Multielectrode array
Encyclopedia
Multielectrode arrays or microelectrode arrays are devices that contain multiple plates or shanks through which neural signals are obtained or delivered, essentially serving as neural interfaces that connect neuron
s to electronic circuitry. There are two general classes of MEAs: implantable MEAs, used in vivo
, and non-implantable MEAs, used in vitro
.
cells create ion
currents through their membranes
when excited, causing a change in voltage
both inside and outside the cell. When recording, the electrode
s on an MEA transduce
the change in voltage
from the environment carried by ions into currents carried by electrons (electronic currents). When stimulating, electrodes transduce electronic currents into ionic currents through the media. This triggers the voltage-gated ion channel
s on the membranes
of the excitable cells, causing the cell to depolarize
and trigger an action potential
if it is a neuron or a twitch if it is a muscle cell.
The size and shape of a recorded signal depend upon several factors: the nature of the medium in which the cell or cells are located (e.g. the medium's electrical conductivity, capacitance
, and homogeneity
); the nature of contact between the cells and the MEA electrode (e.g. area of contact and tightness); the nature of the MEA electrode itself (e.g. its geometry, impedance
, and noise); the analog signal processing
(e.g. the system’s gain
, bandwidth, and behavior outside of cutoff frequencies
); and the data sampling
properties (e.g. sampling rate
and digital signal processing
). For the recording of a single cell that partially covers a planar electrode, the voltage at the contact pad
is approximately equal to the voltage of the overlapping region of the cell and electrode multiplied by the ratio the surface area
of the overlapping region to the area of the entire electrode, or:
assuming the area around an electrode is well-insulated and has a very small capacitance associated with it. The equation above, however, relies on modeling the electrode, cells, and their surroundings as an equivalent circuit diagram
. An alternative means of predicting cell-electrode behavior is by modeling the system using a geometry-based finite element analysis in an attempt to circumvent the limitations of oversimplifying the system in a lumped circuit element diagram.
An MEA can be used to perform electrophysiological experiments on tissue slices or dissociated cell cultures. With acute tissue slices, the connections between the cells within the tissue slices prior to extraction and plating are more or less preserved, while the intercellular connections in dissociated cultures are destroyed prior to plating. With dissociated neuronal cultures, the neurons spontaneously form networks
.
It can be seen that the voltage amplitude
an electrode experiences is inversely
related to the distance from which a cell depolarizes. Thus, it may be necessary for the cells to be cultured or otherwise placed as close to the electrodes as possible. With tissue slices, a layer of electrically passive dead cells form around the site of incision due to edema
. A way to deal with this is by fabricating an MEA with three-dimensional electrodes fabricated by masking
and chemical etching
. These 3-D electrodes penetrate the dead cell layer of the slice tissue, decreasing the distance between live cells and the electrodes. In dissociated cultures, proper adherence of the cells to the MEA substrate is important for getting robust signals.
electrodes plated with platinum black
, each spaced 100 µm apart from each other. Myocytes harvested from embryo
nic chicks were dissociated and cultured onto the MEAs, and signals up to 1 mV high in amplitude were recorded. MEAs were constructed and used to explore the electrophysiology of snail ganglia independently by G. Gross and his colleagues in 1977 without prior knowledge of Thomas and his colleagues’ work. In 1982, Gross observed spontaneous electrophysiological activity from dissociated spinal cord
neurons, and found that activity was very dependent on temperature. Below about 30˚C signal amplitudes decrease rapidly to relatively small value at room temperature
.
Before the 1990’s, significant entry barriers existed for new laboratories that sought to conduct MEA research due to the custom MEA fabrication and software they had to develop. However, with the advent of affordable computing power and commercial MEA hardware and software, many other laboratories were able to undertake research using MEAs.
The standard type of in vitro MEA comes in a pattern of 8 x 8 or 6 x 10 electrodes. Electrodes are typically composed of indium tin oxide
or titanium
and have diameters between 10 and 30 μm. These arrays are normally used for single-cell cultures or acute brain slices.
One challenge among in vitro MEAs has been imaging them with microscopes that use high power lenses, requiring low working distances on the order of micrometers. In order to avoid this problem, “thin”-MEAs have been created using cover slip glass. These arrays are approximately 180 μm allowing them to be used with high-power lenses..
