh, E. D. Jansen et al., “Optical parameter variability in laser nerve stimulation: a study of
pulse duration, repetition rate, and wavelength,” IEEE Transactions on Biomedical Engineering, 54(6), 1108-1114
(2007).
[62] G. I. Wenzel, S. Balster, K. Zhang et al., “Green laser light activates the inner ear,” Journal of Biomedical Optics,
14(4), 044007-044007-6 (2009).
[63] C. E. Tedford, S. DeLapp, S. Jacques et al., “Quantitative analysis of transcranial and intraparenchymal light
penetration in human cadaver brain tissue,” Lasers Surg Med, 47(4), 312-22 (2015).
[64] T. A. Henderson, and L. D. Morries, “Near-infrared photonic energy penetration: can infrared phototherapy
effectively reach the human brain?,” Neuropsychiatr Dis Treat, 11, 2191-208 (2015).
[65] M. A. Naeser, P. I. Martin, M. D. Ho et al., “Transcranial, Red/Near-Infrared Light-Emitting Diode Therapy to
Improve Cognition in Chronic Traumatic Brain Injury,” Photomed Laser Surg, 34(12), 610-626 (2016).
[66] M. R. Hamblin, “Shining light on the head: Photobiomodulation for brain disorders,” BBA Clin, 6, 113-124
(2016).
[67] A. E. Saltmarche, M. A. Naeser, K. F. Ho et al., “Significant Improvement in Cognition in Mild to Moderately
Severe Dementia Cases Treated with Transcranial Plus Intranasal Photobiomodulation: Case Series Report,”
Photomed Laser Surg, (2017).
[68] D. W. Barrett, and F. Gonzalez-Lima, “Transcranial infrared laser stimulation produces beneficial cognitive and
emotional effects in humans,” Neuroscience, 230, 13-23 (2013).
[69] H. Fröhlich, “The extraordinary dielectric properties of biological materials and the action of enzymes,”
Proceedings of the National Academy of Sciences, 72(11), 4211-4215 (1975).
[70] G. J. Wilmink, and J. E. Grundt, “Invited review article: current state of research on biological effects of terahertz
radiation,” Journal of Infrared, Millimeter, and Terahertz Waves, 32(10), 1074-1122 (2011).
[71] I. A. Titushkin, V. S. Rao, W. F. Pickard et al., “Altered calcium dynamics mediates P19-derived neuron-like cell
responses to millimeter-wave radiation,” Radiat Res, 172(6), 725-36 (2009).
[72] V. Pikov, X. Arakaki, M. Harrington et al., “Modulation of neuronal activity and plasma membrane properties
with low-power millimeter waves in organotypic cortical slices,” J Neural Eng, 7(4), 045003 (2010).
[73] S. Romanenko, P. H. Siegel, D. A. Wagenaar et al., “Effects of millimeter wave irradiation and equivalent thermal
heating on the activity of individual neurons in the leech ganglion,” J Neurophysiol, 112(10), 2423-31 (2014).
[74] S. Ol'shevskaia Iu, A. S. Kozlov, A. K. Petrov et al., “Influence of terahertz (submillimeter) laser radiation on
neurons in vitro,” Zh Vyssh Nerv Deiat Im I P Pavlova, 59(3), 353-9 (2009).
[75] J. S. Olshevskaya, A. S. Ratushnyak, A. K. Petrov et al., "Effect of terahertz electromagnetic waves on neurons
systems." 210-211.
[76] E. N. Harvey, “The effect of high frequency sound waves on heart muscle and other irritable tissues,” American
Journal of Physiology(1), 284-290 (1929).
[77] F. Fry, “Production of reversible changes in the central nervous system by ultrasound,” Science, 127, 83-84
(1958).
[78] P. H. Tsui, S. H. Wang, and C. C. Huang, “In vitro effects of ultrasound with different energies on the conduction
properties of neural tissue,” Ultrasonics, 43(7), 560-5 (2005).
