Implantable Stimulator Manual[03-JAN-25] Our implantable stimulators are designed to provide electrical or optical stimulation for laboratory mice and rats. They can provide pulses of current for direct electrical stimulation of nerve and brain tissue, or they can provide pulses of current to an Implantable Light-Emitting Diode (ILEDs) for optogenetic stimulation of nerve and brain tissue. The Implantable Stimulator-Transponders (ISTs, A3041), which comes in several sizes and configurations, hosts a crystal radio, a telemetry transmitter, a current source, and an embedded microprocessor. The A3041 stimulator is designed for long-term experiments that require intermittent stimulus. When deployed as an electrical stimulator, the IST stimulus leads will be terminated with some kind of stimulus electrode wire, or with pins that connect to a simulus electrode. When deployed as an optogenetic stimulator, the stimulus leads will be terminated with pins that connect to the ILED. Thus the ILEDs are an necessary, but separate, component in the implantable optogenetic stimulator.
The IST provides stimulation, acknowledgement, battery monitoring, synchronizing signal, and user-progrsam upload all by radio control. It receives commands through its loop antenna using its on-board crystal radio. It transmits signals through the same antenna using our Subcutaneous Transmitter (SCTs) telemetry protocol. Our SCTs, meanwhile, provide wireless, long-term, continuous monitoring of biopotentials to accompany intermittent stimulation. When we have both a sensor and a stimulator implanted in an animal, we can generate stimuli in response to sensor events. This real-time response to sensor data with a stimulus is what we call closed-loop control. Watching for seizure onset in EEG, and responding to seizure onset with twenty seconds of electrical pulses applied to the brain, is an example of a closed-loop system.
For electrical stimulation, the IST drives a bipolar stimulation electrode with constant-current pulses. For optical stimulation, it drives one of our implantable lamps with pulses of current. Our Surface-Mount Light-Emitting Diodes (SMLEDs) come in red, green, and blue. These are designed to be fastened to the surface of an organ and illuminate the tissue within. Our Fiber-Coupled Light-Emitting Diodes (FCLEDs) are designed to be mounted to the skull for illumination of deeper brain tissue.
[03-JAN-25] Our Implantable Light-Emitting Diodes (ILEDs) provide optical stimulation for experiments in optogenetics. Our Surface-Mount Light-Emitting Diodes (SMLEDs) come in red, green, and blue. They are designed to be fastened to the surface of an organ and illuminate the tissue within. Our Fiber-Coupled Light-Emitting Diodes (FCLEDs) come in green and blue. They are designed to be anchored to the skull and provide illumination deeper in the brain.
All ILEDs are equipped with sockets that accept the pins at the end of stimulator leads. To implant the stimulator and ILED for brain stimulation, we make an incision in the flank of the animal for the stimulator, tunnel the wires with pins under the skin to the animal's skull, and connect the pins to our ILED, which we then cement in place.
The FCLEDs are a light-emitting diode with a fiber-optic light guide glued to its surface. The light guide carries roughly half the LED's light a to a tapered glass tip, where the light is emitted in all directions. The light guide can be four to ten millimeters long. It allows us to deliver optical stimulation to tissue several millimeters below the surface.
For the FCLED we make a small hole in the skull for the fiber to pass through and cement the base of the fiber to the skull. For the SMLED we make a larger hole so that we can mount the epoxy dome of the SMLED directly in the hole. A blue FCLED required only 1-ms pulses of 15 mA at 10 Hz to provoke optogenetic response, while a blue SMLED required 10-ms pulses of 15 mA at 10 Hz.
[03-JAN-25] For electrical stimulation, we can use any of the electrodes or terminations in our Electrodes and Termination catalog. We have not yet manufactured a twisted pair of stainless steel wires for a bipolar stimulation electrode, but we understand that such electrodes are commonly deployed for electrical stimulation, and we will be happy to design and build one for an interested customer.
[24-OCT-24] The Telemetry Control Box (TCB-B16) needs only one Power over Ethernet (PoE) connection for power and communication. It provides sixteen coaxial antennas that receive telemetry signals and transmit commands to radio-controlled devices such as ISTs. The Stimulator Tool provides the software interface we need to program and control the ISTs.
With the Stimulator Tool, we define a stimulus by specifying a number of pulses, the length of each pulse, and the period of the pulses. One minute of 10-ms pulses at 10 Hz would be 600 pulses, each 10 ms, with period 100 ms. We specify the current of the pulses with another number between zero and fifteen. Consult the IST circuit manual for how these numbers relate to the current and voltage limits of the stimulus. We specify if the stimulus is to be random or regular. In a random stimulus, the pulses can occur anywhere within each period window, at random. We find that random stimuli do not invoke optogenetic response, while regular stimuli do. Random stimuli have the potential to act as a control stimulus.