In another special design, 60 electrodes are split into 6 x 5 arrays separated by 500 μm. Electrodes within a group are separated by 30 um with diameters of 10 μm. Arrays such as this are used to examine local responses of neurons while also studying functional connectivity of organotypic slices.
Spatial resolution is one of the key advantages of MEAs and allows signals sent over a long distance to be taken with higher precision when a high-density MEA is used. These arrays usually have a square grid pattern of 256 electrodes that cover an area of 2.8 by 2.8 mm.
In order to obtain quality signals electrodes and tissue must be in close contact with one another. The perforated MEA design applies negative pressure
to openings in the substrate so that tissue slices can be positioned on the electrodes to enhance contact and recorded signals.
The three major categories of implantable MEAs are microwire, silicon
- based, and flexible microelectrode arrays. Microwire MEAs are largely made of stainless steel
or tungsten
and they can be used to estimate the position of individual recorded neurons by triangulation. Silicon-based microelectrode arrays include two specific models: the Michigan and Utah arrays. Michigan arrays allow a higher density of sensors for implantation as well as a higher spatial resolution than microwire MEAs. They also allow signals to be obtained along the length of the shank, rather than just at the ends of the shanks. In contrast to Michigan arrays, Utah arrays are 3-D, consisting of 100 conductive silicon needles. However, in a Utah array signals are only received from the tips of each electrode, which limits the amount of information that can be obtained at one time. Furthermore, Utah arrays are manufactured with set dimensions and parameters while the Michigan array allows for more design freedom. Flexible arrays, made with polyimide
, parylene
, or benzocyclobutene
, provide an advantage over rigid microelectrode arrays because they provide a closer mechanical match, as the Young’s modulus of silicon is much larger than that of brain tissue, contributing to shear-induced inflammation
.
, resulting in a depolarization of the intracellular environment which propagates down the axon
. This ion flux through the cellular membrane generates a sharp change in voltage in the extracellular environment, which is what the MEA electrodes ultimately detect. Thus, voltage spike counting and sorting is often used in research to characterize network activity.
ing include:
Furthermore, in vitro arrays are non-invasive when compared to patch clamping because they do not require breaching of the cell membrane.
With respect to in vivo arrays however, the major advantage over patch clamping is the high spatial resolution. Implantable arrays allow signals to be obtained from individual neurons enabling information such as position or velocity
of motor movement that can be used to control a prosthetic device.
There are also several biological responses to implantation of a microelectrode array, particularly in regards to chronic implantation. Most notable among these effects are neuronal cell loss, glial scarring, and a drop in the number of functioning electrodes. The tissue response to implantation is dependent among many factors including size of the MEA shanks, distance between the shanks, MEA material composition, and time period of insertion. The tissue response is typically divided into short term and long term response. The short term response occurs within hours of implantation and begins with an increased population of astrocytes and glial cells surrounding the device. The recruited microglia
then initiate inflammation and a process of phagocytosis of the foreign material begins. Over time, the astrocytes and microglia recruited to the device begin to accumulate, forming a sheath surrounding the array that extends tens of micrometres around the device. This not only increases the space between electrode probes, but also insulates the electrodes and increases impedance measurements. Problems with chronic implantation of arrays have been a driving force in the research of these devices. One novel study examined the neurodegenerative effects of inflammation caused by chronic implantation. Immunohistochemical markers showed a surprising presence of hyperphosphorylated tau, an indicator of Alzheimer’s disease, near the electrode recording site. The phagocytosis of electrode material also brings to question the issue of a biocompatibility response, which research suggests has been minor and becomes almost nonexistent after 12 weeks in vivo. Research to minimize the negative effects of device insertion includes surface coating of the devices with proteins that encourage neuron attachment, such as laminin
, or drug eluting
substances.
The nature of dissociated neuronal networks does not seem to change or diminish the character of its pharmacological response when compared to in vivo models, suggesting that MEAs can be used to study pharmacological effects on dissociated neuronal cultures in a more simple, controlled environment. A number of pharmacological studies using MEAs on dissociated neuronal networks, e.g. studies with ethanol
.
In addition, a substantial body of work on various biophysical aspects of network function was carried out by reducing phenomena usually studied at the behavioral level to the dissociated cortical network level. For example, the capacity of such networks to extract spatial and temporal features of various input signals, dynamics of synchronization , sensitivity to neuromodulation
and kinetics of learning using closed loop regimes . Finally, combining MEA technology with confocal microscopy
allows for studying relationships between network activity and synaptic remodeling .
