Nonresonant powering of injectable nanoelectrodes enables wireless deep brain stimulation in freely moving mice methods
Aim. Evidence-backed execution summary for Nonresonant powering of injectable nanoelectrodes enables wireless deep brain stimulation in freely moving mice methods from Nonresonant powering of injectable nanoelectrodes enables wireless deep brain stimulation in freely moving mice.
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INTRODUCTION
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- Schematic demonstrating two-phase magnetoelectricity in materials made from magnetostrictive and piezoelectric materials that are strain-coupled ( A ). Schematic demonstrating the rationale for using a large DC magnetic field overlaid with an AC field to generate optimal magnetoelectric output ( B ). Diagram of meth...
MATERIALS AND METHODS
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- The objective of this study was to assess the potential of MENPs to wirelessly modulate neuronal activity via a magnetoelectric response to an applied magnetic field. This was approached by applying a magnetic field to the MENPs (and control nanoparticles) and measuring (i) their output electric signaling, (ii) thei...
INTRODUCTION
Schematic demonstrating two-phase magnetoelectricity in materials made from magnetostrictive and piezoelectric materials that are strain-coupled ( A ). Schematic demonstrating the rationale for using a large DC magnetic field overlaid with an AC field to generate optimal magnetoelectric output ( B ). Diagram of meth...
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- Schematic demonstrating two-phase magnetoelectricity in materials made from magnetostrictive and piezoelectric materials that are strain-coupled ( A ). Schematic demonstrating the rationale for using a large DC magnetic field overlaid with an AC field to generate optimal magnetoelectric output ( B ). Diagram of meth...
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RESULTS
We next measured the electrical output of MENPs under an applied magnetic field to characterize their magnetoelectric response. MENPs were measured as a sintered, poled pellet by attaching electrodes and measuring the output voltage via a lock-in amplifier (fig. S1). While this method does not allow us to take measurements of the magnetoelectric effect at the nanoscale, it can validate whether our material is magnetoelectric, and has previously been used to evaluate magnetoelectricity in core-shell particles ( - ). A pellet containing only MSNPs was used as a negative control. To optimize our ME output, we applied a small AC magnetic field with a larger DC bias field along the same axis ( ). This orientation was used to align the magnetic domains, axis of magnetostriction, and piezoelectric poling axis to sum the magnetoelectric output along our measured axis. Application of a s...
DISCUSSION
An important finding in this study that corresponds with previous work in magnetoelectric materials is that the magnetoelectric output had a low dependence on the input, carrier AC field frequency ( ). While α ME increases sharply near the mechanical resonance frequency of magnetoelectric materials, α ME otherwise remains relatively constant ( ). In this study, our carrier magnetic signals were far from the resonant frequency range of nanoscale materials (140 Hz versus GHz range). Previous neural device technologies based on piezoelectric and magnetoelectric materials have often relied on carrier frequencies that provide resonant coupling for remote powering (,, ). However, this fundamentally creates an inverse correlation between device sizes as compared to carrier frequency and possible tissue penetration depth. As a result, such devices have been unable to demonstrate n...
DISCUSSION
A key finding of this work is that resonant coupling-independent remote powering of a neural device yields sufficient electrical activity to modulate brain activity. This decouples the relationship between device size and potential powering depth, enabling nanoscale materials to modulate deep brain tissue. Modeling of carrier signal transmission through tissue to magnetoelectric devices would benefit future device design and elucidate limitations on tissue penetration to human-scale deep brain targets. Furthermore, future work will be necessary to understand how the carrier frequency is propagated by the MENPs into a stimulating signal that is received by neurons, as temporal control of stimulation is the key to the therapeutic effects of DBS (, ). The exact mechanism of neuronal modulation also remains an open question. Hence, future work will be necessary to learn more about...
Stereotactic nanoparticle administration
Buprenorphine (0.1 mg/kg) was subcutaneously injected half an hour before surgery as an analgesic. Inhalational anesthesia was induced and maintained with isoflurane (Abbot Laboratories, Maidenhead, UK) at 4% and 1.5 to 3%, respectively. After adequate induction of the anesthesia, the mouse was placed in a small animal stereotaxic frame (Stoelting, Dublin, Ireland) and fixed by ear bars with zygoma ear cups (Kopf, Los Angeles, USA) and a mouse gas anesthesia head holder (Stoelting, Dublin, Ireland). To maintain body temperature at 37°C throughout the whole procedure, the mouse was placed on a thermoregulator pad. An ocular lubricant was applied to prevent drying of the eyes. A subcutaneous injection of 1% Lidocaine (Streuli Pharma, Uznach, Switzerland) at the incision side was given for local anesthesia.
