Constandinou T G

Georgiou P

Toumazou C

Triantis I F

English

Spiral - Imperial College Digital Repository

Spiking Chemical Sensor (SCS): A new platformfor neuro-chemical sensingPantelis Georgiou∗, Iasonas F. Triantis†, Timothy G. Constandinou† and Chris Toumazou††Institute of Biomedical Engineering, ∗Department of Electrical and Electronic EngineeringImperial College London SW7 2AZ, UKEmail:{pg200, i.triantis, t.constandinou, c.toumazou}@imperial.ac.ukAbstract— A spiking chemical sensor (SCS) is presented fordetection of neurogenic ion concentration associated with activenerve fibres in nerve bundles. Based on the ”integrate-and-fire”circuit, the SCS uses a chemically-modified ISFET front endencoding the sense data in the spike domain. Used in an array,it provides a spatio-temporal map of chemical activity aroundthe nerve bundle which may be relayed off chip using lowpower asynchronous communication hardware. The circuit isshown to be tunable to yield a linear relation with either pHor actual hydrogen ion concentration. Furthermore, its compactpixel footprint in addition to efficient use of the sensing surface,makes it ideal for use in neuro-chemical imaging.I. INTRODUCTIONDevices for monitoring neural activity can be used fora range of applications including studies of neurophysiol-ogy and neuropathology, diagnostics, drug monitoring andrehabilitation [1]. Although nerve conduction is based onionic current flow, most neural monitoring studies focus onbioelectric recording (recording of electroneurogram or ENG)with very few studies using ionic sensing in-vitro or in-vivo.This is almost entirely due to the conventional apparatus forion sensing in chemical laboratories being cumbersome, slowand innapropriate for small concentrations [2].ISFET (Ion Sensitive Field Effect Transistor) based chem-ical sensors, first introduced by Bergveld [2], have gainedconsiderable interest due to their ion sensitivity, fast temporalresponse, compact size and prospect of monolithic integration[3]. Although much of the initial literature predicted ISFETsto be mainly used as future tools for electrophysiologicalmeasurements, the sensors were not further developed forbiomedical applications in particular, but rather for ion sensingin general [2].In order to develop an ISFET-based interface for mea-suring neurogenic ion concentration variations [4], certaincustomization is needed. The main requirements of a neuro-chemical interface include robustness, compactness, spatio-temporal selectivity and ionic specificity. To achieve this,custom designed ISFETs based on CMOS technology are inte-grated with compact local processing to realise an “intelligentchemical sensor”. This can be combined with a multitude ofsuch sensors in an array, providing spatio-temporal sensingand the added advantage of sensor failure immunity (byredundancy). The next step is to characterise the sensors by pHmeasurements which can then be adjusted to be selective tospecific ions that relate to neural conduction. Although ISFETsare intrinsically sensitive to hydrogen ions, the selectivity maybe changed by depositing various ionophores on the surface[5].Fig. 1. Potassium ion sensing from a nerve bundle. The ISFET array is usedto generate a spatio-temporal map of chemcial activity.Presented here is an integrated chemical image sensorwith local signal conditioning and pre-processing circuitry.Fabricated in a commercially available CMOS technology, theSCS includes an ISFET-based device modified for potassiumion sensitivity in addition to bias, drive and signal conversioncircuitry. Moreover, a matrix of sensors has been tesselated ona single chip, forming the basis of a chemical image sensorand additionally improving robustness and accuracy throughredundancy. Furthermore, by embedding additional local pro-cessing, added functionality can be realised in chemical senseapplications, such as spatiotemporal chemical filtering, multi-chemical sensing and action potential detection from neuralensembles.In neural sensing systems a significant portion of powerdissipation and chip area is attributed to the ADC and thedigital signal processing. In order to overcome this issue, aneuromimetic circuit has been adopted to perform the pro-cessing of the recorded bio-signals and convert them to a formthat is compatible an external device. The processing circuitryadopted within this sensor is a low power ”integrate-and-fire”neuron circuit, (I&F), proposed by Indiveri [6], encoding thesensor information in the spike domain with multiple sensorfusion and off-chip transmission facilitated using a standardAER (Address Event Representation) [7] protocol.Proceedings of the 3rd InternationalIEEE EMBS Conference on Neural EngineeringKohala Coast, Hawaii, USA, May 2-5, 2007ThD1.151-4244-0792-3/07/$20.00©2007 