MEAs have been used to interface neuronal networks with non-biological systems as a controller. For example, a neural-computer interface can be created using MEAs. Dissociated rat cortical neurons were integrated into a closed stimulus-response feedback loop to control an animat in a virtual environment.. A closed-loop stimulus-response system has also been constructed using an MEA by Dr. Potter, Dr. Mandhavan, and Dr. DeMarse, and by Mark Hammond, Kevin Warwick
, and Ben Whalley in the University of Reading
. About 300,000 dissociated rat neurons were plated on an MEA, which was connected to motors and ultrasound
sensors on a robot, and was conditioned to avoid obstacles when sensed. Along these lines, Shimon Marom and colleagues in the Technion hooked dissociated neuronal networks growing on MEAs to a Lego MindStorms
robot; the visual field of the robot was classified by the network, and commands were delivered to the robot wheels such that it completely avoids bumping into obstacles . link to movie. Interestingly, this "Braitenberg Vehicle"
was used to demonstrate the indeterminacy
of reverse neuro-engineering showing that even in a simple setup with practically unlimited access to every piece of relevant information, it was impossible to deduce with certainty the specific neural coding
scheme that was used to drive the robots behavior.
MEAs have been used to observe network firing in hippocampal slices.
, cochlear implants, and cardiac pacemaker
s. Deep brain stimulation (DBS) has been effective at treating movement disorders such as Parkinson's disease
, and cochlear implants have helped many to improve their hearing by assisting stimulation of the auditory nerve. Because of their remarkable potential, MEAs are a prominent area of neuroscience research. Research suggests that MEAs may provide insight into processes such as memory formation and perception and may also hold therapeutic value for conditions such as epilepsy
, depression, and obsessive-compulsive disorder
. Clinical trials using interface devices for restoring motor control after spinal cord injury or as treatment for ALS
have been initiated in a project entitled BrainGate (see video demo: BrainGate). MEAs provide the high resolution necessary to record time varying signals, giving them the ability to be used to both control and obtain feedback from prosthetic devices, as was shown by Kevin Warwick
, Mark Gasson
and Peter Kyberd
. Research suggests that MEA use may be able to assist in the restoration of vision by stimulating the optic pathway
.
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s to electronic circuitry. There are two general classes of MEAs: implantable MEAs, used in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
, and non-implantable MEAs, used in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
.
Theory
Neurons and muscleMuscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
cells create ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
currents through their membranes
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
when excited, causing a change in voltage
Voltage
Voltage, otherwise known as electrical potential difference or electric tension is the difference in electric potential between two points — or the difference in electric potential energy per unit charge between two points...
both inside and outside the cell. When recording, the electrode
Electrode
An electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit...
s on an MEA transduce
Transduction
Transduction is a mechanism whereby genetic material may be transferred from the genes of a bacterium to another bacterium. This may include the actual covalent-bonding of new genetic markers...
the change in voltage
Voltage
Voltage, otherwise known as electrical potential difference or electric tension is the difference in electric potential between two points — or the difference in electric potential energy per unit charge between two points...
from the environment carried by ions into currents carried by electrons (electronic currents). When stimulating, electrodes transduce electronic currents into ionic currents through the media. This triggers the voltage-gated ion channel
Voltage-gated ion channel
Voltage-gated ion channels are a class of transmembrane ion channels that are activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons, but are common in many types of cells....
s on the membranes
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
of the excitable cells, causing the cell to depolarize
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
and trigger an action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
if it is a neuron or a twitch if it is a muscle cell.
The size and shape of a recorded signal depend upon several factors: the nature of the medium in which the cell or cells are located (e.g. the medium's electrical conductivity, capacitance
Capacitance
In electromagnetism and electronics, capacitance is the ability of a capacitor to store energy in an electric field. Capacitance is also a measure of the amount of electric potential energy stored for a given electric potential. A common form of energy storage device is a parallel-plate capacitor...
, and homogeneity
Homogeneous (chemistry)
A substance that is uniform in composition is a definition of homogeneous. This is in contrast to a substance that is heterogeneous.The definition of homogeneous strongly depends on the context used. In Chemistry, a homogeneous suspension of material means that when dividing the volume in half, the...
