![C H A P T E R 1
Wireless Integrated Neurochemical and
Neuropotential Sensing
Mohsen Mollazadeh, Kartikeya Murari, Christian Sauer,
Nitish Thakor, Milutin Stanacevic, and Gert Cauwenberghs
1.1 Introduction
Since the first use of multisite electroencephalography experiments by W. Grey Wal-
ter in the 1930s [1], instrumentation for monitoring the physiological state of the brain
has undergone tremendous advances. Instrumentation, electrodes, and analysis tools
are continually being developed for the basic research as well as clinical applications.
Today, among several other stellar achievements, it is possible to locate the focal
origin of epilepsy with millimetric precision [2] and to control prosthetic devices with
thought alone [3]. Most of the advances made both in the clinical and research fields
have been based on analyzing the electrical activity of the brain. While the majority
of information flow in the nervous system is electrical, neural processing and trans-
mission also have a chemical aspect, mediated by neurotransmitters [4]. These crucial
chemical messengers are an integral part of the nervous system. Deficits and imbal-
ances in this system have serious neurological consequences such as Parkinson’s dis-
ease, epilepsy, and so on.
General principles in the design of VLSI circuits for biomedical instrumentation
are extensively covered elsewhere in this edited volume. This chapter describes com-
ponents for a multimodal wireless monitoring system and their integration into a
system capable of recording and telemetering both electrical and neurochemical
activity from multiple sites.
1.2 Neurochemical Sensing
1.2.1 A Review of Neurotransmitters
Neurotransmitters are chemical messengers that conduct signals along the electrically
insulating parts of nervous pathways [5] i.e. from one neuron to another, across gaps
called synapses. Neurotransmitters may be either excitatory or inhibitory. That is,
they may be of a type that fosters the initiation of a nerve impulse in the receiving
neuron, or they may inhibit such an impulse. Within the cells, neurotransmitter
molecules are packaged in vesicles and released by rapid exocytosis upon the arrival
of a nerve impulse. Then they diffuse across the synaptic gap to bind neurotransmit-
ter receptors or other ligand gated ion channels and stimulate or inhibit the firing
of the postsynaptic neuron. Figure 1.1 shows a schematic of a synapse and shows
how the electrical and chemical signals are related.
1](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-20-320.jpg)
![Neurotransmitters are crucial in ensuring the proper functioning of neural path-
ways. Imbalances or malfunctions of neurotransmitters leads to several debilitating
nervous disorders like Parkinson’s disease (due to lack of Dopamine [6]), bipolar
depression (due to Serotonin imbalance [7]), and so on. The study of neurotransmit-
ters is paramount in understanding the mechanism of neural pathways and diseases.
Numerous methods like optical [8] (detecting light emitted by reactions), immuno-
chemical [9] (detecting tracer compounds attached to neurotransmitters), liquid
chromatography [10] (chemical separation of neurotransmitters) are used to detect
and measure neurotransmitter activity. Electrochemical sensing of certain electroac-
tive neurotransmitters (e.g. nitric oxide, dopamine) is very attractive due to high
sensitivity, rapidity, and the ability to perform distributed measurements [11, 12].
1.2.2 Electrochemical Analysis and Instrumentation
Among the first applications of electrochemical analysis in biological sensing was the
Clark oxygen sensor [13] patented in 1956. Electrochemical detection makes use of
chemical redox reactions characterized by a transfer of electrons among the reacting
species [14]. The reaction occurs at an electrode (the working electrode) surface that
is held at some voltage (VREDOX) with respect to a reference electrode. Usually the sys-
tem requires a third electrode, a counter electrode, to maintain the voltage difference
in the presence of potential drops across the solution being monitored. The transferred
electrons constitute a current that is proportional to the concentration of the species
2 Wireless Integrated Neurochemical and Neuropotential Sensing
1
2
3
4
5
6
Figure 1.1 Schematic of a synapse showing the interplay between electrical and chemical
signaling. Electrical signals (1), cause neurotransmitter containing vesicles to dock (2) and release
the messengers (3). These bind to receptors (4) that cause downstream changes (5) in ion
channels that initiate electrical signaling.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-21-320.jpg)
![being analyzed and the surface area of the electrode. Typically, in electrochemical
analysis VREDOX is the independent variable and the redox current is measured. There
are several modes of analyses [14], two of the major kinds being cyclic voltammetry
and chronoamperometry. In the former, VREDOX is swept periodically over a given
voltage interval while the redox current is measured. This results in an I-V signature
of the species and is useful to obtain the potential difference at which the redox reac-
tion is maximal. In chronoamperometry, or more simply, amperometry, current is
measured as a function of time while the voltage difference is held constant at the opti-
mal redox potential for maximum sensitivity obtained by cyclic voltammetry. This is
the preferred mode of analysis for monitoring concentrations over time.
