Neuromodulation Techniques: Concepts and Limits

• Neuromodulation shows promise in neural prosthetics, medical treatments, and neural research.
• Electrical neural stimulation (ENS) is commonly used, but alternative methods exist.
• This paper reviews ENS and other neuromodulation techniques, focusing on their concepts, implementation, and limitations to inform system design.

Introduction

• Neuromodulation is a multi-billion dollar industry with expected future growth, spurred by initiatives like the Human Brain Project and the BRAIN Initiative.
• Neuromodulation has three main applications:
• Prosthetics: Replacing impaired sensory, motor, or cognitive functions (e.g., cochlear implants).
• Therapy: Neurally regulating organs for medical benefits (e.g., diabetes, hypertension, epilepsy, Parkinson's disease).
• Neuroscience Research: Investigating neuron and neural network functions.
• These applications involve stimulating or blocking action potentials (APs) in the nervous system
• Electrical Neural Stimulation (ENS) has been a key neuromodulation technique.
• Recent advances in alternative methods could improve clinical applications.
• The paper covers the current state of neuromodulation methods, including their advantages, limitations, implementation, and applicability.

Biophysics of Action Potential Generation

• Neuronal cell membranes have a phospholipid bilayer and ion pumps, creating a charge separation and a resting membrane potential between -60 and -80 mV.
• Neural stimulation depolarizes the cell membrane.
• If depolarization reaches a threshold, voltage-gated sodium channels open, causing a positive feedback loop that leads to full membrane reversal and action potential creation.
• This depolarization spreads to nearby membranes, propagating the action potential along the neuron.
• Voltage-gated sodium and potassium channels are important for neuromodulation
• Transmembrane currents include:
• Depolarizing (negative current, e.g., sodium or calcium ions).
• Hyperpolarizing (positive current, e.g., potassium ions).
• An axon coated in myelin has ion exchange limited to Nodes of Ranvier, resulting in action potentials seeming to "leap" from node to node.
• Myelination decreases membrane capacitance, increasing AP propagation speed.
• Neural cells are modeled as spatially extended electrically active objects divided into equipotential compartments.
• The change in charge inside a compartment is: dQ/dt = -I(ionic) + I(intracell) + I(injected)
• Replacing Q = C(m)U in the equation results in the Hodgkin-Huxley type equation: Cm(dVm/dt) = ∑I(ion,k) + ∑G(ai)(V(ext,i) - V(ext)) + I(injected) - (V(m) + V(rest))(dCm/dt)
• I(ionic) represents ion channel and pump currents, I(intracell) represents internal cell current influx, and I(injected) represents external injected currents.
• V(m) is the reduced membrane voltage, V(rest) is the resting voltage, and G(ai) is axoplasm conductance.
• The ionic current of type k is: I(ion,k) = ğ(k)ξ^p(k)η^q(k)(V(m) – E(k))
• ğ(k) is max conductance, ξ and η are activation and inactivation variables, p(k) and q(k) are exponents, and E(k) is the reversal potential.
• Activation (ξ) and inactivation (η) are described by differential equations: dξ/dt = [ α(k)(V(m), t)(1 − ξ) – β(k)(V(m), t)·ξ ]
• α(k)(Vm, t) and β(k)(Vm, t) are voltage and time-dependent rate functions that are influenced by ion species concentration.
• For optogenetic ion channels, these equations depend on light flux.
• For synaptic currents, the equations depend on neurotransmitter concentration.
• Membrane kinetics and channel conductance are temperature-dependent.
• Equations include a thermic coefficient (Φ) as a multiplier: Φ = Q((T-T0)/10)
• Q10 is a constant for kinetics and permeability increase with a 10°C temperature increase.
• The model assumes a negligible extracellular potential from neuron activity.
• Ionic pumps quickly restore ionic gradients, making reversal potentials constant.

Neuromodulation Modalities

• Depolarization is initiated in a number of ways.
• Six classes are discussed, including operation principles and implementation, contrasting parameters in Table 1.

Direct Electrical

• Electrodes apply a potential gradient across a neuron, leading to intracellular ionic current flow and localized membrane depolarization and hyperpolarization.
• Applying a different potential gradient causes cell membrane hyperpolarization to block action potential propagation.
• Complex mechanisms for stimulation, inhibition, and selectivity involve waveforms that exploit ion channel time constants.
• Anode break stimulation comes from differences in sodium gate change rate.
• Safety, energy efficiency, area, spatial resolution, and programmability are key considerations for direct electrical stimulation.
• Safety is determined by electrode material biocompatibility and minimizing harmful electrochemical product creation.
• Limiting the charge rate and amount, maximum potential difference, and residual charge on electrodes achieves safety.
• Large DC blocking capacitors improve safety but increase size/weight, while capacitor-free designs are being researched.
• Electrode size (around 0.1 mm diameters) affects spatial resolution.
• Spatial resolution depends on electrode proximity to the target tissue.
• Stimulation strength increases with distance, activating non-target neurons.
• Time between stimulation and action potential generation (AP latency) depends on voltage-gated ion channel activation time and varies depending on ionic types, typically in milliseconds.
• Increasing stimulator programmability is a research trend-offering control over stimulus waveform to change efficacy.
• Potential gradients are generated using voltage, current, or charge-controlled stimulators:

Voltage Controlled

• Applying voltage between two electrodes is the simplest method for direct neural stimulation, consuming low power.
• Lack of charge control leads to electrode degradation and toxic redox products.
• Clinically used in deep brain stimulation (DBS) and muscular stimulation where low power consumption and therapeutic effectiveness are important.