); the nature of contact between the cells and the MEA electrode (e.g. area of contact and tightness); the nature of the MEA electrode itself (e.g. its geometry, impedance
Electrical impedance
Electrical impedance, or simply impedance, is the measure of the opposition that an electrical circuit presents to the passage of a current when a voltage is applied. In quantitative terms, it is the complex ratio of the voltage to the current in an alternating current circuit...
, and noise); the analog signal processing
Analog signal processing
Analog signal processing is any signal processing conducted on analog signals by analog means. "Analog" indicates something that is mathematically represented as a set of continuous values. This differs from "digital" which uses a series of discrete quantities to represent signal...
(e.g. the system’s gain
Gain
In electronics, gain is a measure of the ability of a circuit to increase the power or amplitude of a signal from the input to the output. It is usually defined as the mean ratio of the signal output of a system to the signal input of the same system. It may also be defined on a logarithmic scale,...
, bandwidth, and behavior outside of cutoff frequencies
Cutoff frequency
In physics and electrical engineering, a cutoff frequency, corner frequency, or break frequency is a boundary in a system's frequency response at which energy flowing through the system begins to be reduced rather than passing through.Typically in electronic systems such as filters and...
); and the data sampling
Sampling (signal processing)
In signal processing, sampling is the reduction of a continuous signal to a discrete signal. A common example is the conversion of a sound wave to a sequence of samples ....
properties (e.g. sampling rate
Sampling rate
The sampling rate, sample rate, or sampling frequency defines the number of samples per unit of time taken from a continuous signal to make a discrete signal. For time-domain signals, the unit for sampling rate is hertz , sometimes noted as Sa/s...
and digital signal processing
Digital signal processing
Digital signal processing is concerned with the representation of discrete time signals by a sequence of numbers or symbols and the processing of these signals. Digital signal processing and analog signal processing are subfields of signal processing...
). For the recording of a single cell that partially covers a planar electrode, the voltage at the contact pad
Contact pad
Contact pads are designated surface areas of a printed circuit board or die of an integrated circuit. Possibilities to contact to pads include soldering, wirebonding, Flip chip mounting, or probe needles....
is approximately equal to the voltage of the overlapping region of the cell and electrode multiplied by the ratio the surface area
Surface area
Surface area is the measure of how much exposed area a solid object has, expressed in square units. Mathematical description of the surface area is considerably more involved than the definition of arc length of a curve. For polyhedra the surface area is the sum of the areas of its faces...
of the overlapping region to the area of the entire electrode, or:
assuming the area around an electrode is well-insulated and has a very small capacitance associated with it. The equation above, however, relies on modeling the electrode, cells, and their surroundings as an equivalent circuit diagram
Circuit diagram
A circuit diagram is a simplified conventional graphical representation of an electrical circuit...
. An alternative means of predicting cell-electrode behavior is by modeling the system using a geometry-based finite element analysis in an attempt to circumvent the limitations of oversimplifying the system in a lumped circuit element diagram.
An MEA can be used to perform electrophysiological experiments on tissue slices or dissociated cell cultures. With acute tissue slices, the connections between the cells within the tissue slices prior to extraction and plating are more or less preserved, while the intercellular connections in dissociated cultures are destroyed prior to plating. With dissociated neuronal cultures, the neurons spontaneously form networks
Biological neural network
In neuroscience, a biological neural network describes a population of physically interconnected neurons or a group of disparate neurons whose inputs or signalling targets define a recognizable circuit. Communication between neurons often involves an electrochemical process...
.
It can be seen that the voltage amplitude
Amplitude
Amplitude is the magnitude of change in the oscillating variable with each oscillation within an oscillating system. For example, sound waves in air are oscillations in atmospheric pressure and their amplitudes are proportional to the change in pressure during one oscillation...
an electrode experiences is inversely
Inverse relation
In mathematics, the inverse relation of a binary relation is the relation that occurs when you switch the order of the elements in the relation. For example, the inverse of the relation 'child of' is the relation 'parent of'...
related to the distance from which a cell depolarizes. Thus, it may be necessary for the cells to be cultured or otherwise placed as close to the electrodes as possible. With tissue slices, a layer of electrically passive dead cells form around the site of incision due to edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
. A way to deal with this is by fabricating an MEA with three-dimensional electrodes fabricated by masking
Photomask
A photomask is an opaque plate with holes or transparencies that allow light to shine through in a defined pattern. They are commonly used in photolithography.-Overview:...
and chemical etching
Etching (microfabrication)
Etching is used in microfabrication to chemically remove layers from the surface of a wafer during manufacturing. Etching is a critically important process module, and every wafer undergoes many etching steps before it is complete....