The Stimulator Tool allows us to request acknowledgements for each command, in which case the Receiver Instrument, i it is running, will pick out the acknowledgement and the Stimulator Tool will confirm that the command was received. The Stimulator Tool will also transmit a general identification request that all ISTs in range will respond to by transmitting their identity numbers. The Stimulator Tool will transmit a battery measurement requests as well, and present the results of the measurement.
Each IST contains its own OSR8 microprocessor running a main program, but also capable of running code provided by its user. The Stimulator Tool also allows us to assemble, upload, and run programs on an IST. These programs are written in the OSR8 assembly language. The Stimulator Tool manual provides example code. Editing, testing, uploading and running user programs is simple with the Stimulator Tool's built-in Transmit Panel. The A3041 stimulator provides 2 KByte of volatile user-program memory. When the A3041 goes to sleep, it forgets its user program, so we must upload it again as part of our experimental procedure. Future ISTs will provide non-volatile user program memory so that we can upload complex programs and have them be available as soon as the IST wakes up.
[03-JAN-25] We implant the IST subcutaneously, and tunnel its leads to the stimulus location. Most often, we will equip the leads with pins that will plug into sockets on a bipolar electrical stimulus electrode, or plug into an implantable light-emitting diode (ILED).
If we are performing an optogenetic experiment with an ILED, we may also be recording EEG or some other biometric signal with an SCT implanted seprately in the same animal. If so, we must make sure the ILED drive signal does not corrupt the sensor signal with what we call lamp artifact. We plug the stimulator pins into the ILED, cover them with a thin layer of dental cement or vetbond, lower the ILED into position, and cover thoroughly with dental cement to secure the ILED and further insulate its stimulus pins from the rest of the body. With care, we can provide insulation adequate to reduce the lamp artifact to below a few microvolts. If we are not careful, the lamp artifact can tens of microvolts. For an explanation of how lamp artifact arises even when we have separate implants, see Sources of Lamp Artifact. For video and EEG recordings made with an IST and SCT during optogenetic response, see Examples of Optogenetic Response
[31-AUG-23] Development of the IST began in 2012 with the development of an Implantable Sensor with Lamp (ISL) for use in rats. Work on the ISL for rats was funded by the Wellcome Trust via Dimitri Kullmann at the Institute of Neurology (ION) at University College London (UCL). We collaborated with Dimitri Kullmann, Robert Wykes, and Matthew Walker, all of ION/UCL. The Implantable Sensor with Lamp (A3030) was a failure in that we were unable to isolate the sensor input from the lamp voltage. When implanted in an animal, we found the sensor signal was usually corrupted by lamp artifact of at least 1 mVpp. In 2019 we began work on a mouse-sized implantable stimulator-transponder (IST) with funding from the Fitzgerald Laboratory at UCL and OSI's research budget. This IST was the first device to include only a stimulator. In 2020 we began work on a mouse-sized ISL with the support of a Small Business Innovation Research (SBIR) Phase I grant from the National Institute of Health (NIH), in collaboration with the Schaffer Laboratory at Cornell University. The Implantable Sensor with Lamp (A3037) was a success in that it was small enough to implant in a mouse, and reduced the lamp artifact to less than 100 μVpp. Nevertheless, when it came to initiating optogenetic response and recording electroencephalogram (EEG) in mice, we used IST in conjunction with SCTs, not the ISL.
In 2022 our application for Phase II funding from the NIH was declined for the second time. The reviewers saw no particular need for the stimulator and sensor to be combined in one device, and we agree with them. The animal trials we conducted in 2021 at ION/UCL and Cornell University demonstrated that 1-ms, 15-mW pulses of blue light delivered by an FCLED at 10 Hz were sufficient to invoke optogenetic response. Our expectation had been that 10-ms pulses would be required. With the stimulus power requirement ten times lower than we expected, we were able to switch from lithium-ion batteries as a power source to lithium primary cells. The latter have three times the charge capacity per unit volume as the former, allowing us to triple our operating life. In 2022, we used OSI's research budget to design and test the Implantable Stimulator-Transponder (A3041). The A3041, along with the A3036IL implantable lamps, are the final result of our ten years of work on implantable stimulators. The A3041 is small, long-lasting, corrosion-resistant, and provides both electrical and optogenetic stimulation. We have abandoned our plans to make a combined sensor and stimulator, but you will find our old ISL page here.
In the summer of 2023 we assembled a set of A3041AV1 and worked on discovering bugs in their firmware and hardware. We found that the CR1025 battery is inadequate to power up the A3041AV1 assembly after a few weeks of implantation. We must use the larger CR1225 and CR1620 batteries. We discovered several other problems with the circuit, such as its inability to turn off after being asked to transmit a synchronizing signal of too high a sample rate. We solved all these problems and added to the A3041 the ability to receive and run user-programs. We reduced the hibernation current of the device to less than 1 μA and its sleep current to less than 5 μA. The result is what we believe to be a versatile and long-lasting implantable stimulator for intermittent stimulation experiments.