The instrumentation used for electrochemical analysis is called a potentiostat.
There are various methods used, namely voltametry amperometry, cyclic voltametry
and amperometry. As the name signifies, in the voltametric method the VREDOX is
held at a specified value (or waveform) while simultaneously measuring the current.
The schematic of a basic potentiostat is shown in Figure 1.2. The reaction occurs
between the working and the reference electrodes so the drop VRE-WE is the potential
of interest. The output voltage of an opamp of gain A is given by:
eOUT = A (e+ – e–) (1.1)
Let VCELL denote the drop between the counter and working electrodes and the
subscripts CE, WE and RE denote the counter working, and the reference electrodes,
respectively.
Since WE is grounded, single ended potentials are referred to it. Thus, e+ =
VREDOX, e– = VRE-WE and eOUT = VCE-WE = VCELL. Substituting in Eqn. (1.1),
VCELL = A (VREDOX – VRE-WE) (1.2)
VRE-WE = VREDOX – VCELL / A (1.3)
VRE-WE ~ VREDOX as A → ∞ (1.4)
Thus, the potential drop between the reference and the working electrodes is
forced to the preset value VREDOX, which appears across the reaction media, and the
redox current being forced through the counter electrode is measured.
1.2 Neurochemical Sensing 3
Counter
electrode
+
−
+
− Working
electrode
Reference
electrode
VREDOX
Figure 1.2 Schematic of a basic three-terminal potentiostat for neurochemical sensing by
measurement of neurotransmitter-activated redox currents.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-22-320.jpg)
![1.2.3 VLSI Multichannel Potentiostat
Typically utilized benchtop potentiostats are used for electroanalytical biosensing
that offer a poor match in terms of footprint, power consumption, sensitivity, paral-
lel scalability, etc. CMOS VLSI potentiostats having one or a few channels have been
developed in the past to record from electrochemical sensors [15–19]. Custom
potentiostats for biosensing applications can be reduced to a two-terminal setup,
with just the working and reference electrodes. The counter electrode is not needed
since the expected redox currents are very small due to very low physiological con-
centrations of analytes leading to negligible voltage drops across the solution.
The system diagram for one channel of a multichannel VLSI potentiostat [20]
is shown in Figure 1.3.
Each channel essentially integrates the redox current for a certain conversion
period and then digitizes the result. The circuit consists of a charge-mode incremen-
tal delta-sigma analog-to-digital converter [21] with time-multiplexing digital gain
modulation to extend the dynamic range that is needed for physiological monitor-
ing. Figure 1.4 shows the implementation and the timing diagram for the front end.
The redox current is integrated on the capacitor C1. C1 can be digitally set to 100fF
or 1.1pF to accommodate a wide range of redox currents while maintaining reason-
able conversion times. The capacitor C2 provides a low input impedance virtual
ground node that is charged to VREDOX at the beginning of a conversion period. The
single bit digital to analog converter is implemented using switched current sources
realized by the transistors M1 and M2. These transistors are always turned on to
decrease the effects of charge injection noise. Transistors M3, M4, M5, and M6 are
minimum size switches that direct the reference current into either the integrator or
the reference voltage source. The high gain amplifier is a cascoded inverter operat-
ing in the subthreshold region. In a standard ΔΣ modulator, the reference current Iref
is either added to or subtracted from the input current Iin and Iin ± Iref is integrated
during the entire time. This forces the input and reference currents to be of the same
magnitude. To allow for a wider range of input currents, a programmable gain of
the input current is introduced by controlling the integration time of the reference cur-
rent using a clock, dsClk, that has a programmable duty cycle. The reference current
is integrated only when dsClk is high, while the input current is integrated through
4 Wireless Integrated Neurochemical and Neuropotential Sensing
Counter Shifter
From previous
channel
To next
channel
Time modulation feedback
{ 1,0}
±
{ 1}
±
{ ,0}
±INF 1 bit
D/A
dsClk
+
+
−
−
VMID
IIN
Figure 1.3 Block diagram of a single channel of the VLSI potentiostat showing the ΔΣ modulator
with the time modulation feedback. From [18] with permission, © IEEE 2007.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-23-320.jpg)
![the whole period of the clock dsClk. The duty cycle of dsClk represents the gain of
input current with respect to the reference current, enabling multiple scales with the
same reference current. In Figure 1.4, this digital gain is represented by the logic
gates feeding into the transistors M3 and M4 and M5 and M6. The integration
period and the rate of sampling the input current are set by the clock intClk. The
clocks intClk1 and intClk2 are non-overlapping clocks derived from intClk. intClk1e
is a copy of intClk1 with the rising edge following and the falling edge preceding
those of intClk1. The ratio of periods of the clocks dsClk and intClk represents the
oversampling ratio (OSR) of the ΔΣ modulator. The decimator is implemented as
the simple accumulate and dump circuit. The number of active (logic one) output bits
of the ΔΣ modulator are counted using a 16-bit counter during one conversion period.