[79] R. T. Mihran, F. S. Barnes, and H. Wachtel, “Temporally-specific modification of myelinated axon excitability in
vitro following a single ultrasound pulse,” Ultrasound Med Biol, 16(3), 297-309 (1990).
[80] P. C. Rinaldi, J. P. Jones, F. Reines et al., “Modification by focused ultrasound pulses of electrically evoked
responses from an in vitro hippocampal preparation,” Brain Res, 558(1), 36-42 (1991).
Proc. of SPIE Vol. 10194 101941L-10
Downloaded From: http://proceedings.spiedigitallibrary.org/pdfaccess.ashx?url=/data/conferences/spiep/92914/ on 05/23/2017 Terms of Use: http://spiedigitallibrary.org/ss/termsofuse.aspx
[81] M. R. Bachtold, P. C. Rinaldi, J. P. Jones et al., “Focused ultrasound modifications of neural circuit activity in a
mammalian brain,” Ultrasound Med Biol, 24(4), 557-65 (1998).
[82] W. J. Tyler, Y. Tufail, M. Finsterwald et al., “Remote excitation of neuronal circuits using low-intensity, low-
frequency ultrasound,” PLoS ONE, 3(10), e3511 (2008).
[83] O. Naor, S. Krupa, and S. Shoham, “Ultrasonic neuromodulation,” J Neural Eng, 13(3), 031003 (2016).
[84] Y. Tufail, A. Matyushov, N. Baldwin et al., “Transcranial pulsed ultrasound stimulates intact brain circuits,”
Neuron, 66(5), 681-694 (2010).
[85] Y. Tufail, A. Yoshihiro, S. Pati et al., “Ultrasonic neuromodulation by brain stimulation with transcranial
ultrasound,” nature protocols, 6(9), 1453-1470 (2011).
[86] R. L. King, J. R. Brown, W. T. Newsome et al., “Effective parameters for ultrasound-induced in vivo
neurostimulation,” Ultrasound Med Biol, 39(2), 312-31 (2013).
[87] P. S. Yang, H. Kim, W. Lee et al., “Transcranial focused ultrasound to the thalamus is associated with reduced
extracellular GABA levels in rats,” Neuropsychobiology, 65(3), 153-160 (2012).
[88] E. Mehic, J. M. Xu, C. J. Caler et al., “Increased anatomical specificity of neuromodulation via modulated
focused ultrasound,” PLoS One, 9(2), e86939 (2014).
[89] G.-F. Li, H.-X. Zhao, H. Zhou et al., “Improved anatomical specificity of non-invasive neuro-stimulation by high
frequency (5MHz) ultrasound,” Scientific Reports, 6, 24738 (2016).
[90] S. S. Yoo, A. Bystritsky, J. H. Lee et al., “Focused ultrasound modulates region-specific brain activity,”
Neuroimage, (2011).
[91] W. Lee, S. D. Lee, M. Y. Park et al., “Image-guided focused ultrasound-mediated regional brain stimulation in
sheep,” Ultrasound in Medicine & Biology, 42(2), 459-470 (2016).
[92] T. Deffieux, Y. Younan, N. Wattiez et al., “Low-intensity focused ultrasound modulates monkey visuomotor
behavior,” Current Biology, 23(23), 2430-2433 (2013).
[93] M. D. Menz, Ö. Oralkan, P. T. Khuri-Yakub et al., “Precise neural stimulation in the retina using focused
ultrasound,” The Journal of Neuroscience, 33(10), 4550-4560 (2013).
[94] W. Legon, T. F. Sato, A. Opitz et al., “Transcranial focused ultrasound modulates the activity of primary
somatosensory cortex in humans,” Nat Neurosci, 17(2), 322-329 (2014).
[95] W. Lee, H. Kim, Y. Jung et al., “Image-guided transcranial focused ultrasound stimulates human primary
somatosensory cortex,” Scientific reports, 5, 8743 (2015).
[96] W. Lee, H.-C. Kim, Y. Jung et al., “Transcranial focused ultrasound stimulation of human primary visual cortex,”
Scientific Reports, 6, 34026 (2016).
