Despite rising interest in remote magnetic neural stimulation techniques, there are questions concerning their mechanisms and effects on neuronal activities such as changes in action potential thresholds. Electrophysiological measurement which is the gold standard to understand ion channel activities can be used to validate and verify the effectiveness of magnetic neural modulation methods. However, the high background noise from electric-magnetic field interactions have made it technically challenging for electrophysiological measurements to be performed in the presence of magnetic fields. Here, I describe using 3D printing to overcome the high background noise. With this, I hope that it can promote conversations between neuroscientists and suppliers of electrophysiological instruments to introduce services and products to facilitate experiments to enhance the neuroscience community’s knowledge on magnetic neural stimulation techniques.
Conventional methods to manipulate neuronal activities include the use of electrodes and chemicals.(1) However, these techniques often lead to global and not local stimulation, hence complicating data interpretation. These limitations have motivated the rise of optogenetics which offers an unprecedented way for real-time interface with neurons remotely. Optogenetics allows targeted activation or inhibition of neuronal activities with high specificity.(2) Nonetheless, this technique necessitates complex modification of exogenous genes to express photo-sensitive ion channels or the delivery of photo-sensitive ligands to specific receptors on neurons which are either irreversible or require a long time for effects to diminish.(3) Optical approaches in general are still limited by the poor penetration of visible light into deep tissues and resolution hinges heavily on the precision of the optical fibers used for light delivery(4). To overcome some of these limitations of optogenetics, a few groups have come up with novel, competing technologies by exploiting the properties of magnetic nanoparticles (MNPs) and magnetic fields (Fig. 1).
Fig. 1 Timeline showing the developments of magnetic modulation of neuronal circuits. The different mechanisms are color-coded.(5)
2.0 Magnetic Neural Stimulation Techniques 2.1 Thermal
Thermogenetics refer to the use of heat via alternating magnetic fields to activate genetically transfected heat-sensitive ion channels such as TRPV1, thus allowing influx of ions to modulate cellular activities.(3)
Huang et al. first demonstrated in 2010 that magnetic field heating could elicit action potentials in primary hippocampal neurons that express TRPV1.(6) Two years later, Stanley and co-workers reported the use of similar method to regulate insulin production in mice.(7) The same group recently published a similar strategy to activate glucose-sensing neurons to induce feeding.(8) They also compared this method of magnetic stimulation and optogenetics and found their method to induce changes in feeding behaviors faster in neurons. Early last year, Chen et al. demonstrated the possibility of remotely exciting in vivo neuronal circuits using thermogenetics.(9)
Technologies described in section 2.1 utilized alternating magnetic fields to generate heat while in this section, magnetic fields are provided by permanent magnets and are static. In both methods, magnetic fields were used, highlighting the flexibility and potential of for remote magnetic control of neuronal circuits. Stanley et al. utilized static magnetic fields to mechanically perturb intracellularly produced TRPV1-tethered ferritin iron oxide MNPs.(10) The magnetic force was transduced into mechanical force to open TRPV1 channels, resulting in a rise in cellular calcium level and proinsulin secretion by the cells. At the same period, Wheeler and co-workers also employed a similar strategy by synthesizing a magnetically-sensitive actuator termed Magneto2.0 that consisted of TRPV4 again fused to ferritin to control brain circuits in zebrafishes and mice.(11) Additionally, Tay et al. described the use of 100 nm starch-coated ferromagnetic nanoparticles (fMNPs) that preferentially localized at the cell membrane to trigger calcium influx in cortical neural networks seeded onto a micro-fabricated substrate with high magnetic gradient.(12)
Collectively, these results suggest that there is rising interest in remote control of neuronal activities with static and alternating magnetic fields that offer high spatiotemporal resolution.(13) This interest is also reflected in increasing numbers of conference sessions devoted specifically to magnetic neural control. One example is the 2017 Materials Research Society® Fall Meeting Magnetic Neural Modulation session.