The conversion period is programmable and is represented by the period of the pro-
grammable clock intClk. At the end of each conversion cycle, the counter value is
written to the output parallel-in serial-out shift register and a new conversion cycle
begins with the cleared counter. The registers for all the channels are daisy-chained to
obtain a single output bit stream. The register is read out asynchronously at any time
during the conversion cycle. Figure 1.5 (a) shows the normalized digital outputs of
the chip for input currents over six orders of magnitude. An illustrative example
of the operation of one channel of the chip is shown in Figure 1.5 (b). In vitro
monitoring of the neurotransmitter dopamine was performed using commercially
1.2 Neurochemical Sensing 5
Vp
Vn
D
dsClk
dsClk
D
VDD
VREDOX
Vmid
Vint
scale
intClk 1
intClk 2
intClk 1e
Iin
VREDOX
intClk 1e
VREDOX
Ca
C1
−A
Cb
C1
C2
scale
M1
M2
M3 M4
M5 M6
Figure 1.4 Implementation level diagram of the ΔΣ modulator. From [18] with permission,
© IEEE 2007.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-24-320.jpg)
![available electrochemical sensors (CF30-250, WPI, FL). Different concentrations of
dopamine were added to a stirred phosphate buffered saline (PBS) solution and the
chip output was observed after equilibrating.
1.3 Neuropotential Sensing
While synapses transfer information locally in insulating gaps through electrochem-
ical signaling as described in the previous section, information is transmitted over a
longer range in the form of electrical action potentials traveling across the central
nervous system. The electrical activity of the brain can be recorded from within the
brain (spike or local field potentials), the surface of the brain (electrocorticogram or
ECoG), or from the scalp (electroencephalogram or EEG). These signals encode infor-
mation about the state of the brain which potentially can be extracted by signal pro-
cessing methods. Thus, electrophysiology-based recording systems can be used to
understand the mechanism underlying brain function as well as help paralyzed
patients using a brain-computer interface [3]. Another common application area is
6 Wireless Integrated Neurochemical and Neuropotential Sensing
−14 −12 −10 −8 −6
−5
−4
−3
−2
−1
0
log(Iin(A))
Normalized
digital
output
Iin>0
Iin<0
Figure 1.5 Measured results from the potentiostat chip: (a) characterization data for input
currents over six orders of magnitude and (b) calibration curve obtained for monitoring
micromolar dopamine concentration in vitro. From [18] with permission, © IEEE 2007.
(a)
0 5 10 15 20
0
100
200
300
400
Dopamine (mM)
Current
(pA)
Measured
Linear fit
(b)](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-25-320.jpg)
![the recording of electrocorticograms in clinical investigation of neurological disorders
such as epilepsy. However, due to the large-scale instrumentation needed to imple-
ment EEG recording systems, these systems are currently mostly used inside hospi-
tals. In all these applications, miniaturized recording systems are required so that
they can be integrated into the daily lives for those who need it.
In this section, we limit the discussion to ECoG and EEG signals, and present
VLSI interface circuitry for these signals. Discussion on spike signals and associated
circuitry can be found in the following chapters.
1.3.1 Physiological Basis of EEG/ECoG
The brain is an extremely complex system, constantly carrying out information
transfer and processing. The neural system works through the interactions between
large assemblies of neurons in the central nervous system (CNS) and the peripheral
neural system. At the cellular level, neurons transfer and process the information
via the action potentials and neural firing (also known as spikes). When this kind
of electrical activity transfers to the surface of the cortex and to the surface of the
scalp, it can be recorded and processed to reveal the information contained in the
signal.
