DISTRIBUTED NEUROCHEMICAL SENSING: IN VITRO EXPERIMENTS G. Mulliken 1 , M. Naware 1 , A. Bandyopadhyay 2 , G. Cauwenberghs 1 , N. Thakor 1 1 BME Dept. Johns Hopkins University School of Medicine, Baltimore, MD 21205 2 ECE Dept. Johns Hopkins University, Baltimore, MD 21218 ABSTRACT Experimental results characterizing a VLSI multi-channel potentiostat sensor system designed for sensing distributed neurotransmitter activity are presented. Neurotransmitter concentration is electrochemically transduced using an external carbon fiber electrode. Resultant current is processed by an integrated potentiostat, consisting of a current amplification stage, current-mode delta-sigma A/D converter, and counting decimator. Electrical characterization has shown that the VLSI potentiostat is sensitive to picoampere levels of input current. Furthermore, both static and dynamic neurochemical measurements of dopamine are verified in vitro, proving the utility of the device for brain slice studies. Lastly, a biologically inspired experiment, whereby the catabolism of dopamine is emulated with the addition of the catechol-o-methyl transferase (COMT) enzyme to modulate dopamine levels in vitro. 1. INTRODUCTION Understanding the onset and progression of neurological injury or its pathological response demands a detailed knowledge of the neurotransmitter mechanisms underlying these processes. While advances in electrophysiology have borne significant insights into how the brain processes information ‘electrically’, far less progress has been made in mapping the concurrent, chemical manifests of neural activity. By quantifying the spatiotemporal concentration of neurotransmitters in real time, distributed neurochemical sensors will provide an enhanced perspective from which to study the role of neurotransmitters in brain injury and its sequelae. The ability to electrochemically sense neurotransmitter activity from multiple electrodes carries with it a formidable instrumentation challenge, demanding the implementation of numerous potentiostats in parallel. Use of multiple benchtop potentiostats offers a crude and impractical solution, consuming significant area on the laboratory bench, dissipating large amounts of power, and offering no flexibility for in vivo experimentation. Alternatively, a highly integrated VLSI chip can provide the same processing capability on a single substrate less than 2 mm 2 in area [1]. Furthermore, a VLSI implementation will drastically reduce power consumption, decrease manufacturing costs, and minimize noise associated with unnecessary wiring. A few attempts have been made to develop VLSI potentiostats. However, in all cases, the designs have included only a single channel [2-4]. Lastly, future innovative sensor systems can be realized to target in vivo applications, combining sensors and microelectronics onto a single substrate and wirelessly transmitting neurochemical information for remote processing. 2. SYSTEM ARCHITECTURE The VLSI potentiostat operates in a two-electrode configuration, which is sufficient for neurotransmitter measurements since the voltage drop (IR) due to fluid resistance is negligible for the very small current levels being sensed. That is, a counter electrode to eliminate current flow into the reference electrode is obviated since the current levels are so small [5]. Each channel employs a working electrode, which is maintained at virtual ground. Additionally, a single reference electrode is biased at -E redox with respect to the working electrodes. Thus the redox potential of the neurotransmitter being oxidized is maintained between all working electrodes and the reference electrode. 2.1 Chip Architecture Each potentiostat channel consists of a current amplification stage, with input current conveyor and programmable gain current mirrors, and a current-mode delta-sigma A/D converter, with counting decimator. A register buffer and shift register provide an asynchronous bit-serial output. The potentiostat architecture is shown in Figure 1. The chip operates in the subthreshold region to provide high sensitivity for the wide range of expected input currents and to decrease power consumption. Circuit implementation details are presented in [1]. Figure 1. Potentiostat chip architecture [1]. Electrochemical measurements of neurotransmitter generally transduce currents on the order of picoamperes to nanoamperes [4, 6]. Input current in each channel is amplified to the microampere range and passed to a delta-sigma A/D converter to digitize the signal. The oversampled binary output of the delta- sigma modulator is decimated using a binary counter. The