Current Controlled

• Current controlled stimulation controls current flow by using varying potentials across electrodes.
• Charge-balanced waveforms are used by calibrating current sources and using H-bridges or DC blocking caps.
• Controlling current wastes more power, affecting tissue.
• Used in cochlear implants/research publications.
• Transcranial Direct Current Stimulation (tDCS) studies CNS physiology in humans.
• Safe, non-invasive, but low spatial resolution.

Charge Controlled

• Combines voltage stimulation with a capacitor to control charge delivered to electrodes.
• Offers a biocompatibility and power consumption balance between current and voltage controlled stimulation.
• Not yet in clinical use.

Magnetic

• Similar to direct electrical stimulation, but potential gradients are induced by changing magnetic fields (>1T).
• Typically implemented transcutaneously (e.g., Transcranial Magnetic Stimulation (TMS).
• Absence of electrochemical issues is an advantage, but selectivity is poor, and peak power consumption is high.
• Improving focus depends on stimulation coil redesign.
• Micro-TMS (μTMS) reduces spatial resolution by tenfold.
• Fully implantable stimulator is limited by large power usage.
• Hand-held TMS treats stroke/depression.
• Caution required for implanted metal because metal can be heated by eddy current.

Optogenetic

• Light-sensitive proteins (“opsins”) are genetically inserted into cell membranes.
• These proteins act as light-activated ion pumps, channels, or enzymes for optical manipulation of electrical and biochemical processes.
• Named "Method of the Year 2010" by Nature Methods.
• Channelrhodopsin stimulates neural activity, and halorhodopsin inhibits it.
• Wide range of opsins with varying properties have since been discovered and parallel development in techniques for genetic manipulation.
• Wireless systems using up to 25 channels are showing promise.
• Genetically modifying neurons presents safety and ethics issues for human use.
• Unclear how quickly new ion channels would be expressed in the PNS with long axons.
• Variations in gene expression can lead to different responses for the same stimulus.
• The high precision and ability to selectively express opsins in target neuron types makes this a highly attractive tool for neuroscience.

Thermal

• Thermal modulation comes from temperature-induced changes in transmembrane capacitance and non-uniform changes in ionic channel conductance dynamics.
• Rapid localized heating results in ionic current flow, depolarization and action potential initiation by influence membrane capacitance.
• Stimulus is proportional to the speed of temperature change.
• Slow heating changes ionic channels and Na+/K+ dynamics influence action potential initiation and propagation. Thermal damage may occur.
• Thermal changes can be optically-induced and can use nanoparticle stimulation.

Optically Induced Thermal Modulation

• Rapid heating is achieved by using near-infrared light on a nerve or neuron.
• This enables an AP latency of ms and spatial resolution of 10 µm.
• Stimulation and damage thresholds are close for some neurons.

Microwave/RF Heating of Nanoparticles

• Magnetic nanoparticles absorb RF radiation to heat surrounding tissue.
• Can be combined with proteins, focally heating target cells.
• Poor temporal resolution, unclear safety.

Acoustic/Mechanical

• Acoustic modulation is an emerging method using on-off modulated ultrasound waves for action potentials from retinal and brain cells.
• Mechanical deformations impacting ion channels, membrane capacitances, and neurons aren't well understood.
• Potential for non-invasive Deep Brain Stimulation.
• Non-invasive: offers better spatial resolution.

Chemical

• Microfluidics controls the chemical environment around neurons: modulating transmembrane potentials.
• Can induce/suppress action potential generation.
• Achieving high resolution can be challenging.
• Suited to applications requiring long term effect, e.g., Deep Brain Stimulation.

Neurotransmitter Modulation

• Neurotransmitter molecules are released near synapses: altering post-synaptic potential and affecting neuronal transmission.
• Selective sensitivity of neurons to neurotransmitters facilitates targeting; limited applicability in the PNS (where synapses are absent).

Ionic Concentration

• Sequestration/release of ions near a neuron disrupts gradients in membranes, modulating neural transmission.
• May reduce required stimulation thresholds using other techniques.

Discussion

• Choosing a neuromodulation method for clinical application is by three main considerations:
• Safety: The safety of methods is primary. All techniques cause potential harm, but optogenetics and nanoparticle-based thermal face particular challenges.
• The suitability of method to the application: Suited to electrical or optogenetic for precise control, suited to electrical, magnetic, chemical, or thermal.
• Suitability to specific use case: Transcranial electrical/magnetic modulation or an acoustic/mechanical solution. Portable prioritizes frequent invasive favored electric modulation.
• Electrical neural stimulation is the most mature and capable.
• ENS represents opportunity for competing methods.
• This review identifies a range of techniques that each demonstrate unique strengths.
• For example, Chemical modulation using neurotransmitter release offers a degree of cellular specificity. The shift from ENS is a trend in a few applications, with alternatives offering cellular specific niches.
• More trends with examples include (combining current stimulation with voltage control to reduce power). The days of just using electrical stimulation may be numbered.