Description and timelines of animal experimental procedures
We first adjusted optimal concentration of MENPs. Three doses were tested, including 25, 50, and 100 mg/ml. Mice were randomly assigned to either 25, 50, or 100 mg/ml test groups ( n = 8) and received stereotactic injection of MENPs (fig. S4A). Animals were monitored for signs of sub- or epidural hemorrhage, neurological symptoms of the injection, welfare (weight, responsiveness, and water intake), and discomfort/pain. No animals were eliminated from the experiments due to failing these criteria. Fourteen days after the surgery, mice were euthanized for immunohistochemical (IHC) analysis of the brain as described below. Five brains were randomly selected for IHC. Sections belonging to one mouse were excluded as tissue ruptured during processing. Brain sections were processed using antibodies raised against astrocytes and microglia (fig. S4, B and C). Another series of brain sections w...
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To achieve wireless signal transmission to injectable devices, we have used magnetoelectric nanoelectrodes, which couple magnetic and electric signals ( ). Technologies using ma...
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Schematic demonstrating two-phase magnetoelectricity in materials made from magnetostrictive and piezoelectric materials that are strain-coupled ( A ). Schematic demonstrating t...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
Here, we report wireless DBS in mice using injectable, magnetoelectric nanoelectrodes. They are implanted into the subthalamic area via stereotactic infusion, and powered using...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
We characterized the magnetoelectric response of the nanoelectrodes as a sintered pellet, particularly looking at electrical output as input magnetic field changed. While a magn...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
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- Summary statistics and between-group or across-timepoint comparisons
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To achieve wireless signal transmission to injectable devices, we have used magnetoelectric nanoelectrodes, which couple magnetic and electric signals ( ).
from paperScoring or quantification
Quantify the primary readouts for this experiment: To achieve wireless signal transmission to injectable devices, we have used magnetoelectric nanoelectrodes, which couple magnetic and electric signals ( ). Technologies using ma...; Schematic demonstrating two-phase magnetoelectricity in materials made from magnetostrictive and piezoelectric materials that are strain-coupled ( A ). Schematic demonstrating t...; Here, we report wireless DBS in mice using injectable, magnetoelectric nanoelectrodes. They are implanted into the subthalamic area via stereotactic infusion, and powered using...; We characterized the magnetoelectric response of the nanoelectrodes as a sintered pellet, particularly looking at electrical output as input magnetic field changed. While a magn....
from paperStatistical comparison
To achieve wireless signal transmission to injectable devices, we have used magnetoelectric nanoelectrodes, which couple magnetic and electric signals ( ). Technologies using ma...; We first assessed this in neuronal cells in vitro, measuring intracellular Ca 2+ as a second messenger of electrophysiological activity. As we showed earlier that both the large...
from paperReporting output
Report representative outputs alongside summary comparisons for To achieve wireless signal transmission to injectable devices, we have used magnetoelectric nanoelectrodes, which couple magnetic and electric signals ( ). Technologies using ma..., Schematic demonstrating two-phase magnetoelectricity in materials made from magnetostrictive and piezoelectric materials that are strain-coupled ( A ). Schematic demonstrating t..., Here, we report wireless DBS in mice using injectable, magnetoelectric nanoelectrodes. They are implanted into the subthalamic area via stereotactic infusion, and powered using..., We characterized the magnetoelectric response of the nanoelectrodes as a sintered pellet, particularly looking at electrical output as input magnetic field changed. While a magn....
inferred from protocolStructured statistical methods
To achieve wireless signal transmission to injectable devices, we have used magnetoelectric nanoelectrodes, which couple magnetic and electric signals ( ). Technologies using ma...; We first assessed this in neuronal cells in vitro, measuring intracellular Ca 2+ as a second messenger of electrophysiological activity. As we showed earlier that both the large...
