| Tapered Fibers | Metric Generation | Microprocessor Design | Radio-Frequency Controller |
Open Source Instruments Inc. (OSI) proposes to develop an Implantable Sensor with Lamp (ISL) in collaboration with the Institute of Neurology (ION) of University College London (UCL). This device will monitor electroencephalography (EEG) in a laboratory animal, identify epileptic seizures using an on-board microprocessor, and shine light upon an area of the animal's brain in response to these seizures. In order to facilitate the development of autonomous seizure detection and response, the device will also be able to transmit the EEG signal to an antenna outside the animal's body, and it will be able to receive instructions from another antenna outside the animal's body.
The problems associated with sensing, amplifying, filtering, and transmitting the EEG signal from within a water-proof, fatigue-resistant, battery-powered device implanted within a live animal are formidable. We have, however, solved these problems with our Subcutaneous Transmitter (SCT). We proposed the development of the SCT in 2004, developed it in collaboration with ION from 2005 to 2009, and prepared a paper describing the system in 2010. This paper was published in 2011.
We now propose to enhance the SCT by adding a crystal radio to receive instructions from outside the animal, expanding the on-board logic so that it can act as a microprocessor, and adding a capacitor bank and charge pumps that will provide power to a light-emitting diode (LED). We propose to combine the LED with a tapered glass fiber and two EEG electrodes so that the tip of the fiber can illuminate the same brain tissue monitored by the electrodes. The illumination will be of a wavelength and energy density suitable to stimulate opsins such as channelrhodopsin and halorhodopsin. The main body of the device will reside beneath the skin of the animal's abdomen while the electrodes and LED will be attached to the skull. Four flexible leads running from the skull to the device will connect the LED to its power source and the electrodes to their amplifier.
At OSI we have four employees committed to working on the ISL development. These are Kevan Hashemi, electrical engineer and president of OSI, Michael Bradshaw, electrical engineer and secretary of OSI, Michael Collins, physics graduate and employee of OSI, and James Bensinger, physics professor and treasurer of OSI. Michael Collins is our expert on optical fiber stretching, polishing, and coating. Michael Bradshaw is an electrical engineer and will start his involvement by developing the process by which we attach a bare LED die to a fiber. Kevan Hashemi designed the SCT circuits, and will do the same for the ISL. James Bensinger will work on mechanical pieces, such a the head fixture and circuit enclosures.
Our objective is to produce a device meeting the following specification.
| Property | Limit |
|---|---|
| Volume | 4.0 ml |
| Weight | 6 g |
| EEG Input Impedance | 10 MΩ (Note 1) |
| EEG Dynamic Range | ±10 mV (Note 1) |
| EEG Bandwidth | 160 Hz (Note 1) |
| EEG Sample Rate | 512 SPS (Note 1) |
| Lamp Instantaneous Power | 10 mW |
| Lamp Max Pulse Duration | 10 ms |
| Lamp Maximum Average Power | 1 mW |
| Lamp Wavelength | Fixed in range 400-800 nm |
| Classification Frequency | 1 Hz (Note 3) |
| Operating Range | 1 m in Faraday Enclosure |
| Shelf Life | 10 wks for 10% loss of battery capacity |
| Operating Life | 2 wks (Note 2) |
| Device Cost | $1000 US |
| Devices per Transceiver | 8 |
| Transceiver Cost | $4000 |
Our specification is based upon our Conceptual Design. For example, we propose that the metrics required by event classification are calculated not by Fourier transforms and computer algorithms, but by micro-power band-pass filters and non-linear electronic circuits soldered. It is this use of micro-power analog circuits that makes event classification possible at 1 Hz without draining the battery within a few hours.
Here are what we see as the greatest technical challenges we must overcome in the course of the ISL development.
If we fail to overcome any of these challenges, our failure will result in a new challenge. Our budget and schedule is designed to allow us to accommodate one or two failures among the above list, and still produce a useful device. For example, if we fail to use the lamp power lead as an effective antenna for radio reception on the device, we will have to find an alternative antenna arrangement, perhaps by adding another antenna outside the device's main body. This antenna will have to be encapsulated and it will have to fit within the animal's body along with the existing transmission antenna.
