**5.1. Readout with magnetic particle/liquid-crystal composites**

There are several ways that magnetic particles can report on local electrical fields. The most promising in terms of field sensitivity takes advantage of liquid crystals, whose orientation can be used to detect low local electrical fields, for example, at a few volts per meter [25]. For purposes of comparison, voltage-sensitive dyes report on changes on the orders of kilovolts per meters (e.g., tens of millivolts across a 5-nm membrane) [26]. The high spatial and electrical field resolution of liquid crystals enables mapping of electronic layers with a sub-micron resolution [27]. Magnetic nanoparticles have been used to make the liquid crystals more sensitive to electric fields (dielectric permittivity) [28]. The liquid crystals' change in orientation (due to changes in local electric fields) can be transferred to magnetic particles, as validated with X-ray scattering methods (**Figure 4**) [29]. This orientation changes the local magnetic susceptibility, which can be detected with proton MRI (**Figure 5**) [30]. With MRI, we have detected electric fields as low as 20 V/m with this method.

#### **5.2. Readout with piezoelectric magnetic particles**

Particles have been built with magnetic cores and piezoelectric shells, where the magnetic moment of the core changes in response to an applied electric field. These magnetic moment

> changes can be read out with proton MRI (**Figure 6**). The same particles can be used to generate electric fields in response to an applied magnetic field (discussed subsequently in

> **Figure 5.** MRI of novel contrast agent. MRI results with no voltage applied (A) and with voltage applied (B). A 5% change in MRI signal is observed with electric fields of 20 V/m (comparable to the field within 10 μm of neurons).

> **Figure 4.** X-ray diffraction experiments with liquid crystal/magnetic particle composites (LC-MNP). Top: LC-MNP films placed in X-ray beam. Bottom: X-ray scattering measurements reveal changes in liquid crystal layer-to-layer spacings

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Spintronic devices act as nano-valves that convert electrical currents into radiofrequency (RF) waves. The devices are also sensitive to applied magnetic fields, which is important since the particles can thereby be localized by applying magnetic gradients (as in MRI). We have shown that a single nano-sized on-chip spintronic device can convert electrical currents in the microamp range into radio waves that can be detected centimeters away [33]. Spintronic devices can be ganged synchronously to amplify signals [34]. The micro-amp range is probably too low to detect the state of single neurons, but might be appropriate for tracts. Work needs to be done (e.g., with template-guided synthesis) on freeing the spintronic devices from substrates

Section 6) [20, 31, 32].

based on applied voltage.

**5.3. Readout with spintronic particles**

**Figure 3.** Spatial resolution of low-field MRI with high magnetic gradient strength. Left: spin echo sequence of a water phantom with 7-μm pixels in 2D projection. Right: calculation of spatial resolution of 30 μm.

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**Figure 4.** X-ray diffraction experiments with liquid crystal/magnetic particle composites (LC-MNP). Top: LC-MNP films placed in X-ray beam. Bottom: X-ray scattering measurements reveal changes in liquid crystal layer-to-layer spacings based on applied voltage.

**Figure 5.** MRI of novel contrast agent. MRI results with no voltage applied (A) and with voltage applied (B). A 5% change in MRI signal is observed with electric fields of 20 V/m (comparable to the field within 10 μm of neurons).

changes can be read out with proton MRI (**Figure 6**). The same particles can be used to generate electric fields in response to an applied magnetic field (discussed subsequently in Section 6) [20, 31, 32].

#### **5.3. Readout with spintronic particles**

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

There are several ways that magnetic particles can report on local electrical fields. The most promising in terms of field sensitivity takes advantage of liquid crystals, whose orientation can be used to detect low local electrical fields, for example, at a few volts per meter [25]. For purposes of comparison, voltage-sensitive dyes report on changes on the orders of kilovolts per meters (e.g., tens of millivolts across a 5-nm membrane) [26]. The high spatial and electrical field resolution of liquid crystals enables mapping of electronic layers with a sub-micron resolution [27]. Magnetic nanoparticles have been used to make the liquid crystals more sensitive to electric fields (dielectric permittivity) [28]. The liquid crystals' change in orientation (due to changes in local electric fields) can be transferred to magnetic particles, as validated with X-ray scattering methods (**Figure 4**) [29]. This orientation changes the local magnetic susceptibility, which can be detected with proton MRI (**Figure 5**) [30]. With MRI, we have

Particles have been built with magnetic cores and piezoelectric shells, where the magnetic moment of the core changes in response to an applied electric field. These magnetic moment

**Figure 3.** Spatial resolution of low-field MRI with high magnetic gradient strength. Left: spin echo sequence of a water

phantom with 7-μm pixels in 2D projection. Right: calculation of spatial resolution of 30 μm.

to detect as few as 1000 particles.

146 Evolving BCI Therapy - Engaging Brain State Dynamics

**5.1. Readout with magnetic particle/liquid-crystal composites**

detected electric fields as low as 20 V/m with this method.

**5.2. Readout with piezoelectric magnetic particles**

Spintronic devices act as nano-valves that convert electrical currents into radiofrequency (RF) waves. The devices are also sensitive to applied magnetic fields, which is important since the particles can thereby be localized by applying magnetic gradients (as in MRI). We have shown that a single nano-sized on-chip spintronic device can convert electrical currents in the microamp range into radio waves that can be detected centimeters away [33]. Spintronic devices can be ganged synchronously to amplify signals [34]. The micro-amp range is probably too low to detect the state of single neurons, but might be appropriate for tracts. Work needs to be done (e.g., with template-guided synthesis) on freeing the spintronic devices from substrates

administration) in desired locations or with diffusely delivered particles that can be addressed selectively. In the next sections, we list various candidate magnetic particles for brain stimula-

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Anecdotal surgical data from the placement of deep-brain stimulation leads have shown that mechanical vibration can stimulate neurons [39, 40]. Cultured neuron studies have demonstrated mechanoreceptors that react by opening calcium channels [41]. Invertebrate experiments suggest that externally applied magnetic gradients can wiggle magnetic particles

With appropriately designed piezomagnetic particles, externally applied magnetic fields can be applied to the particles in order to generate powerful electric fields focally (e.g., strong enough to electroporate cells) [32]. Indirect evidence of global brain stimulation has been col-

Recent innovations in harvesting harvesting from mechanical motion have been driven because of the proliferation of wearable devices. Some of the principles of energy harvesting can be reversed in order to generate electrical currents and voltages. Electrets, which rely on changes in capacitance to generate power, are very efficient vibrational energy harvesters. Liquid crystals have been used as electrets for energy harvesting [43]. Typically, liquid crystals require very high magnetic fields to change their capacitance, but the addition of magnetic

**Figure 7.** Magnetic particle neurostim-ulation visualized with manganese-enhanced MRI (MEMRI). Particles were injected behind the left eye of crawfish and stimulated for 3 min using magnetic wiggling of particles. Increased MEMRI

tion, some of which overlap the prior section for brain readout.

**6.1. Mechanical stimulation with magnetic particles**

enough to cause nerve stimulation (**Figure 7**) [42].

**6.2. Composite piezoelectric/magnetic particles**

**6.3. Electret-based magnetic particles**

signal is seen in the left brain.

lected through electroencephalography of animals [20].

**Figure 6.** Voltage-sensitive MRI signal from piezo-magnetic particle.

for deployment as a contrast agent. The spintronic particles can be used in a reverse mode for stimulation (with radio-frequency energy converted to low-frequency currents) again with the possibility of localization with applied magnetic gradients [35].