EEG/ECoG is the prevailing method to record the dynamics of the brain’s larger-
scale electrical activity. While the origin of the activities recorded by scalp electrodes
lie in the action potentials of cortical neurons, it is generally agreed that the ECoG
and EEG signals are generated by excitatory postsynaptic potentials (EPSP) [22]. Yet,
the origins of the generated rhythms in these electrical signals are not fully under-
stood. The recorded electrical signals are the result of aggregation of excitatory and
inhibitory postsynaptic potentials (EPSPs and IPSPs) across large volumes of neural
tissue that undergo volume conduction before they reach the cortical surface for
ECoG recording, and that undergo further spatial signal smearing through bone
and tissue conduction before reaching the scalp for EEG recording. The effect of
volume conduction is that of both spatial and temporal filtering, removing high-
frequency components and masking individual spike waveforms.
The effect of this signal aggregation also reveals patterns of synchronous activ-
ity that are indicative of mental states and hence are useful in brain state monitoring.
Electrical recordings from the surface of the brain demonstrate continuous oscilla-
tory activity with different intensities and patterns. The intensities of the ECoG can
be as large as 10 mV while EEG recordings are usually around 100 mV due to the
attenuation through the skull and skin. The frequencies of these waves range from
0.5 to 100 Hz and their character is highly dependent on the degree of activity in the
cerebral cortex. For example, brain waves change markedly between states of wake-
fulness and sleep. Depending on brain state and mental activity, brain waves could
be irregular without discernable patterns, or distinct spatiotemporal patterns could
manifest. Some of these are characteristics of specific abnormalities of the brain
such as epilepsy. Others occur under normal healthy conditions and can be typically
classified as belonging to one of four major wave groups, based on their frequency
content: Delta (0.5–4 Hz), Theta (4–8 Hz), Alpha (8–12 Hz), Beta (12–30 Hz), and
Gamma (>40 Hz) [23].
1.3 Neuropotential Sensing 7](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-26-320.jpg)
![1.3.2 Interface Circuitry
EEG/ECoG signals have very low amplitudes in the mV voltage range that require
amplification before any signal processing. The inputs to the amplifier can be con-
nected in three different methods: between each two electrodes (bipolar), between
one monopolar lead and a distant reference electrode (usually attached to one or both
ear lobes), or between one electrode and the average of all. In the last method, the
system reference is formed by connecting all scalp recording locations through equal
high resistances to a common point [23].
The application requirements call for the following specifications on the
instrumentation amplifier: low input-referred voltage noise (< 2 mVrms), low leakage
current (< 1 pA), high common mode rejection ratio (CMRR > 80 dB), high input
impedance (> 1 MΩ), high power supply rejection ratio (PSRR > 90 dB), and high iso-
lation mode rejection ratio (IMRR > 120 dB). For digitized electrophysiology record-
ing systems, control over quantization error in analog-to-digital conversion (ADC),
sensitivity, and filter cutoff frequency should also be considered [24].
The amplified EEG/ECoG signals need to be filtered to remove noise and out-
of-band frequency signals. EEG spectra typically span a 0–125 Hz signal band-
width, whereas ECoG spectra extend to higher frequencies (500 Hz or larger) and
require larger bandwidth filters. Routine EEG should be acquired at least at a sam-
ple rate of 250 Hz, to accommodate the 0–125 Hz signal band. Higher sampling rates
are often used to account for finite roll-off of anti-alias filtering and for improved
noise suppression. Further filtering may be required to remove power line artifacts
(50 or 60 Hz). Accounting for the different frequency bands of interest (Alpha, Beta,
Gamma, Theta) in EEG, band selection filters are typically provided by the EEG
recording system. While some systems include band-selection analog filters in the
recording unit, others provide digital filtering in their accompanying utility software.
In light of these considerations, we describe efficient VLSI implementation of
EEG/ECoG electrophysiology recording systems for micropower implantable use.
Figure 1.6 shows the functional block diagram for one channel of a multi-channel
8 Wireless Integrated Neurochemical and Neuropotential Sensing
C1
C1 C2
C2
M1
M1
Vin+
Vin−
vhpf
vhpf
Time modulation
feedback
Adaptive offset
cancellation
Counter
Shifter
From previous
channel
To next
channel
Continuous-time g − ΔΣ
C
m
+
+
+
−
−
−
Figure 1.6 Block functional diagram for one channel of the biopotential sensing chip.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-27-320.jpg)
![VLSI biopotential interface chip. Each channel integrates a dedicated ADC to relax
the precision requirements on signal transmission over a wireless link and thus min-
imize the net power consumption. The channel comprises a bandpass filtering ampli-
fier, Gm-C incremental ΔΣ analog-to-digital converter, decimating counter, and
daisy-chained parallel-to-serial output register.