3.0 Compatibility of Electrophysiological Measurements with Magnetic Fields
Despite increasing popularity of magnetic techniques for neural stimulations, there are unanswered questions about its mechanism and the effects of magnetic fields on neuronal activities. In a meeting held in Janelia Farm (Genetic Manipulation of Neuronal Activity IV, Oct 16-19, 2016), prominent scientists including Peter Hegemann (inventor of optogenetics) and Jeffrey Friedman (inventor of magnetogenetics) concluded that to instill greater confidence in magnetic neuromodulation techniques, there needs to be validation with electrophysiological data. Specifically, neuroscientists want to understand (1) whether magnetic fields enhance the opening probability of mechano-sensitive ion channels as hypothesized, (2) what is the mechanism of magnetic neural stimulation techniques i.e. membrane stretching or perturbation of cytoskeleton or both and (3) whether magnetic fields also affect other cellular activities such as neural excitability and cell death, before future use of magnetic techniques for neural modulation.
The previous questions arise as all published literature on magnetic neural stimulation techniques do not offer any electrophysiological data which is the gold standard method to understand how ion channels activities, including those which are sensitive to magnetic forces, affect cellular states such as membrane potential and voltage to elicit action potential.
Here, I would like to focus on technical and financial challenges to create an electrophysiological set-up compatible with use of magnetic fields, which could potentially explain why electrophysiological experiments were not performed.
3.1 High background noise from electric-magnetic field interactions
One of the best ways to understand the effects of magnetic fields on ion channel opening probability is to perform single ion channel conductance measurement. However, this is an experiment that requires highly sensitive set-up i.e. background noise
Electric-magnetic field interactions significantly amplify background noises. Consequently, it becomes technically challenging to perform single ion channel conductance electrophysiological measurements. Even with proper ‘Earthing’ and using Faraday cage, the background noise in the presence of magnetic fields is more than 100 pA from personal experience. Furthermore, as the coupling of magnetic fields with electrophysiological measurements has been largely unexplored, many technical manuals for reducing noise do not touch on magnetic-electrical field interactions, except for electromagnetic waves of electrical powerlines (50-60 Hz).(15) To perform such experiments, neuroscientists would therefore have to commit significantly resources to purchase more expensive or sensitive instruments which can be prohibitive. However, there is a cheaper solution from using 3D printing.
3.2 Overcoming background noise from electric-magnetic field interactions with 3D printing
3D printing, or the technically, additive manufacturing, is the process to create 3D objects.(16) There are a few variations of this technique but they all require users to create models for printing followed by sending the models to a printer that will ‘print’ the design by adding materials layer by layer. Advances in this technique has allowed printing of polymers, metals and even biological tissues.(17)
There is a huge price range for 3D printers from a few hundreds to even millions depending on the applications and scale of dimensions to be ‘printed’. For the purpose of minimizing electricmagnetic field interactions, 3D printers that ‘print’ objects using polymers can be purchased cheaply as they are the most common ones in market. In addition, to shield components of electrophysiological and magnetic instruments, the dimensions are usually more than milli-meters scale, and thus do not require highly precise 3D printers.
3.3 Roles of electrophysiological suppliers
While 3D printers are now more widely used, many neuroscience laboratories might be hesitant to take it up due to perception that it might be difficult to operate or it will be under-utilized. Also, neuroscience labs will require members to use software that they are unaccustomed to, to design models for 3D printing. This is where suppliers of electrophysiological instruments can help by providing the service of designing models, followed by printing the models for labs.
Undeniably, there is rising interest in remote modulation of neuronal network activities using magnetic fields.(8, 9, 11, 12, 18) These innovations are especially exciting considering mounting interest in understanding brain complexity such as through the Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) initiative by the U.S. National Institutes of Health and Human Brain Project by the European Union. To further the use of magnetic modulation, electrophysiological validation is important to convince the community of the utility and mechanism of this new class of neural modulation technique. Suppliers of electrophysiological instruments can help by providing 3D object design and 3D printing services to create shields of electrical and magnetic components to minimize background noise during single ion channel conductance measurements.
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