**5. Neuronal readout**

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].

For magnetic particles to become widely used, the particles must have a negligible potential for toxicity [16]. This very high bar is reflected in the Food and Drug Administration's (FDA) classification of devices for the brain as class III, requiring a premarket approval (PMA) application. In comparison, devices for the peripheral nervous system are often treated as class II devices. Note that particles are often treated by the FDA as drugs, although in Europe, they may be treated as devices. Studies of ex vivo vital rodent brain slices have shown that the presence of magnetic particles does not cause a measurable disruption of function [17]. In fact, it is not unusual for humans living in industrial cities to have magnetic particles in their brains, with no known related diseases [18]. It is also very common for humans over 50 years of age to have radio-dense "calcifications" in the basal ganglia, again with no definite disease association [19]. Small animal studies have examined the toxicity of magnetoelectric particles with no adverse effects [20].

Traditionally, implantable medical devices for neurostimulation have been built with CMOS processes (like other electronic devices). This approach is not scalable to nano-sized products that are needed for noninvasive access. Most of the magnetic particle literature was contributed in the field of bioassays, where particle uniformity is not critical. However, for medical applications (e.g., magnetic particle imaging), lack of particle uniformity is often a limiting factor [21].

**3. Particle toxicity**

144 Evolving BCI Therapy - Engaging Brain State Dynamics

**4. Particle fabrication**

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 detector-size limitations.

Our working hypothesis is that the magnetic readout of contrast materials with magnetic resonance imaging (or the related field of magnetic particle imaging) is the way to go. With fast high magnetic gradients, magnetic resonance imaging (MRI) can achieve 30 μm spatial resolution (**Figure 3**) and kHz temporal resolution. In the past, it was believed that such rapid changes of magnetic fields would induce unwanted neurological stimulation, but we have shown in a prospective human study that if the frequency is high enough, such effects do not occur [23]. Magnetic particle imaging should theoretically be able to detect a single particle; however, experimentally, this has been difficult to achieve because of prior limits on gradient strength and particle uniformity [21, 24]. We have found that with very fast MRI pulse sequences that directly measure the reduction in local proton signal decay time, it is possible to detect as few as 1000 particles.