[97] M. Plaksin, E. Kimmel, and S. Shoham, “Cell-type-selective effects of intramembrane cavitation as a unifying
theoretical framework for ultrasonic neuromodulation,” eNeuro, 3(3), (2016).
[98] B. Krasovitski, V. Frenkel, S. Shoham et al., “Intramembrane cavitation as a unifying mechanism for ultrasound-
induced bioeffects,” Proc Natl Acad Sci U S A, 108(8), 3258-63 (2011).
[99] S. Zhang, L. Yin, and N. Fang, “Focusing ultrasound with an acoustic metamaterial network,” Physics Reviews
Letters, 102(19), 194301-194304 (2009).
[100] J. Li, L. Fok, X. Yin et al., “Experimental demonstration of an acoustic magnifying hyperlens,” Nat Mater,
(2009).
[101] A. Spadoni, and C. Daraio, “Generation and control of sound bullets with a nonlinear acoustic lens,” Proc Natl
Acad Sci U S A, 107(16), 7230-4 (2010).
[102] K. J. Parker, and M. A. Alonso, “Longitudinal iso-phase condition and needle pulses,” Optics Express, 24(25),
28669-28677 (2016).
[103] Y. Hertzberg, O. Naor, A. Volovick et al., “Towards multifocal ultrasonic neural stimulation: pattern generation
algorithms,” J Neural Eng, 7(5), 056002 (2010).
[104] O. Naor, Y. Hertzberg, E. Zemel et al., “Towards multifocal ultrasonic neural stimulation II: design
considerations for an acoustic retinal prosthesis,” J Neural Eng, 9(2), 026006 (2012).
[105] T. Carter, S. A. Seah, B. Long et al., [UltraHaptics: multi-point mid-air haptic feedback for touch surfaces] ACM,
St. Andrews, Scotland, United Kingdom(2013).
[106] R. Sodhi, I. Poupyrev, M. Glisson et al., “AIREAL: interactive tactile experiences in free air,” ACM Trans.
Graph., 32(4), 1-10 (2013).
Proc. of SPIE Vol. 10194 101941L-11
Downloaded From: http://proceedings.spiedigitallibrary.org/pdfaccess.ashx?url=/data/conferences/spiep/92914/ on 05/23/2017 Terms of Use: http://spiedigitallibrary.org/ss/termsofuse.aspx
... The most representative technologies considering the acquisition of brain waves are Electroencephalography (EEG), Functional Magnetic Resonance Imaging (fMRI), Magnetoencephalography (MEG), Electrocorticography (ECoG), and neural dust. On the other hand, focusing on brain stimulation techniques, the most relevant ones are Transcranial Magnetic Stimulation (TMS), Transcranial Electrical Stimulation(tES), Transcranial Focused Ultrasound (tFUS), Deep Brain Stimulation (DBS), and neural dust (Tyler et al., 2017;Polanía et al., 2018). ...
... Regarding the stimulation of neurons, TMS is a technology that generates electrical fields within the brain, reaching the cortex and aiming to modulate brain activity and behavior. This technology obtained FDA approval in 2018 to treat depression and headaches (Tyler et al., 2017). TMS has also been used for testing dynamic communication between interconnected areas of the brain (Polanía et al., 2018) and cognitive aging (Gomes-Osman et al., 2018). ...
... It has been reported that tES can enhance and perturb cognitive processes, such as creative problem solving or working memory, when applied to different brain regions. Furthermore, it can improve working memory performance and motor behavior (Tyler et al., 2017;Polanía et al., 2018). Although these technologies are promising, they are not mature enough for their use in humans in terms of reliability and reproducibility (Tyler et al., 2017;Bikson et al., 2018). ...