We fully expect to encounter other unforeseen technical challenges. If these challenges are part of the design and production of the device described above, we will attempt to overcome them within the budget and schedule we propose below. For example, in our SCT development, we encountered unforeseen problems with reliable reception from our radio-frequency transmitters. This is the sort of problem that we must overcome within the proposed budget. On the other hand, if the device as specified turns out to be inadequate to attain success, we will ask to modify the budget and schedule to accommodate these new challenges. For example, in our SCT development, we agreed to develop a bare circuit board that ION would encapsulate for implantation. It turned out that the preparation of electrode leads, the choice of electrodes, and the encapsulation of the circuit, were all formidable technical challenges, which we were obliged to overcome with an additional two years of work.
The development schedule lays out a sequence of stages, each of which contains one or more projects. The final stage is the delivery of ten functioning ISL devices meeting the above specification. Each stage will proceed as follows.
We do not expect ION to order the next stage until their tests of the prior stage are complete, nor is OSI obliged to accept an order for the next stage until OSI is satisfied that ION has completed all necessary tests and has received payment for the previous stage.
In the table below, we give the estimated duration of each stage in weeks. This is time OSI has to complete the development work from the day it receives ION's purchase order for the stage. The total development time will be greater than the sume of the stage times because OSI must await results from ION before continuing work. We estimate the entire development will take three years.
| Project | Cost (k$US) | Duration (wks) |
|---|---|---|
| Stage One: Tethered Control | 6 | 5 |
| Stage Two: Conceptual Design | 15 | 5 |
| Stage Three: Implantable Lamp | 40 | 30 |
| Stage Four: Detailed Design | 50 | 30 |
| Stage Five: First Prototype ISL | 10 | 10 |
| Stage Six: Second Prototype ISL | 10 | 10 |
| Stage Seven: Working ISL | 20 | 10 |
| Total | 151 | ≈150 |
We give the cost of each project in thousands of US dollars at the end of its description. We will accept purchase orders in US dollars for these amounts. In the past, however, ION has preferred to place orders in UK pounds. In that case, OSI will generate a quotation for the project in UK pounds at the time ION is ready to place its order, and will accept the order in UK pounds. Because of the length of the project, and the variability in the exchange rate between US dollars and UK pounds, OSI is not willing to quote the entire development in UK pounds.
The first step in the development is to allow the existing fiber-coupled lasers and LEDs at ION to be controlled from the LWDAQ. We will design and build two Lamp Control Heads (A2060L) and write Event Handler software for the Event Classifier. The circuits and software will allow ION to monitor EEG with a subcutaneous transmitter, detect EEG events, and flash the tethered fiber-optic lamp in response to these events.
Deliverables: Two Lamp Control Heads (A2060). Event Handler software.
Tests at ION: Detect seizures in live animals and flash the lamp in real time. Confirm that this detection and control is quick enough and reliable enough to find and stop a significan number of seizures.
The Conceptual Design will describe the proposed ISL device and its accompanying data acquisition and control system. The conceptual design must provide a credible basis for the development, with promising solutions to all its technical challenges. These solutions must be such that, when combined together and successful, they cooperate to produce a device that meets the final ISL specification. To fullfil Stage One, OSI will complete the conceptual design and ship a hard copy to ION. We will also post the document on our website, so that it will become public and will preclude any other institution attempting to patent any original ideas the design might contain.
Deliverables: Hard Copy of
Tests at ION: Confirm that the conceived instrument will answer their needs. Check the optical and biological calculations.
In order to establish the viability of our conceptual design, we concentrate upon three of the design's biggest technical challenges: the micro-power radio receiver, the coupling of an LED to a fiber, and the efficient delivery of power to the LED from a battery. We will combine all three into one encapsulated, implantable device, which we will call the Implantable Lamp. By means of a LWDAQ-controlled radio-frequency transmitter, we will be able to flash the LED from the LWDAQ software. The fiber will not be tapered, but it will emit roughly 10 mW at its tip. Therefore this device can be used as a radio-controlled stimulator of opsin's in an animal's brain. When combined with a Subcutaneous Transmitter (A3019D), the Implantable Lamp acts as a primitive form of Implantable Sensor with Lamp.
Deliverables: Five Implantable Lamps with fibers of various diameters and LEDs of various colors. LWDAQ-controlled radio-frequency transmitter to turn on the LEDs.
Tests at ION: Test reliability of micro-power radio reception in a moving animal. Confirm stimulation of opsins by the LED light. Measure disturbance of EEG recording by LED flashes within a living animal. Confirm water-proofing of LED encapsulation.
In Stage Four, we complete the detailed design of the ISL by means of test circuits and more advanced versions of the Implantable Lamp.