IEEE. 126This paper is organised as follows. First, one of the targetapplications is explained, specifically spatio-temporal selectiv-ity in nerve bundle interfacing, which was the motivation formaking an array of spiking chemical sensors. The advantagesof chemical neural sensing and the circuit used are alsospecified. This is followed by the circuit implementation inweak inversion CMOS and explanation of how sensor linearityis achieved for both pH and hydrogen ion concentration.Implementation of the ISFET sensor in standard CMOStechnology is also explained followed by a discussion andconcluding remarks.II. THEORYA. Neural ConductionBased on nerve conduction theory, the membrane of a“firing” neuron exchanges ions with the surrounding extra-cellular space, through so called ion-pumps. The firing ofa group of nerves in one or more fascicles (a group ofnerves) creates ionic currents that flow between the fasciclesto the extracellular space [8], which generate detectable ENGsignals. Thus, localised ionic concentration variations takingplace during an action potential occurrence can be detectedusing modified ISFETs (i.e chemFETs), tailored for specificion selectivity, close to the active nodes of Ranvier, Fig. 1.The potential benefits of neurochemical sensing using arraysversus conventional bioelectric recording methods includeincreased myoelectric interference immunity, fascicle-specificmonitoring, and distinction between sensory and motor signalswhen both take place in a nerve bundle [4].0 21 3 4 5 6time (ms)300-10500-70Membrane potential (mV)Conductance (mS/cm2)repolarizationhyperpolarisationdepolarizationK+ conductanceaction potentialFig. 2. Change in conductance in sodium and potassium when an actionpotential occurs [9]B. Ion SensingConsidering there is an outflow of potassium ions for eachaction potential, having an array of chemFETs in close prox-imity with the nerve bundles allows for detection in variationof potassium concentration as the action potential propagates.Fig. 2 depicts the measured change in ionic conductancewhen potassium and sodium ions are flowing in and outof the neuron during an action potential. Chemical spatio-temporal mapping of these events along the nerve allows bothidentification of signal direction, but also neuron diameters bythe speed of propagation. The first allows for discriminationbetween motor or sensory signals and the latter allows forsignal association with different categories of organs or musclegroups.Development of chemFETs by ISFET modification has beenreported in [10]. Fig. 3 shows calibration curves conductedusing potassium chemFETs from IMT, Neuchatel Switzerland.The results demonstrate the appropriateness of ISFET basedpotassium sensors for sensing concentrations well within therange observed during neural conduction (typically 5mM -150mM [8]).Fig. 3. Potassium chemFET calibration curve.C. Integrate and FireIntegrate and fire as its name suggests integrates a sensorycurrent on a capacitive node creating a spike or digital pulseafter a threshold has been reached resetting the capacitor. Asa result sensor information, in this case concetration of ions,is conveyed in the frequency domain (spike rate), i.e. pulseposition modulation (PPM).Encoding the sensor data in the spike domain has the advan-tages of improved versatility in dynamic range (i.e. tradabilitybetween dynamic range and response time), robustness in sig-nal integrity, in addition to inherent compatibility to address-event encoding. AER is an established, asynchronous methodof relaying single-bit data from multiple pixels by transmittingaddress-events i.e. the pixel co-ordinates of the active pixel.This reduces bandwidth and therefore also power, as it is anevent-driven (data-dependant) architecture, in addition to beingeasily scalable for sparse data sets [7]. Relaying the chemicalinformation in this fashion using an array of SCSs allows forenergy efficient spatio-temporal mapping of potassium varia-tions across the nerve bundles for the applications mentioned.III. CIRCUIT DESCRIPTIONFig. 4 shows the schematic of the SCS (excluding the AERhandshake switches). The circuit comprises of a custom ISFETdevice, the H-Cell module [11] and a leaky integrate and fireneuron [6]. The ISFET device sinks an output current whichis dependant on the pH of the solution. This is due to thebinding of hydrogen ions to the silicon nitride surface (CMOSpassivation layer) above the gate forming a capacitive couplingwith the Ag/AgCl reference electrode [2]. The ISFET is biasedin the weak inversion region of operation to minimise power127CQ1VrefIOIISFETIsensorIleakVmemVsfVrfrIfbIresetVinVo1Vo2VspkVddM1M2M3M4M5M6 M7M8M9M10M11M12M13M14M15M16M17M18Fig. 4. Circuit schematic of chemical pixel sensor. The circuit comprises ofthe H-cell with the ISFET sensor and a leaky integrate and fire neuron circuit.10 20 30−0.500.511.522.53time (msec)Voltage (V)Vtrfr tchrgFig. 