. These 3-D electrodes penetrate the dead cell layer of the slice tissue, decreasing the distance between live cells and the electrodes. In dissociated cultures, proper adherence of the cells to the MEA substrate is important for getting robust signals.
History
The first implantable arrays were microwire arrays developed in the 1950s. The first experiment involving the use of an array of planar electrodes to record from cultured cells was conducted in 1972 by C.A. Thomas, Jr. and his colleagues. The experimental setup used a 2 x 15 array of goldGold
Gold is a chemical element with the symbol Au and an atomic number of 79. Gold is a dense, soft, shiny, malleable and ductile metal. Pure gold has a bright yellow color and luster traditionally considered attractive, which it maintains without oxidizing in air or water. Chemically, gold is a...
electrodes plated with platinum black
Platinum black
Platinum black is a fine powder of platinum with good catalytic properties. The name of platinum black is due to its black color....
, each spaced 100 µm apart from each other. Myocytes harvested from embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
nic chicks were dissociated and cultured onto the MEAs, and signals up to 1 mV high in amplitude were recorded. MEAs were constructed and used to explore the electrophysiology of snail ganglia independently by G. Gross and his colleagues in 1977 without prior knowledge of Thomas and his colleagues’ work. In 1982, Gross observed spontaneous electrophysiological activity from dissociated spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
neurons, and found that activity was very dependent on temperature. Below about 30˚C signal amplitudes decrease rapidly to relatively small value at room temperature
Room temperature
-Comfort levels:The American Society of Heating, Refrigerating and Air-Conditioning Engineers has listings for suggested temperatures and air flow rates in different types of buildings and different environmental circumstances. For example, a single office in a building has an occupancy ratio per...
.
Before the 1990’s, significant entry barriers existed for new laboratories that sought to conduct MEA research due to the custom MEA fabrication and software they had to develop. However, with the advent of affordable computing power and commercial MEA hardware and software, many other laboratories were able to undertake research using MEAs.
Types
Microelectrode arrays can be divided up into subcategories based on their potential use: in vitro and in vivo arrays.In vitro arrays
Indium tin oxide
Indium tin oxide is a solid solution of indium oxide and tin oxide , typically 90% In2O3, 10% SnO2 by weight. It is transparent and colorless in thin layers while in bulk form it is yellowish to grey...
or titanium
Titanium
Titanium is a chemical element with the symbol Ti and atomic number 22. It has a low density and is a strong, lustrous, corrosion-resistant transition metal with a silver color....
and have diameters between 10 and 30 μm. These arrays are normally used for single-cell cultures or acute brain slices.
One challenge among in vitro MEAs has been imaging them with microscopes that use high power lenses, requiring low working distances on the order of micrometers. In order to avoid this problem, “thin”-MEAs have been created using cover slip glass. These arrays are approximately 180 μm allowing them to be used with high-power lenses..
In another special design, 60 electrodes are split into 6 x 5 arrays separated by 500 μm. Electrodes within a group are separated by 30 um with diameters of 10 μm. Arrays such as this are used to examine local responses of neurons while also studying functional connectivity of organotypic slices.
Spatial resolution is one of the key advantages of MEAs and allows signals sent over a long distance to be taken with higher precision when a high-density MEA is used. These arrays usually have a square grid pattern of 256 electrodes that cover an area of 2.8 by 2.8 mm.
In order to obtain quality signals electrodes and tissue must be in close contact with one another. The perforated MEA design applies negative pressure
Pressure
Pressure is the force per unit area applied in a direction perpendicular to the surface of an object. Gauge pressure is the pressure relative to the local atmospheric or ambient pressure.- Definition :...
to openings in the substrate so that tissue slices can be positioned on the electrodes to enhance contact and recorded signals.
In vivo arrays
Silicon
Silicon is a chemical element with the symbol Si and atomic number 14. A tetravalent metalloid, it is less reactive than its chemical analog carbon, the nonmetal directly above it in the periodic table, but more reactive than germanium, the metalloid directly below it in the table...