Amplifier
The front-end amplifier used is a fully differential version of the design presented in
[25]. The amplifier midband gain is set to 40 dB by ratio of capacitors (C1 = 20pF
and C2 = 200fF). The PMOS transistors M1 and M2 provide large resistance in the
GΩ range for sub-Hz cutoff highpass filtering and AC coupling of the input [25].
Transistor sizing of the fully differential, two-stage amplifier is optimized for low
input-referred noise. The gate bias Vhpf controls the highpass cutoff frequency, rang-
ing from 0.2 Hz to 95 Hz. The lowpass cutoff frequency ranges from 120 Hz to 8.2
kHz, and is gm1/2pACc set by the transconductance of the first stage gm1 propor-
tional to bias current Ibiasp, midband gain of the amplifier A, and by the compensa-
tion capacitance Cc between first and second stage [26].
Analog-to-Digital Converter
The choice of ADC topology in the design is determined by several factors that
include the nature of the signal and system level considerations in the interface. One
could choose to provide a single ADC for the entire system, which requires multi-
plexing the output of the amplifiers at high rate. This increases the power require-
ments of the amplifier, which needs to drive a large load because of the high switching
rate. A more energy-efficient alternative choice is to include one ADC per channel as
shown in Figure 1.6. High efficiency requires the design of the ADC to be optimized
for high density of integration, and for accuracy rather than speed in the conver-
sion. Algorithmic and ΔΣ ADCs are suitable for this design, and offer a further
advantage of adjustable resolution through global control of clocking waveforms.
The functional diagram of a Gm-C incremental ΔΣ implementing variable-resolution
ADC is shown also in Figure 1.6. The core of the ΔΣ ADC is identical to the one
implemented in the potentiostat for neurochemical sensing presented in the previ-
ous section [20], offering also the benefit of a digitally selectable gain using time-
modulation feedback. A transconductance element, implemented with an nMOS
differential pair OTA and current mirror, converts the differential output of the
EEG preamplifier to a current Iin, which is continuously integrated by the ΔΣ input
stage. The continuous integration in the Gm-C ΔΣ avoids the need for sampling and
for anti-alias filtering. A second nMOS OTA provides an offset current Ioffset that
adaptively compensates for OTA and current feedback mismatch in the ADC. The
MSB from the decimator adjusts the direction of Ioffset through an integrator imple-
mented by a charge pump, one update per conversion cycle. Larger or more frequent
updates in Ioffset make it possible to further filter 1/f noise outside the signal band.
The digital output of all the channels can then be decimated and shifted out in
a daisy-chain fashion for a serial readout.
To characterize the accuracy in the overall response including front-end ampli-
fication/filtering and ADC quantization, Figure 1.7 shows the power spectrum of
1.3 Neuropotential Sensing 9](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-28-320.jpg)
![transmit data to and from the implantable system. In this section, we will review the
basics of power harvesting through magnetic coupling and give circuit designs for
telemetry and powering in CMOS.
1.4.1 Introduction to Inductive Coupling
The operational frequency of the telemetry system and its impact on tissue absorption
in the body are important design considerations. The human body comprises differ-
ent layers of tissue with variable conductivity and permeability. High-frequency
energy is absorbed by the body while low-frequency energy is reflected [27]. In a
frequency region between 1 and 20 MHz, maximum energy passes through the body.
Therefore, the design of the telemetry system is constrained to operation frequencies
in this range. As a special case of interest, assume an operation frequency of 4 MHz.
The corresponding wavelength is 75 meters, precluding the use of antennas that
require much larger apertures than practically possible in an implant. Power and
information can however be transmitted through inductive coupling between two
coils that are placed relatively close to one another. These coils can be sized signif-
icantly smaller than the wavelength since transmission of data and power is mediated
through coupling in magnetic field, rather than through electromagnetic radiation
and wave propagation.
In two inductively coupled coils, a current generated in the primary coil induces
a current in the secondary coil, proportional to the first current. The proportion of
power that is transferred is quantified by the coupling factor, k, which ranges between
0 and 1 (100%) depending on geometrical factors and material properties of the
coupling medium (air, tissue, bone, hair, etc.). Typical coupling factors in trans-
formers with optimized coupling are usually around 0.5 (50%), with parasitic cou-
pling and absorption in surrounding media contributing to the power losses in
transmission. For telemetric power and data transfer between implant and reader/
host coils, the coupling is relatively weak, resulting in much lower coupling factors.
In order to understand the effect of design parameters on coupling efficiency in power
transfer, we need to quantify the magnetic field strength induced and carried between
the two coils. The magnetic field produced by a primary circular coil of radius R1
at distance x along the perpendicular axis is:
where N is the number of windings, and I is the current supplied through the coil.