Chapter
Full-text available
Brain-Computer Interfaces (BCIs) have experienced a considerable evolution in the last decade, expanding from clinical scenarios to sectors such as entertainment or video games. Nevertheless, this popularization makes them a target for cyberattacks like malware. Current literature lacks comprehensive works focusing on cybersecurity applied to BCIs and, mainly, publications performing a rigorous analysis of the risks and weaknesses that these interfaces present. If not studied properly, these potential vulnerabilities could dramatically impact users' data, service availability, and, most importantly, users' safety. Because of that, this work introduces an evaluation of the risk that each BCI classification already defined in the literature presents to raise awareness between the readers of this chapter about the potential threat that BCIs can generate in the next years if comprehensive measures, based on standard mechanisms, are not adopted. Moreover, it seeks to alert academic and industrial stakeholders about the impact these risks could have on future BCI hardware and software.
... Brain-Computer Interfaces (BCIs) emerged in the 1970s with the goal of acquiring and processing users' brain activity to later perform specific actions over external machines or devices [1]. After several decades of research, this functionality has been extended by enabling not only neural activity recording, but also stimulation [2], [3]. Fig. 1 describes the general components and processes defining a c 2019 IEEE. ...
... Taking into consideration the acquisition of brain waves, the most representative technologies are EEG, Functional Magnetic Resonance Imaging (fMRI), Magnetoencephalography (MEG), Electrocorticography (ECoG), and neural dust [12], [18], [24], [25]. On the other hand, focusing on brain stimulation techniques, the most relevant ones are Transcranial Magnetic Stimulation (TMS), Transcranial Electrical Stimulation (tES), Transcranial Focused Ultrasound (tFUS), Deep Brain Stimulation (DBS), and neural dust [3], [26]. All these families generate cybersecurity risks, where we detect issues related to their temporal and spatial resolution. ...
... Regarding the stimulation of neurons, Transcranial Magnetic Stimulation (TMS) is a technology that generates electrical fields within the brain, reaching the cortex, and aiming to modulate brain activity and behaviour. This technology has obtained FDA approval in 2018 to treat depression and headaches [3]. TMS has also been used for testing dynamic communication between interconnected areas of the brain [26] and cognitive ageing [28]. ...
Preprint
Full-text available
BCIs have significantly improved the patients' quality of life by restoring damaged hearing, sight and movement capabilities. After evolving their application scenarios, from medicine to entertainment, the trend of these interfaces is breaking new frontiers enabling new innovative brain-to-brain and brain-to-the-Internet communication paradigms. The increment in the possibilities offered by BCIs generates an attractive terrain for attackers, since users' personal information and physical integrity could be under risk. This article presents a comprehensive work to understand BCIs, their software cybersecurity concerns and future challenges. We initiate the article by reviewing the state-of-the-art of BCIs from the availability, confidentiality, integrity, and safety risks associated with their most well-known classifications. After that, we review the existing architectural versions of the BCI life-cycle and homogenise them in a new approach that overcomes the limitations of the current ones. A survey of the cybersecurity attacks affecting each phase of the BCI cycle is performed to analyse the impacts and countermeasures documented in the literature. Furthermore, new unexplored attacks concerning each phase are presented as well. After that, we review documented cyberattacks affecting the deployments of the BCI cycle, as well as their impacts and countermeasures. Like in the BCI design, new opportunities, in terms of cyberattacks and countermeasures, missed by the literature, are documented. Finally, we reflect on lessons learned, highlighting research trends and future challenges concerning cybersecurity on BCIs.
... This concept has been researched for decades and can now not only record brain activity but also stimulate it. Figure 1 describes the general BCI cycle that manages recording and stimulating neurons in the brain [2], [3]. ...
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Brain Computer Interface BCI is a real-time communication system that connects the brain and external devices. The BCI system can directly convert the information sent by the brain into com- mands that can drive external devices and replace human limbs or language organs to achieve hu- man communication with the outside world and the external environment Control. In other words, the BCI system can replace the normal peripheral nerve and muscle tissue to achieve communi- cation between the human and the computer or between the human and the external environment. The objective of this paper is to assist the network security for the BCI applications to identify brain activities in a secure real-time mode.To achieve this, we proposed the design of a Radio Fre- quency Identification RFID-based system having semi− active RFID tags placed outside the brain on the scalp transmit the collected brain activities wirelessly to a devise SC (Scanner Controller) consist of mini-reader and timer integrated together for every patient. Additionally, the paper im- plemented a novel system prototype interface called BCI Identification System (BCIIS) to assist the patient in the identification process. Given the benefits of RFID, we believed that if the idea is adopted and implemented by industry, it could enhance and provide secure BCI applications.