The initial one or two millimeters of our optical fiber will carry light into the animal's brain. This initial length must be mirror-coated on the outside to retain the light injected by the LED. We must learn how to silver-coating of short, cylindrical fibers. We must establish a supplier for the silver-coating chemicals, which can be explosive. We will strive for a smooth, uniform mirror finish. We may need to apply a thin outer coating of silicone or epoxy. We must learn how to cut and polish the silvered fibers.
In order to produce tapered fibers, we need to make a fiber-stretching stand, in which a gas flame heats a length of fiber and motors move and stretch the heated glass until the taper is formed. We will design and build such a device and equip it with a flame so sharp at its tip that we will be able to make 1-mm long conical fiber tips.
Once we are able to make simple fiber tips, we will investigate the relationship between profile and light distribution, and so arrive at stretching algorithms that produce the optimal light distribution.
Deliverables: Five Implantable Lamps with mirrored, tapered fiber tips.
Tests at ION: Confirm stimulation of opsins by the LED light. Confirm that we can implant the fiber tip.
The ISL will calculate interval metrics not by microprocessor but by non-linear analog circuits operating continuously upon the EEG signal. At this stage we design the first version of the circuits and we test them with an artificial EEG signal generator, which we build ourselves. This generator will use several hours of recorded EEG and play it back through the analog circuits. Once we are satisfied with the metrics produced by the analog circuits, we will write a Neuroarchiver Processor script that calculates these metrics from recorded EEG. This Processor will allow us to start developing seizure detection libraries that will work with the metrics produced by the analog circuits of the ISL.
Deliverables: Processor script that emulates analog metric generation. An artificial EEG generator.
Tests at ION: Develop event library to detect a seizures in recorded EEG based upon the ISL's analog metric generation.
We will build an eight-bit microprocessor in programmable logic and equip it with memory to store programs and event libraries. The microprocessor will decode and respond to incoming instructions from the crystal radio. It will be able to transmit not only the EEG signal picked up by the ISL electrodes, but also slower data. The slower data it will transmit using the same messages it uses for EEG transmission, but with the reserved channel number fifteen, and transmitting only a few such messages per second. Thus for this stage we must implement and perfect the long-planned use of channel fifteen for slow meta-data.
Deliverables: A breadboard ISL circuit that transmits like a subcutaneous transmitter, but will also perform event detection and respond to commands from its crystal receiver by flashing the lamp or transmitting messages on channel fifteen.
Tests at ION: With the help of an artificial EEG generator, set up the ISL breadboard circuit and learn how to control it with the Neuroarchiver.
We will design and build a final version of the radio frequency transmitter that controls the ISL through the ISL's crystal radio. This transmitter will be a LWDAQ device separate from the Data Receiver that records EEG signals from SCTs and ISLs. Faraday enclosures will be of the same design as for the SCT system, but must be equipped with two holes, one for the receiving antenna, and the other for the transmitting antenna. This controller will be an enhanced version of the one that we delivered with the Implantable Lamp. It will allow the LWDAQ to upload ISL programs for transmission to the ISL, and it will support whatever encoding and checksums we find are necessary to make the communication secure.
Deliverables: RF Controller.
Tests at ION: Test the new controller with the breadboard ISL microprocessor circuit.
We make the first implantable ISL prototype. This will combine the radio receiver, the LED power supply, the microprocessor, and the EEG sensing and transmission circuits. It will be equipped with a tapered fiber tip glued to an LED and joined with the two EEG electrodes to form a single skull-mounting fixture. At this stage, we do not expect the software or firmware of the ISL to be fully operational. The intention of the first prototype is to confirm that the battery lasts long enough, the encapsulation is secure, the fiber taper does not break, that communication between the LWDAQ and the implanted device is secure, and that the quality of the EEG recorded is not compromised severely by flashing the lamp.
Deliverables: Five encapsulated ISL prototypes.
Tests at ION: Implant in live animals and test.
The second prototype will provide on-board metric processing and event detection. It may be slightly too large, and we expect it to have other minor problems that we can fix with one more design iteration.
Deliverables: Five encapsulated ISL prototypes.
Tests at ION: Implant in live animals and test.
This is the final version of the ISL, and to end the development, we will delivery ten of them to ION.
Deliverables: Ten encapsulated ISL prototypes.
Tests at ION: None. We assume these are ready for real experiments.
We believe the above program is realistic in both its cost and schedule. With active cooperation from ION, we hope to deliver the first set of functioning ISLs within three years. These devices will be able to perform autonomous seizure detection and optical stimulation while implanted in a live animal. Among other things, the ISLs will provide a basis for studying ways to stop localized seizures with the help of opsins.