For a secondary coil placed parallel to the primary coil and centered along the same
axis at distance x, the induced current can be derived from estimating the magnetic
flux through the secondary coil, resulting in an approximate expression for the cou-
pling factor [28]:
k
R R
R R R x
=
+
1
2
2
2
1 2 1
2 2 3
( )
H
NIR
R x
=
+
1
2
1
2 2 3
2 ( )
1.4 RF Telemetry and Power Harvesting in Implanted Devices 11](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-30-320.jpg)
![processes, Q should be around 100. This on the other hand limits the bandwidth
of the system since wb = wc /Q, so for a center frequency of 4 MHz, the maximum
bandwidth is 40 kHz. This is acceptable because of the slow sensing application
targeted here. Also, note that the high voltage levels generated in the primary coil
are safe for use and do not pose a danger to the subject or others handling the sys-
tem because the high impedance of the high-Q telemetry system carries relatively lit-
tle power.
As presented, the coupling between coils provides for inductive power transfer
from the reader coil to the implant coil. Different methods for data transmission from
the interface circuitry at the implant to the reader coil are available. Here, we con-
sider ohmic load modulation, using the same inductive link to transmit the acquired
data upstream as used to transmit power downstream. Other methods such as capac-
itive load modulation and active transmission can be used, although each has its
own drawbacks.
Data transmission using ohmic load modulation in an inductively coupled system
is accomplished simply by changing the load resistance of the implant. Generally,
this is achieved by switching a second resistor loading the implant coil, in addition
to the resistive load of the implant interface circuits, as shown in Figure 1.8 (c). The
switched insertion of the resistor changes the current in the implanted coil, which
in turn changes the impedance and hence the current in the reader coil. This current
is sensed using transimpedance circuits at the reader, and this simple ASK data
transmission scheme is further decoded.
1.4.2 Telemetry System Architecture and VLSI Design
The VLSI power harvesting and telemetry system at the minimum should include
these subunits: rectifier, regulator, clock and data recovery, and data encoder. Figure
1.9 shows the block diagram of such a system. The transmitter coil can be driven
by a high-efficiency class-E transmitter. A full wave rectifier followed by a low-pass
circuit recovers a dc voltage. Figure 1.10 (a) shows an example of a rectifier circuit
implemented in a AMI 0.5 mm CMOS process [29].
When voltage on side A of the coil is higher than that of side B, M2, and M3
are shut off while M1 and M4 are turned on. This ties the low voltage side of the coil
to ground while passing the high voltage. The situation is reversed when B is higher
than A. The use of pMOS transistors prevents latch-up inducing collector currents
from occurring and removes the necessity of using additional components. This
voltage is dependent on the load and not suitable for driving the active circuitry. A
regulated supply voltage is required to ensure proper operation of the circuitry. Fig-
ure 1.10 (b) shows an example circuit diagram of a regulator. The output voltage
is stabilized proportional to voltage reference through a negative feedback. The ref-
erence voltage can be generated from rectified voltage by a supply independent ref-
erence circuit made out of CMOS devices only. Note that this topology requires a
minimum current to be drawn from the output for proper operation of the circuitry.
Since most implantable systems are mixed-signal systems, it is preferred to have two
regulators on the chip to separate analog from digital supply and minimize the switch-
ing noise in the analog part.
1.4 RF Telemetry and Power Harvesting in Implanted Devices 13](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-32-320.jpg)
![14 Wireless Integrated Neurochemical and Neuropotential Sensing
Data
recovery
Power
transmitter
Data
recovery
Data
encoding
Modulation
Command
generation
Data
Power
Data
Power
supply
Clock
Control
Clock
recovery
Rectification
Voltage
regulation
Figure 1.9 Block diagram of the RF power harvesting and telemetry system. From [29] with
permission, © IEEE 2005.
Vrectified
M1 M2
M4
Coil
M3
B
A
C
(a)
(b)
–
+
Vrectified
Vref
Vdd
M1
C
Figure 1.10 (a) Rectifier and (b) regulator circuit diagram. From [29] with permission, © IEEE
2005.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-33-320.jpg)
![In order to test the coupling and determine the maximum power transfer, the
transmitter and receiver coils were placed close together and moved apart. As shown
in Figure 1.11, distances between 10 mm and 100 mm were tested. The chip was
loaded such that it would produce 0.7 mA when the voltage was enough to operate
the regulator. With this load the chip was able to provide the desired regulated volt-
age with a distance of up to 3 cm between the two coils. The RMS voltage on the
coil, the rectified voltage, and the regulated voltage were recorded. At low current
draw the rectified voltage follows the coil RMS voltage fairly closely. The two val-
ues diverge when more current is drawn from the regulator. When the rectified volt-
age drops to the regulated value, the PMOS controlling current is completely on. This
ties the regulated voltage to the rectified, while affecting the coil voltage slightly less.
