A Block-Capable and Module-Extendable 4-Channel Stimulator for Acute Neurophysiology

Objective This paper describes the design, testing and use of a novel multichannel block-capable stimulator for acute neurophysiology experiments to study highly selective neural interfacing techniques. This paper demonstrates the stimulator’s ability to excite and inhibit nerve activity in the rat sciatic nerve model concurrently using monophasic and biphasic nerve stimulation as well as high-frequency alternating current (HFAC). Approach The proposed stimulator uses a Howland Current Pump circuit as the main analogue stimulator element. 4 current output channels with a common return path were implemented on printed circuit board using Commercial Off-The-Shelf components. Programmable operation is carried out by an ARM Cortex-M4 Microcontroller on the Freescale freedom development platform (K64F). Main Results This stimulator design achieves ±10 mA of output current with ±15 V of compliance and less than 6 µA of resolution using a quad-channel 12-bit external DAC, for four independently driven channels. This allows the stimulator to carry out both excitatory and inhibitory (HFAC block) stimulation. DC Output impedance is above 1 MΩ. Overall cost is less than USD 450 or GBP 350 and device size is approximately 9 cm × 6 cm × 5 cm. Significance Experimental neurophysiology often requires significant investment in bulky equipment for specific stimulation requirements, especially when using HFAC block. Different stimulators have limited means of communicating with each other, making protocols more complicated. This device provides an effective solution for multi-channel stimulation and block of nerves, enabling studies on selective neural interfacing in acute scenarios with an affordable, portable and space-saving design for the laboratory. The stimulator can be further upgraded with additional modules to extend functionality while maintaining straightforward programming and integration of functions with one controller.

dataloggers [6]. 12 Based on these observations the following list of features and constraints were used 13 to guide the design of a stimulator meeting all requirements for acute excitatory and 14 inhibitory stimulation: 15 • High Compliance Voltage to accommodate kilo-ohm scale load impedances 16 • High Full-Scale Current to reach potentially high nerve fibre block thresholds 17 • High Current resolution to enable users to carry out precise stimulation or output 18 arbitrary current waveforms without distortion 19 • High Bandwidth to provide high-frequency block waveforms without distortion 20 • Multiple independent channels to stimulate multiple areas of a nerve concurrently In addition to these targets, special consideration was given to flexible programming 6 and scripting to give the user complete control over the operation of the stimulator.   The stimulator system was designed to ensure that in experimental setups there is at 3 most a single earth point in contact with the nerve tissue. As neural signal acquisition 4 devices often ground the experimental setup with earth ground to reduce noise, the 5 stimulator must be battery powered (see Figure 9). Separating the microcontroller 6 and stimulator power domains allows recording neural signals using devices on the 7 microcontroller power domain, as shown Figure 2. This enables isolated recording and 8 stimulation using a single device. The PC used to control the stimulator is electrically 9 isolated from the stimulator itself, as other devices may also be connected to the same 10 computer for signal acquisition or experimental automation, or the computer may itself 11 be connected to earth ground in the case of a desktop. Such a setup prevents ground 12 loops, stimulation interfering with recording and improves setup flexibility. 13 The power supply was chosen for maximum flexibility. Using 5 V as an input voltage 14 for the system allows laptops and portable phone and tablet power banks to be used 15 to supply power, providing long operating life which can be easily sourced. To achieve 16 ±15 V compliance at the stimulator output, the output voltage of the power supply 17 was chosen as ±18 V which allows a wide range of operational amplifiers to be used.

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The ADP5070 dual output switch-mode power supply provided a compact and efficient 19 solution for this with manageable output ripple. Manufacturer recommended values 20 were used for all power supply components and assembled using the recommended 21 layout. High frequency noise at the output was filtered using ferrite beads, and shielded inductors were used to reduce EMI emissions that could interfere with sensitive nodes in 1 the Howland Current Pump. For precision voltage references such as ADC references, 2 Low drop-out (LDO) components were used to filter out noise from higher voltage 3 supplies. To provide an isolated power supply to the microcontroller power domain, a 4 NXJ2S0505MC-R7 (MURATA Power Solutions) isolated 5 V to 5 V DC-DC converter 5 was used. 6 To allow devices on different power domains to transfer data, the microcontroller's 7 Serial Peripheral Interface was used together with a 6-channel digital isolator as shown