- based, and flexible microelectrode arrays. Microwire MEAs are largely made of stainless steel
Steel
Steel is an alloy that consists mostly of iron and has a carbon content between 0.2% and 2.1% by weight, depending on the grade. Carbon is the most common alloying material for iron, but various other alloying elements are used, such as manganese, chromium, vanadium, and tungsten...
or tungsten
Tungsten
Tungsten , also known as wolfram , is a chemical element with the chemical symbol W and atomic number 74.A hard, rare metal under standard conditions when uncombined, tungsten is found naturally on Earth only in chemical compounds. It was identified as a new element in 1781, and first isolated as...
and they can be used to estimate the position of individual recorded neurons by triangulation. Silicon-based microelectrode arrays include two specific models: the Michigan and Utah arrays. Michigan arrays allow a higher density of sensors for implantation as well as a higher spatial resolution than microwire MEAs. They also allow signals to be obtained along the length of the shank, rather than just at the ends of the shanks. In contrast to Michigan arrays, Utah arrays are 3-D, consisting of 100 conductive silicon needles. However, in a Utah array signals are only received from the tips of each electrode, which limits the amount of information that can be obtained at one time. Furthermore, Utah arrays are manufactured with set dimensions and parameters while the Michigan array allows for more design freedom. Flexible arrays, made with polyimide
Polyimide
Polyimide is a polymer of imide monomers. The structure of imide is as shown. Polyimides have been in mass production since 1955...
, parylene
Parylene
Parylene is the tradename for a variety of chemical vapor deposited poly polymers used as moisture and dielectric barriers. Among them, Parylene C is the most popular due to its combination of barrier properties, cost, and other processing advantages.Parylene is green polymer chemistry...
, or benzocyclobutene
Benzocyclobutene
Benzocyclobutene is a benzene ring fused to a cyclobutane ring. It has chemical formula 88.BCB is frequently used to create photosensitive polymers. BCB-based polymer dielectrics may be spun on or applied to various substrates for use in Micro Electro-Mechanical Systems and microelectronics...
, provide an advantage over rigid microelectrode arrays because they provide a closer mechanical match, as the Young’s modulus of silicon is much larger than that of brain tissue, contributing to shear-induced inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
.
Data processing methods
The fundamental unit of communication of neurons is, electrically, at least, the action potential. This all-or-nothing phenomenon is believed to originate at the axon hillockAxon hillock
The axon hillock is a specialized part of the cell body of a neuron that connects to the axon. As a result, the axon hillock is the last site in the soma where membrane potentials propagated from synaptic inputs are summated before being transmitted to the axon. For many years it was believed...
, resulting in a depolarization of the intracellular environment which propagates down the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
. This ion flux through the cellular membrane generates a sharp change in voltage in the extracellular environment, which is what the MEA electrodes ultimately detect. Thus, voltage spike counting and sorting is often used in research to characterize network activity.
Advantages
In general, the major strengths of in vitro arrays when compared to more traditional methods such as patch clampPatch clamp
The patch clamp technique is a laboratory technique in electrophysiology that allows the study of single or multiple ion channels in cells. The technique can be applied to a wide variety of cells, but is especially useful in the study of excitable cells such as neurons, cardiomyocytes, muscle...
ing include:
- Allowing the placement of multiple electrodes at once rather than individually
- The ability to set up controls within the same experimental setup (by using one electrode as a control and others as experimental)
- The ability to select different recordings sites within the array
- The ability to simultaneously receive data from multiple sites
Furthermore, in vitro arrays are non-invasive when compared to patch clamping because they do not require breaching of the cell membrane.
With respect to in vivo arrays however, the major advantage over patch clamping is the high spatial resolution. Implantable arrays allow signals to be obtained from individual neurons enabling information such as position or velocity
Velocity
In physics, velocity is speed in a given direction. Speed describes only how fast an object is moving, whereas velocity gives both the speed and direction of the object's motion. To have a constant velocity, an object must have a constant speed and motion in a constant direction. Constant ...
of motor movement that can be used to control a prosthetic device.