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Objective: Optical fiber devices constitute significant tools for the modulation and interrogation of neuronal circuitry in the mid and deep brain regions. The illuminated brain area during neuromodulation has a direct impact on the spatio-temporal properties of the brain activity and depends solely on the material and geometrical characteristics of the optical fibers. In the present work, we developed two different flexible polymer optical fibers (POFs) with integrated microfluidic channels (MFCs) and an ultra-high numerical aperture (UHNA) for enlarging the illumination angle to achieve efficient neuromodulation. Approach: Three distinct thermoplastic polymers: polysulfone (PSU), polycarbonate (PC), and fluorinated ethylene propylene (FEP) were used to fabricate two step-index UHNA POF neural devices using a scalable thermal drawing process. The POFs were characterized in terms of their illumination map as well as their fluid delivery capability in phantom and adult rat brain slices. Main results: A 100-fold reduced bending stiffness of the proposed fiber devices compared to their commercially available counterparts has been found. The integrated MFCs can controllably deliver dye (trypan blue) on-demand over a wide range of injection rates spanning from 10 nL/min to 1000 nL/min. Compared with commercial silica fibers, the proposed UHNA POFs exhibited an increased illumination area by 17% and 21% under 470 and 650 nm wavelength, respectively. In addition, a fluorescent light recording experiment has been conducted to demonstrate the ability of our UHNA POFs to be used as optical waveguides in fiber photometry. Significance: Our results overcome the current technological limitations of fiber implants that have limited illumination area and we suggest that soft neural fiber devices can be developed using different custom designs for illumination, collection, and photometry applications. We anticipate our work to pave the way towards the development of next-generation functional optical fibers for neuroscience.
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Brain-computer interfaces (BCIs) have significantly improved the quality of life of many people through, but not limited to, helping with various medical conditions. Given the recent development of BCIs to enable brain-to-internet and brain-to-brain communication a possibility for cybercriminals is generated, posing tremendous risk to the personal information and health of an individual. This paper presents characterizations of security attacks described in literature, along with their impact and countermeasures.
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Transcranial electric stimulation (TES) is an emerging technique, developed to non-invasively modulate brain function. However, the spatiotemporal distribution of the intracranial electric fields induced by TES remains poorly understood. In particular, it is unclear how much current actually reaches the brain, and how it distributes across the brain. Lack of this basic information precludes a firm mechanistic understanding of TES effects. In this study we directly measure the spatial and temporal characteristics of the electric field generated by TES using stereotactic EEG (s-EEG) electrode arrays implanted in cebus monkeys and surgical epilepsy patients. We found a small frequency dependent decrease (10%) in magnitudes of TES induced potentials and negligible phase shifts over space. Electric field strengths were strongest in superficial brain regions with maximum values of about 0.5 mV/mm. Our results provide crucial information of the underlying biophysics in TES applications in humans and the optimization and design of TES stimulation protocols. In addition, our findings have broad implications concerning electric field propagation in non-invasive recording techniques such as EEG/MEG.
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Ultrasonic waves can be non-invasively steered and focused into mm-scale regions across the human body and brain, and their application in generating controlled artificial modulation of neuronal activity could therefore potentially have profound implications for neural science and engineering. Ultrasonic neuro-modulation phenomena were experimentally observed and studied for nearly a century, with recent discoveries on direct neural excitation and suppression sparking a new wave of investigations in models ranging from rodents to humans. In this paper we review the physics, engineering and scientific aspects of ultrasonic fields, their control in both space and time, and their effect on neuronal activity, including a survey of both the field's foundational history and of recent findings. We describe key constraints encountered in this field, as well as key engineering systems developed to surmount them. In closing, the state of the art is discussed, with an emphasis on emerging research and clinical directions.