**2. Brain access**

**1. Introduction**

142 Evolving BCI Therapy - Engaging Brain State Dynamics

Brain-machine interfaces (BMIs) have made great progress as prostheses (e.g., for visionimpaired individuals). Those patients were willing to undergo major surgery, expense, and to have centimeter-scale electrical devices implanted in their nervous systems. The scope of influence of BMI of the future is clearly large, potentially including cognitive enhancement and memory storage, and quite likely with ramifications beyond anybody's present imagination [1, 2]. To fully exploit the power of BMI, some big steps need to be taken. For wide and long-term public use, the invasiveness of the implant procedure and toxicity of the implant materials need to be eliminated. The number of neuronal channels an implanted device must address needs to be increased by many orders of magnitude, and the entire nervous system must be accessible. The spatial resolution should be smaller or equal to the diameter of small groups of neurons (i.e., micron-sized), and the temporal resolution should be faster than or

Most medical researchers attempt to translate therapeutic approaches from animal models to human use. Unfortunately, there are significant barriers to taking this approach to BMI. Optical dyes that are the mainstay of animal research do not work for animals larger than a few centimeters because of light scattering and the photon-stopping power of tissue. The multi-decade-long history of failure to bring optical mammography into clinical practice suggests that light scatter is not a problem that is easily solved [3]. Implanted tethered electrodes and high-intensity-focused ultrasound can only address one section of the nervous system at a time. Genetic manipulation of brain circuitry (e.g., with optogenetic or sonogenetic techniques) has significantly increased our understanding of preclinical neurosciences, but would still require invasive focal delivery of gene vectors, optical fibers, or ultrasonic

Oscillating magnetic fields do not interact much with tissue, especially below several gigahertz in frequency, and therefore penetrate the human head readily. Magnetic resonance imaging methods that examine blood oxygen-level dependency (BOLD) rely on vascular changes that have a poor spatial and temporal resolution. Magnetic resonance imaging (MRI) pulse sequences that read out electrical current (e.g., from Lorentz forces causing neuronal displacement) can detect micro-amp levels (far from the nanoampere currents generated from individual or small neuronal bundles) although technical improvements such as fast magnetic gradients may improve performance in the future [6]. Imaging of electrical currents (magnetoencephalography) is limited to millimeter spatial resolution due to the variable impedance

In this chapter, we summarize contrast-enhancement approaches to BMI that could yield readout and writing of the entire brain with high spatial and temporal resolution. Contrast enhancement from radioactive and other materials has been used in radiology practices for the past century to explore and diagnose diseases of the nervous system. The contrast materials that appear the most promising are based on magnetic nanoparticles, which we attempt

comparable to neurons in the native brain (i.e., sub-millisecond response time).

transducers that would limit wide use in humans [4, 5].

of the brain and the detector resolution [7].

to describe more fully in this chapter.

To date, developers of the smart-dust [8] concept have constructed millimeter-sized particles using wafer-based lithographic methods typically employed for electronic circuitry (e.g., CMOS). Traditional electronic particles below a millimeter in size are difficult to power without a tether to the outside world, because of poor electromagnetic coupling to small antennas. In order to implant or remove electronic particles of these sizes, practitioners need millimetersized holes, requiring either surgery or interventional procedures to go through the vessels or subarachnoid spaces. Because of the potential for damage to eloquent nervous structures, such procedures carry risks and expensive and are therefore inappropriate for wide (e.g., consumer) applications.

As will be discussed below, we and others have formulated contrast solutions containing high concentrations of nano-sized particles with magnetic properties (e.g., spintronic, magnetoelectric) that do not need to rely on traditional approaches to enter or interact with the brain. As in drug delivery, we have shown that nanoscale particles can be delivered intranasally, which is considered a noninvasive administration mode in the clinical literature [9, 10]. The cribriform plate separates the nasal from the cranial cavities, with foramina that decline slightly in size with age, with an overall area of 6 mm2 at age 25 and 4 mm2 at age 66 [11]. Our group and others have demonstrated that magnetic particles with diameters of up to 250 nm readily enter the cranium with the assistance of a 20-mT magnetic gradient, with no appreciable intracranial entry in the absence of an imposed magnetic field (**Figure 1**). Minimally invasive routes other than intranasal are possible, for example, via lumbar puncture or via intravenous administration. However, both of these routes require overcoming countervailing current flows (of cerebrospinal fluid and blood, respectively) that make them less attractive.