Disadvantages
In vitro MEAs are less suited for recording and stimulating single cells due to their low spatial resolution compared to patch clamp and dynamic clamp systems. The complexity of signals an MEA electrode could effectively transmit to other cells is limited compared to the capabilities of dynamic clamps.There are also several biological responses to implantation of a microelectrode array, particularly in regards to chronic implantation. Most notable among these effects are neuronal cell loss, glial scarring, and a drop in the number of functioning electrodes. The tissue response to implantation is dependent among many factors including size of the MEA shanks, distance between the shanks, MEA material composition, and time period of insertion. The tissue response is typically divided into short term and long term response. The short term response occurs within hours of implantation and begins with an increased population of astrocytes and glial cells surrounding the device. The recruited microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
then initiate inflammation and a process of phagocytosis of the foreign material begins. Over time, the astrocytes and microglia recruited to the device begin to accumulate, forming a sheath surrounding the array that extends tens of micrometres around the device. This not only increases the space between electrode probes, but also insulates the electrodes and increases impedance measurements. Problems with chronic implantation of arrays have been a driving force in the research of these devices. One novel study examined the neurodegenerative effects of inflammation caused by chronic implantation. Immunohistochemical markers showed a surprising presence of hyperphosphorylated tau, an indicator of Alzheimer’s disease, near the electrode recording site. The phagocytosis of electrode material also brings to question the issue of a biocompatibility response, which research suggests has been minor and becomes almost nonexistent after 12 weeks in vivo. Research to minimize the negative effects of device insertion includes surface coating of the devices with proteins that encourage neuron attachment, such as laminin
Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...
, or drug eluting
Elution
Elution is a term used in analytical and organic chemistry to describe the process of extracting one material from another by washing with a solvent ....
substances.
In vitro
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
.
In addition, a substantial body of work on various biophysical aspects of network function was carried out by reducing phenomena usually studied at the behavioral level to the dissociated cortical network level. For example, the capacity of such networks to extract spatial and temporal features of various input signals, dynamics of synchronization , sensitivity to neuromodulation
Neuromodulation
In Neuromodulation several classes of neurotransmitters regulate diverse populations of central nervous system neurons...
and kinetics of learning using closed loop regimes . Finally, combining MEA technology with confocal microscopy
Confocal microscopy
Confocal microscopy is an optical imaging technique used to increase optical resolution and contrast of a micrograph by using point illumination and a spatial pinhole to eliminate out-of-focus light in specimens that are thicker than the focal plane. It enables the reconstruction of...
allows for studying relationships between network activity and synaptic remodeling .
MEAs have been used to interface neuronal networks with non-biological systems as a controller. For example, a neural-computer interface can be created using MEAs. Dissociated rat cortical neurons were integrated into a closed stimulus-response feedback loop to control an animat in a virtual environment.. A closed-loop stimulus-response system has also been constructed using an MEA by Dr. Potter, Dr. Mandhavan, and Dr. DeMarse, and by Mark Hammond, Kevin Warwick
Kevin Warwick
Kevin Warwick is a British scientist and professor of cybernetics at the University of Reading, Reading, Berkshire, United Kingdom...
, and Ben Whalley in the University of Reading
University of Reading
The University of Reading is a university in the English town of Reading, Berkshire. The University was established in 1892 as University College, Reading and received its Royal Charter in 1926. It is based on several campuses in, and around, the town of Reading.The University has a long tradition...
. About 300,000 dissociated rat neurons were plated on an MEA, which was connected to motors and ultrasound
Ultrasound
Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Ultrasound is thus not separated from "normal" sound based on differences in physical properties, only the fact that humans cannot hear it. Although this limit varies from person to person, it is...
sensors on a robot, and was conditioned to avoid obstacles when sensed. Along these lines, Shimon Marom and colleagues in the Technion hooked dissociated neuronal networks growing on MEAs to a Lego MindStorms
Lego Mindstorms
The LEGO Mindstorm series of kits contain software and hardware to create small, customizable and programmable robots. They include a programmable 'Brick' computer that controls the system, a set of modular sensors and motors, and LEGO parts from the Technics line to create the mechanical...
robot; the visual field of the robot was classified by the network, and commands were delivered to the robot wheels such that it completely avoids bumping into obstacles . link to movie. Interestingly, this "Braitenberg Vehicle"
Braitenberg Vehicles
A Braitenberg vehicle is a concept conceived in a thought experiment by the Italian-Austrian cyberneticist Valentino Braitenberg to illustrate in an evolutive way the abilities of simple agents. The vehicles represent the simplest form of behavior based artificial intelligence or embodied...
was used to demonstrate the indeterminacy
Underdetermination
In scientific theory, underdetermination refers to situations where the evidence available is insufficient to identify which belief we should hold about that evidence...
of reverse neuro-engineering showing that even in a simple setup with practically unlimited access to every piece of relevant information, it was impossible to deduce with certainty the specific neural coding
Neural coding
Neural coding is a neuroscience-related field concerned with how sensory and other information is represented in the brain by networks of neurons. The main goal of studying neural coding is to characterize the relationship between the stimulus and the individual or ensemble neuronal responses and...
scheme that was used to drive the robots behavior.