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The Howland Current Pump (see Figure 3) was chosen as the stimulator's current source 14 circuit due to it not requiring an H-bridge to provide bidirectional current sourcing and 15 sinking, high speed and a lower number of control signals that must go through a digital isolator to drive the circuit, as only the DAC must be digitally driven during stimulation. 1 The output current equation is as follows for this circuit: A compound amplifier solution in U1 and U2 was chosen to benefit from the low offset 4 of U1 and the output capability of U2, which is a current feedback amplifier. U2 can be 5 placed in either a non-inverting or inverting configuration. The inverting configuration 6 is slightly faster at the cost of significantly higher power consumption for U1 which 7 would source current into the feedback resistors of U2. For this reason a non-inverting 8 configuration was chosen. As the feedback signal depends on the current flowing into 9 R S , any leakage beyond this point will not be compensated for and therefore U3 is used 10 as a buffer to prevent current leakage.   Table 2. As it can be useful to measure stimulation electrode voltage 8 with respect to an electrochemical reference in the nerve bath during stimulation, the 9 dedicated REF connector is available for this. This can be used to determine when 10 stimulation electrodes are polarized outside of the 'water window' for example, indicating 11 that water splitting reactions can occur and change local pH, potentially affecting the also included with the ability to short the capacitor through a switch, for calibration 1 purposes. Figure 4: Circuit schematic for the routing and diagnostic module of the stimulator. CH1-CH4 refer to the output nodes for each stimulation channel. E1-E4 refer to individual electrode connectors for each stimulation channel. REF refers to a reference electrode connector for when the monitoring circuit should measure voltage between an electrochemical reference such as silver-silver chloride and a stimulation electrode, rather than using system ground as a reference. Precisely-timed stimulation is required when multiple sources of stimulation are active 2 simultaneously, for example when current steering or combining stimulation events 3 in multiple locations on the nerve. In order to guarantee precise timing and avoid 4 using processor interrupts which can delay operation for other tasks such as responding 5 to commands or processing recording input during stimulation, the SPI link to the 6 stimulator's quad-channel DAC was driven using microcontroller peripherals only. By   Figure 5: Flowchart describing how stimulation is carried out without processor intervention. The processor is only used at the start and end to configure the eDMA and timers and to halt the timers and reset the eDMA when timing is not critical. with results on Figure 7 showing voltage compliance of ±15 V before noticeable output 3 error.

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To measure output impedance magnitude over frequency, the setup shown on Figure 6 5 was used. The output impedance plot is shown Figure 7 with a cut-off frequency where U AF G is the amplitude of the AFG output sine wave and U measure is the amplitude 13 of the sine wave measured at the terminals of the measuring resistance. A simulation 14 of the circuit was also carried out in LTspice XVII for comparison.     The ability of the stimulator to evoked compound action potentials (CAPs) in the A and   Blocking performance for the stimulator was evaluated in the rat sciatic nerve model 2 using the setup described in Figure 9. A and C fibre recruitment and nerve viability 3 baseline was first measured by stimulating the sciatic nerve with 3× 2500 µA amplitude, 4 cathodic first, biphasic symmetric, current controlled pulses. After three pulses were 5 delivered HFAC block was applied at the stimulation electrode between the stimulating 6 and recording electrodes, corresponding to stimulator channel 2 on Figure 9. Block 7 was applied as a current-controlled square wave at 10 kHz and 6 mA amplitude while 8 stimulation continued using the same parameters at the rate of 1 Hz during block, as 9 shown on Figure 11. Block was then terminated after 15 seconds and stimulation 10 continued for 7 additional pulses to evaluate nerve recovery from block. C fibres appear to recover more slowly from block than A fibres as can be seen during the recovery 1 phase, despite the fact that they are only partially blocked at this block amplitude and 2 frequency in this trial. It was not possible to obtain complete block of C fibres during 3 the stimulator test. 4 Figure 11: Block and recovery trial in which A fibres are completely blocked and C fibres are partially blocked: (a) overview of the trial and timeline starting with initial stimulation without block, application of block and continuing stimulation, and cessation of block with nerve recovery; (b) initial A fibre response; (c) A fibre response at the end of the blocking phase; (d) A fibre response at the end of the recovery phase. (e) initial C fibre response; (f) C fibre response at the end of the block phase; and (g) C fibre response at the end of the recovery phase.

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Achieved specifications for the stimulator with respect to other designs are shown 2 Table 3, however on their own they do not completely describe its strengths and The key strengths of the proposed stimulator design are: 5 (i) Based on Commercial Off-The-Shelf (COTS) components. 6 (ii) Cheap to source and assemble (less than GBP 350 or USD 450).

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(iii) Flexible powering options, including the controlling computer through a dedicated 8 5W USB port.

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(iv) Complete control of output waveform, scripted using any program that can interface 10 with the FTDI Virtual COM Port driver.

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(v) High current output combined with high resolution and voltage compliance.

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(vi) Multiple independent channels that are driven with accurate timing.

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(vii) Feature extendability using additional PCB modules, such as for recording, that 14 can be driven by the microcontroller processor.
While the device allows concurrent current-controlled multi-channel stimulation, this 1 is only possible when stimulation is delivered in a monopolar configuration with a 2 common return electrode connected to stimulator ground, which must be placed away computer, each requiring a USB port and external battery.

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The cutoff frequency for output impedance which is shown Figure 7 is low at only 1 11 kHz and can be attributed to the wide output swing required for U1 as a result of U2 12 being in a non-inverting configuration. However for the purposes of stimulation using 13 cuff electrodes the output impedance is still much higher than the kilo-ohm range at all 14 frequencies of interest, for example the impedance magnitude at 10 kHz is near 40 kΩ, 15 leading to less than 3% error in current output for electrodes having 1 kΩ impedance 16 at that frequency. It is however possible to shift the cutoff frequency to the right for power consumption both on the stimulator module itself by providing ways for the 8 microcontroller to turn off stimulator channels that aren't connected to electrodes, and 9 also by optimizing the power consumption of the microcontroller itself. The former 10 is possible by daisy-chaining additional switches to the SPI channel used for channel 11 output routing, and the latter could benefit from a slower core clock, however this would 12 affect timing performance. Idle power could be further reduced by gating the clock to 13 select peripherals only when they are needed.
14 In terms of performance during electrophysiology experiments, both A and C fibres were 15 able to be stimulated in the ex-vivo rat sciatic nerve model. While A fibre block was 16 achieved C fibre block was only partial as can be seen Figure 10