Once in the intracranial cavity, magnetic particles can be manipulated using magnetic gradients for delivery to specific brain foci. The tracks that such particles make are micron-sized, unlike the millimeter scale holes made during conventional deep-brain stimulation surgery. Magnetic particle manipulation is difficult with a conventional MRI, since it is very hard to create magnetic gradients that can overcome the static MRI field strength. However, our group and others have constructed MRI systems where the static field can be temporarily

**Figure 1.** Transport into brain. Rat olfactory bulb before (left) and after (right) intra-nasal administration of particles under magnetic gradient.

eliminated in order to apply magnetic gradients without interference [12]. The MRI's static magnetic field can then be reapplied to assist in real-time image-guided manipulation.

In the past, it was believed that it was impossible to propel magnetic particles deep within tissues because of the particles' tendency to realign and become attracted to the propelling magnets and because particles tend to dissipate instead of aggregate when being pushed through tissue. With appropriate magnetic pulse sequences, it is possible to transiently polarize the particles in the direction opposite to the propelling magnets ("dynamic inversion"), so that the particles can be delivered deep into tissue [13]. With appropriate particle design choices, it is also possible to twist the particles during propulsion, which assists in penetrating tissues without increasing the particle track diameter [14]. Particles transported interstitially through the brain do not rely on vascular transport and therefore effectively bypass the blood-brain barrier.

Once the particles have been delivered to the intended location in the brain, the average distance between particles and neurons is inversely related to the local particle concentration. The distance between particles and neurons is critical to reading out or writing to the brain, since the electrical field decreases rapidly from kilovolts/meter (across the neuronal membrane) to tens of volts per meter (10 μm from the neuron). It may be possible to decrease the effective particle-neuron distance by coating the particle with materials in configurations that promote penetration of the neural membrane, as has been done with experimental brain electrodes [15].

> We have used template-guided methods to build shape-engineered highly uniform magnetizable particles with features important for transport and effectiveness [22] (**Figure 2**). For example, different sections of the particles can be built with aspect ratios that favor a particular magnetization direction. With appropriate use of precessing magnetic fields, the particles can be drilled through tissue [14]. The template-guided methods are also economical: it is possible to fabricate micromolar quantities of particles for less than \$20 in raw materials. We have evaluated nanoscale spintronic devices for voltage sensing and stimulation, which have very tight tolerances. Transitioning these devices in their current morphologies to templateguided manufacturing (with tolerances of a few nm) may be challenging and may require

> **Figure 2.** Example of template-guided shape-engineered synthesis of magnetic particles. Particles are made via sequential processing of polycarbonate track etched (PCTE) membrane films. PCTE films have pores extending through the thickness of the film. Templates (A) are first partially sealed on one surface with a conductive layer (B), followed by deposition of a polymer (e.g. poly-lactic-co-glycolic acid) shell inside the pores of the PCTE (C). Selectively etching the partially sealing conductive layer (D) and replacing it with a completely sealing conductive layer (E) allows for deposition of a conformal gold layer (F), after which a payload (e.g. liquid-crystal-magnetic composite) can be deposited by vacuum impregnation into the sealed pores of the PCTE film (G). Deposition of a final sealing layer (H), followed by selective etching of the conductive sealing layer (I) and removal of PCTE film (J) results in free-floating particles.

Image-guided Placement of Magnetic Neuroparticles as a Potential High-Resolution...

http://dx.doi.org/10.5772/intechopen.75522

145

Although neurons affect each other over nanoscale distances through chemical means (e.g., neurotransmitters), longer neuronal transmissions are electrical in nature. Noninvasive neuronal sensing in humans has generally employed either electrical methods to detect electrical fields or magnetic methods to detect electrical currents. Noninvasive external measurements of electrical fields from deep in the brain (e.g., with electroencephalography) yield centimeter-scale resolution because of the complicated impedance of the brain and surrounding tissues. Direct measurements of magnetic fields can be obtained with magnetoencephalography, but the resolution is limited to millimeter scales because of

device redesign.

**5. Neuronal readout**

detector-size limitations.