MEAs have been used to observe network firing in hippocampal slices.
In vivo
There are several implantable interfaces that are currently available for consumer use including deep brain stimulatorsDeep brain stimulation
Deep brain stimulation is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain...
, cochlear implants, and cardiac pacemaker
Artificial pacemaker
A pacemaker is a medical device that uses electrical impulses, delivered by electrodes contacting the heart muscles, to regulate the beating of the heart...
s. Deep brain stimulation (DBS) has been effective at treating movement disorders such as Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, and cochlear implants have helped many to improve their hearing by assisting stimulation of the auditory nerve. Because of their remarkable potential, MEAs are a prominent area of neuroscience research. Research suggests that MEAs may provide insight into processes such as memory formation and perception and may also hold therapeutic value for conditions such as epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, depression, and obsessive-compulsive disorder
Obsessive-compulsive disorder
Obsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
. Clinical trials using interface devices for restoring motor control after spinal cord injury or as treatment for ALS
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
have been initiated in a project entitled BrainGate (see video demo: BrainGate). MEAs provide the high resolution necessary to record time varying signals, giving them the ability to be used to both control and obtain feedback from prosthetic devices, as was shown by Kevin Warwick
Kevin Warwick
Kevin Warwick is a British scientist and professor of cybernetics at the University of Reading, Reading, Berkshire, United Kingdom...
, Mark Gasson
Mark Gasson
Mark Gasson is a British scientist and senior research fellow at the Cybernetic Intelligence Research Group, University of Reading, UK. He pioneered developments in direct interfaces between computer systems and the human nervous system, is active in the research fields of robotics and identity and...
and Peter Kyberd
Peter Kyberd
Peter Kyberd is a professor at the University of New Brunswick's Institute of Biomedical Engineering, and a leading authority on control of prosthetic limbs, a subject he has been working on since the late 1980s, including a highly publicised collaboration with Kevin Warwick and Mark Gasson at the...
. Research suggests that MEA use may be able to assist in the restoration of vision by stimulating the optic pathway
Optic nerve
The optic nerve, also called cranial nerve 2, transmits visual information from the retina to the brain. Derived from the embryonic retinal ganglion cell, a diverticulum located in the diencephalon, the optic nerve doesn't regenerate after transection.-Anatomy:The optic nerve is the second of...
.
MEA user meetings
A biannual scientific user meeting is held in Reutlingen, organized by the Natural and Medical Sciences Institute (NMI) at the University of Tuebingen. The meetings offer a comprehensive overview of all aspects related to new developments and current applications of Microelectrode Arrays in basic and applied neuroscience as well as in industrial drug discovery, safety pharmacology and neurotechnology. The biannual conference has developed into an international venue for scientists developing and using MEAs from both industry and academia, and is recognized as an information-packed scientific forum of high quality. The meeting contributions are available as open access proceeding books.See also
- AnimatAnimatAnimats are artificial animals, a contraction of anima-materials. The term includes physical robots and virtual simulations. Animat research, a subset of Artificial Life studies, has become rather popular since Rodney Brooks' seminal paper "Intelligence without representation". The word was coined...
- Artificial pacemakerArtificial pacemakerA pacemaker is a medical device that uses electrical impulses, delivered by electrodes contacting the heart muscles, to regulate the beating of the heart...
- Deep brain stimulationDeep brain stimulationDeep brain stimulation is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain...
- Patch clampPatch clampThe patch clamp technique is a laboratory technique in electrophysiology that allows the study of single or multiple ion channels in cells. The technique can be applied to a wide variety of cells, but is especially useful in the study of excitable cells such as neurons, cardiomyocytes, muscle...
- BioelectronicsBioelectronicsBioelectronics is a recently coined term for a field of research that works to establish a synergy between electronics and biology. One of the main forums for information about the field is the Elsevier journal Biosensors and Bioelectronics, published since 1990...