The next step is to recover the digital clock and commands from the induced
signals. A square wave clock can be extracted from the sinusoidal signal by a chain
of inverters. Slower clocks can also be obtained by dividing the main clock. Figure
1.12 shows the actual measurement of the above circuitry during operation. The
largest voltage (Ch2) is the rectified voltage, followed by the regulated (Ch1) and
than the reference (Ch3) voltages. The recovered 4 MHz clock (Ch4) is shown at
the bottom of the trace.
Data demodulation circuitry depends on the type of modulation implemented
in the base station. For an ASK scheme, an envelope detector followed by an RC fil-
ter is sufficient. Figure 1.13 shows a circuit diagram of such a circuitry. A filter cir-
cuit (C1, R1) reduces the amplitude of this signal to workable levels. The envelope
recovery is performed with 2 NMOS devices (M1, M2), a transconductance ampli-
fier (I1), and several filter circuits (C2, R2, R3) [30]. These serve to remove the car-
rier waveform and leave only the data signal. A high-pass filter (C3, R4) removes any
1.4 RF Telemetry and Power Harvesting in Implanted Devices 15
Coil voltage (RMS)
Rectified voltage ( , dc)
Vrectified
Regulated voltage ( , dc)
Vdd
Distance (mm)
Measured
voltage
(V)
0
1
2
3
4
5
6
7
20 30 40 50 60 70 80 90 100
Figure 1.11 Air coupling at different distances. From [29] with permission, © IEEE 2005.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-34-320.jpg)
![1.5 Multimodal Electrical and Chemical Sensing
Simultaneous detection and sensing of neurochemicals and electrophysiological
field potentials are very useful when studying the interaction between the chemical
synaptic and electrical neuronal activity, both in the healthy and the diseased brain.
The capability to monitor the close interaction between electrical and chemical activ-
ity in vivo is crucial, as in vitro experimentation is deficient in studying network
aspects and environmental factors in awake and behaving animals. Implantable
multi-channel instrumentation with this multi-model capability could provide impor-
tant information regarding neurological conditions where there is an imbalance
between the chemical and electrical activity as in epilepsy [31]. The previous three
sections have described the individual VLSI components that when properly com-
bined comprise a multimodal amperometric/voltametric sensing system. This sec-
tion describes the combination of the three systems and the protocol under which they
co-operate. Figure 1.15 shows the schematic diagram of the system in an implantable
scenario [32].
The principle is to (a) have the power harvesting chip supply power and clocks to
both the potentiostat and the EEG processor; and (b) utilize the telemetry link to
18 Wireless Integrated Neurochemical and Neuropotential Sensing
0 1 2 3 4 5 6 7 8 9 10
−40
−20
0
20
0 1 2 3 4 5 6 7 8 9 10
−20
−10
0
10
0 1 2 3 4 5 6 7 8 9 10
−10
0
10
0 1 2 3 4 5 6 7 8 9 10
0
500
1000
Bit number
Amplitude
(mV)
Figure 1.14 Comparison of data envelopes at frequencies tested for the Miller encoded data stream ‘1
101 001 010’. From the top, data at 1 kbps, data at 5 kbps, data at 10 kbps, and the ideal output Miller
encoded data.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-37-320.jpg)
![1.6 Summary
In this chapter we framed the challenges inherent in wireless monitoring of multi-
modal electrochemical neural activity, and presented a design methodology for an
integrated solution capable of recording and telemetering both electrical and neu-
rochemical activity from multiple sites. The following observations summarize the
message of this chapter:
1. Wireless monitoring of in vivo neural activity using implanted passive
telemetry poses stringent constraints on the available power for sensor
acquisition, signal processing, and transmission of recorded neural activity.
Without on-chip signal compression, signal bandwidth scales with available
power. Transmitted power scales approximately inversely with the square
of the distance between implant and reader, and also depends on coil geom-
etry and coding/decoding schemes. Larger peak activity (but same average
sustained activity) can be supported by including a rechargeable battery
with the implant.