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We next measured the electrical output of MENPs under an applied magnetic field to characterize their magnetoelectric response. MENPs were measured as a sintered, poled pellet by attaching electrodes and measuring the output voltage via a lock-in amplifier (fig. S1). While this method does not allow us to take measurements of the magnetoelectric effect at the nanoscale, it can validate whether our material is magnetoelectric, and has previously been used to evaluate magnetoelectricity in core-shell particles ( - ). A pellet containing only MSNPs was used as a negative control. To optimize our ME output, we applied a small AC magnetic field with a larger DC bias field along the same axis ( ). This orientation was used to align the magnetic domains, axis of magnetostriction, and piezoelectric poling axis to sum the magnetoelectric output along our measured axis. Application of a sinusoidal magnetic field to magnetoelectric materials outputs a sinusoidal electric field with a frequency and duration that matches the input magnetic field. Thus, we could measure this output using a lock-in amplifier ( ). The magnetoelectric coefficient (α ME ), which quantifies the relation...
An important finding in this study that corresponds with previous work in magnetoelectric materials is that the magnetoelectric output had a low dependence on the input, carrier AC field frequency ( ). While α ME increases sharply near the mechanical resonance frequency of magnetoelectric materials, α ME otherwise remains relatively constant ( ). In this study, our carrier magnetic signals were far from the resonant frequency range of nanoscale materials (140 Hz versus GHz range). Previous neural device technologies based on piezoelectric and magnetoelectric materials have often relied on carrier frequencies that provide resonant coupling for remote powering (,, ). However, this fundamentally creates an inverse correlation between device sizes as compared to carrier frequency and possible tissue penetration depth. As a result, such devices have been unable to demonstrate neuronal modulation in deep brain tissue using injectable-sized devices.
A key finding of this work is that resonant coupling-independent remote powering of a neural device yields sufficient electrical activity to modulate brain activity. This decouples the relationship between device size and potential powering depth, enabling nanoscale materials to modulate deep brain tissue. Modeling of carrier signal transmission through tissue to magnetoelectric devices would benefit future device design and elucidate limitations on tissue penetration to human-scale deep brain targets. Furthermore, future work will be necessary to understand how the carrier frequency is propagated by the MENPs into a stimulating signal that is received by neurons, as temporal control of stimulation is the key to the therapeutic effects of DBS (, ). The exact mechanism of neuronal modulation also remains an open question. Hence, future work will be necessary to learn more about the various input parameters (e.g., nanoparticle concentration, magnetic stimulation magnitude, stimulation frequency, and duration) that enable modulation. As the electric field gradient along an axon has been shown to be a key determinant in activation (, ), we hypothesize that the mechanism of a...
Buprenorphine (0.1 mg/kg) was subcutaneously injected half an hour before surgery as an analgesic. Inhalational anesthesia was induced and maintained with isoflurane (Abbot Laboratories, Maidenhead, UK) at 4% and 1.5 to 3%, respectively. After adequate induction of the anesthesia, the mouse was placed in a small animal stereotaxic frame (Stoelting, Dublin, Ireland) and fixed by ear bars with zygoma ear cups (Kopf, Los Angeles, USA) and a mouse gas anesthesia head holder (Stoelting, Dublin, Ireland). To maintain body temperature at 37°C throughout the whole procedure, the mouse was placed on a thermoregulator pad. An ocular lubricant was applied to prevent drying of the eyes. A subcutaneous injection of 1% Lidocaine (Streuli Pharma, Uznach, Switzerland) at the incision side was given for local anesthesia.
We first adjusted optimal concentration of MENPs. Three doses were tested, including 25, 50, and 100 mg/ml. Mice were randomly assigned to either 25, 50, or 100 mg/ml test groups ( n = 8) and received stereotactic injection of MENPs (fig. S4A). Animals were monitored for signs of sub- or epidural hemorrhage, neurological symptoms of the injection, welfare (weight, responsiveness, and water intake), and discomfort/pain. No animals were eliminated from the experiments due to failing these criteria. Fourteen days after the surgery, mice were euthanized for immunohistochemical (IHC) analysis of the brain as described below. Five brains were randomly selected for IHC. Sections belonging to one mouse were excluded as tissue ruptured during processing. Brain sections were processed using antibodies raised against astrocytes and microglia (fig. S4, B and C). Another series of brain sections were stained using standard hematoxylin and eosin (H&E) to evaluate tissue damage at the site of injection (fig. S4D).
Machine-readable layer
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