5. Spike generation period set by charging and discharging of capacitivenodes.consumption and exploit the exponential device characteristic.The output current relation to hydrogen ion concentration isgiven by Eqn. 1 and to pH by Eqn. 3, where Kchem is apH independent constant, n the sub-threshold slope factor, Utis the thermal voltage and a is a dimensionless sensitivityparameter relating the ISFET’s sensitivity to the Nernstianrelationship. The function of the H-cell is to linearise thedrain current to hydrogen ion concentration relationship, asanalysed in [11]. This sensor current is fed directly into theleaky I&F circuit, where the current magnitude representationis translated into the frequency domain (spike rate).IISFET = I0eVrefnUt Kchem[H+]an (1)Kchem = e−γnUt (2)IISFET = I0eVrefnUt Kcheme2.3apHn (3)The spike-rate dependence on the sense current is expressedin Eqn. 4, where Isensor is the linearised sense-current output(from the H-Cell) and is assumed to be considerably largerthan the leakage current Ileak. The maximum frequency,frfr = 1/trfr, is determined by the time taken for the chargeon node V02 to discharge through device M12, allowing forthe capacitor to start charging up again and spike shown inFig. 5. This time is tunable by adjusting voltage Vrfr. Cis the integrating capacitor and V is the voltage at whichthe neuron spikes, i.e. the threshold level at time tchrg =C.V/Isensor. What can be observed from this equation isthat when Isensor << C.V.frfr then fspike increases linearly(with sense current), but as the sense current continues toincrease then fspike converges to the maximum spiking rate(i.e. frfr). Thus, operating the circuit in the linear region ofoperation (where the hydrogen ion concentration is propor-tional to the sense current), gives a linear relation with spikerate when the current range is smaller than C.V.frfr. Whenoperating at current ranges which make the frequency plateauat frfr the current to spike-frequency relation is compressive.Considering that the sense current to pH relation given by Eqn.3, is exponential, operating with similar input currents in thisregion also yield a linear relationship with pH.fspike =Isensor.frfrIsensor + C.V.frfr(4)The feedback current Ifb serves to limit the short-circuitcurrents in the inverters during switching and therefore reduc-ing the power consumption. Furthermore, the voltage bias Vsfdefines the neurons threshold voltage [6].IV. SIMULATED RESULTSThis circuit was simulated using the Spectre simulator(v5.1.41usr2) under the Cadence IC design environment withfoundry supplied models for a commercial 0.35μm CMOSprocess. The ISFET was implemented using a spice behavioralmacro-model derived from fabricated devices. The circuit biasconditions used are as follows: Vref =874 mV, Vsf =Vrfr=400mV and I0=100 nA. These were chosen assuming γ=324 mV,giving an ISFET current of 11.6 nA for pH 7. The spikefrequency dependence on hydrogen ion concentration is shownin Fig. 6.b, with frequency increasing linearly with the ISFETsense current and Fig. 6.a shows spike trains produced for3 different pH values. Fig. 6.c shows the spike frequencydependence on the pH of the test solution, during operation inthe “compressive region”, yielding a linear relationship. Thepeak power consumption at the maximum spike frequency ofoperation was 35μW at 3.3 V supply voltage.V. ISFET FABRICATIONThe ISFET sensors are based on standard MOSFET struc-tures with the polysilicon gate being extended to create thesensing surface of charge, mainly hydrogen ions, binding tothe silicon nitride passivation layer. The methodology used todesign the ISFETs is adopted by Hammond et al [3] where bythe polysilicon gate is connected via the metal layers to thetop metal layer covered by silicon nitride passivation. This isleft floating to be biased by an external reference electrode.The layout of the SCS is shown in Fig 7 with the devicecross section shown on the bottom. The ISFET sensor isdesigned with a large gate area to minimise 1/f noise. The128Transient Response17.0 22.5 28.0 33.5 39.0 44.5 50.0time (ms)4.0−.5V (V)V (V)4.0−.5V (V)V (V)4.0−.5V (V)V (V) net35 (H=1.00e−08)  net35 (H=1.00e−07)  net35 (H=1.00e−06) frequency(VT("/net35"))10−10 10−9 10−8 10−7 10−6 10−5 10−4 10−3H ()105100Y0 ()frequency(VT("/net9"))0 2.5 5.0 7.5 10.0 12.5 15.0VPH ()9.758.0Y0 (E3)a.b.c.Fig. 6. a.) Spike generation for pH 6, 7 and 8. b.) Spike frequencyresponse (linear) with the hydrogen ion concentration of test solution. c.)Spike frequency response (linear) with the pH of the test solution.total pixel size with the I&F circuitry is 65μm x 100μm.Implementing the ISFET in CMOS enables the active gateto be extended to the top metal layer. Furthermore, this isdesigned to cover the entire pixel area, thus achieving a near100% effective fill factor (active sensor area to pixel ratio).The ISFET is then modified for potassium detection bydeposition of a potassium ionophore. A photocurable polymerion-selective membrane based on urethane acrylate with goodadhesion to the sensor surface is applied for direct monitoringof the potassium ion concentration.VI. CONCLUSIONThis paper describes the front-end implementation of anISFET-based chemical sensor with embedded neuromimeticsignal processing. An array of spiking chemical sensors hasbeen designed for monitoring of neural signatures. This wasdeveloped to provide two advanced modes of selectivity;directionality and nerve fibre distinction by diameter. TheISFET has been custom built so that it makes 100% use of thepixel surface. The I&F stage has been designed for minimimalpower and area. The spike rate has been shown to be tunableto be either linear with hydrogen ion concentration or withpH.ACKNOWLEDGMENTThe authors would like to acknowledge Amir Eftekhar andLi Xiaoying for their contributions, Dr. Julius Georgiou of the100μm65μm52μm48μmS DGB ISFETI&F circuit ISFET sensorPassivation (sensing surface)SiNSiO2AlSiO2p-type substrateTop metal layerActive device areaFig. 7. Layout of the chemical pixel.University of Cyprus for providing access to fabricating siliconand Dr. Peter van der Wal of IMT Neuchtel, Switzerland, fortheir potassium chemFET test prototypes.REFERENCES[1] I. Triantis, An Adaptive Amplifier for Cuff Imbalance Correction and In-terference Reduction in Nerve Signal Recording. PhD thesis, UniversityCollege London, London, 2005.[2] P. Bergveld, “Thirty years of isfetology - what happened in the past 30years and what may happen in the next 30 years,” Sensors and ActuatorsB-Chemical, vol. 88, no. 1, pp. 1–20, 2003.[3] P. A. Hammond, D. Ali, and D. R. S. Cumming, “Design of a single-chipph sensor using a conventional 0.6-mu m cmos process,” Ieee SensorsJournal, vol. 4, no. 6, pp. 706–712, 2004.[4] I. Triantis and C.Toumazou, “Advanced mixed-mode nerve cuff inter-face.” GB Patent Number 0613698.0 - patent pending, 2006.[5] A. Bratov, N. Abramova, C. Dominguez, and A. Baldi, “Ion-selectivefield effect transistor (isfet)-based calcium ion sensor with photocuredpolyurethane membrane suitable for ionised calcium determination inmilk,” Analytica Chimica Acta, vol. 408, no. 1-2, pp. 57–64, 2000.[6] G. Indiveri, “A low-power adaptive integrate-and-fire neuron circuit,”in Circuits and Systems, 2003. ISCAS ’03. Proceedings of the 2003International Symposium on, vol. 4, pp. IV–820, 2003.[7] M. Mahowald, VLSI Analogs of Neuronal Visual Processing: A Synthesisof Form and Function. PhD thesis, Caltech Pasadena, California, 1992.[8] J. Malmivuo and R. Plonsey, Bioelectromagnetism: Principles andApplications of Bioelectric and Biomagnetic Fields. Oxford UniversityPress, 1995.[9] A. L. Hodgkin and A. F. Huxley, “A quantitative description of mem-brane current and its application to conduction and excitation in nerve,”Journal of Physiology, vol. 117, pp. 500–554, 1952.[10] E. A. Moschou and N. A. Chaniotakis, “Potassium selective chem-fet based on an ion-partitioning membrane,” Analytica Chimica Acta,vol. 445, no. 2, pp. 183–190, 2001.[11] L. Shepherd and C. Toumazou, “Weak inversion isfets for ultra-lowpower biochemical sensing and real-time analysis,” Sensors and Actua-tors B-Chemical, vol. 107, no. 1, pp. 468–473, 2005.129

A low-power adaptive integrate-and-ﬁre neuron circuit,” in Circuits and Systems,

A quantitative description of membrane current and its application to conduction and excitation in nerve,”

An Adaptive Ampliﬁer for Cuff Imbalance Correction and Interference Reduction in Nerve Signal Recording.

Bioelectromagnetism: Principles and Applications of Bioelectric and Biomagnetic Fields.

Design of a single-chip ph sensor using a conventional 0.6-mu m cmos process,”

Ion-selective ﬁeld effect transistor (isfet)-based calcium ion sensor with photocured polyurethane membrane suitable for ionised calcium determination in milk,”

Potassium selective chemfet based on an ion-partitioning membrane,”

Thirty years of isfetology - what happened in the past 30 years and what may happen

Triantis and C.Toumazou, “Advanced mixed-mode nerve cuff interface.” GB Patent Number 0613698.0 - patent pending,

VLSI Analogs of Neuronal Visual Processing: A Synthesis of Form and Function.

Weak inversion isfets for ultra-low power biochemical sensing and real-time analysis,”

Spiking Chemical Sensor (SCS): A new platform for neuro-chemical sensing

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Spiking Chemical Sensor (SCS): A new platform for neuro-chemical sensing

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