2. Both electrical (neuropotential) and chemical (neurotransmitter) activity
are simultaneously monitored by combining voltage and current measure-
ment with properly designed electrodes and properly controlled biasing and
waveform generation. Redox currents in cyclic voltametry using a potentio-
stat register concentrations of cation-sensitive neurotransmitters selected by
electrode coating and further identified by redox potential. Scalp and
intracranial electrical recording identify EEG and ECoG neuropotentials
at various spatial and temporal scales, from single-neuron spikes in extra-
cellular electrode recording to brain waves extending across the cerebral
cortex. Simultaneous monitoring of these signals at various spatial and tem-
poral scales are important in detection of pathological neural/brain states
such as epilepsy and in the study of Alzheimer’s and other neurodegenera-
tive diseases.
3. A mixed-signal VLSI circuit methodology, with analog front-end acquisi-
tion, amplification and filtering, and with digital bit-serial coding of the
quantized signals, offers low noise acquisition, high fidelity transmission,
and low power operation. By multiplexing and interleaving of bit-serial
data streams, the available wireless transmission bandwidth can be traded
between a lower number of higher bandwidth signals (such as ECoG), or
a larger number of lower bandwidth signals (such as low-frequency EEG,
or distributed neurochemical activity).
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1.6 Summary 23](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-42-320.jpg)
![C H A P T E R 2
Visual Cortical Neuroprosthesis:
A System Approach
Moisés Piedade, José Gerald, Leonel Sousa,
and Gonçalo Tavares
2.1 Introduction
In the last few years there has been a huge effort to develop implantable integrated
stimulators for biomedical applications. Most of these stimulators are in the area
of muscular stimulation (for instance, for heart or limb diseases) [1–5] and in the
area of cortical or nerve stimulations (e.g., for blind/partially blind people or hear-
ing diseases) [6–12]. In all these stimulators, information has to be coded in a format
somewhat similar to the way stimulation is performed prior to the development of
each of the particular diseases. Moreover, with the exception of a few applications
(e.g., pacemakers), long-time performance of the implanted stimulator implies the
power to be provided by the outside unit. It avoids future operations to replace old
batteries, reduces the risk of infections and therefore improves the patient health level.
This poses the need for wireless remote delivery of power and data [10–12].
Microelectronic prostheses that interact with the remaining healthy retina have
been developed to restore some vision to those who suffer from eye diseases, such
as Retinitis Pigmentosa. This type of prosthesis can use sub-retinal devices [13] (to
replace the photoreceptors) or more complex epiretinal devices [14] (for capturing
and processing images that are transmitted to the ganglion cells through an electrode
array) but requires that output neurons of the eye and the optical nerves are in a
healthy state. When this is not the case, these microelectronic prostheses are not
useful and the stimulation has to be performed in the primary visual cortex, directly
to the neurons in higher visual regions of the brain. This is a challenge, because visual
information has to be encoded in a format somewhat similar to the way stimulation
was done prior to the development of total blindness. It is expected that neurons will
adapt to the stimulus in a way that a blind individual will be able to extract from it
information on the physical world [15].
Brindley [16] and Dobelle [17] showed that simultaneous stimulation of multiple
electrodes allowed blind volunteers to recognize simple patterns. This research, how-
ever, also showed that a cortical prosthesis based on a relatively large number of
superficial implanted electrodes requires high currents to produce phosphenes
(more than 1 mA), which leads to problems such as epileptic seizures. To avoid this,
deep intracortical neuro-stimulation should be used, exciting the neurons at a depth
25](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-44-320.jpg)
![between 1 mm and 2 mm, which corresponds to the cortical layers 4 (namely, Ca and
Cb), where signals from the Lateral Geniculate Nucleus (LGN) arrive.
This chapter presents a cortical visual neuroprosthesis for profoundly blind peo-
ple which has been developed within the scope of the CORTIVIS project and sup-
ported by the European Commission [18] and by the Portuguese Foundation for
Science and Technology (FCT) [19].
Figure 2.1 illustrates the basic components of our Cortical Visual Neuroprosthe-
sis approach. The whole system uses a bioinspired visual processing front-end, the
Neuromorphic Encoder, which generates the electrical signals that are transferred
to inside the skull through a RF link, for stimulating an array of penetrating electrodes
implanted into the primary visual cortex. Power to operate the stimulating circuitry
is also provided from the outside through the RF link. This visual neuroprosthesis is
expected to recreate a limited, but useful visual sense in blind individuals, by apply-
ing the electrical signals up to 1024 microelectrodes. In what concerns the neuro-
morphic encoder, the simplest models assume that the neural coding can be reduced
to predicting the firing rate as a function of the sensory stimulus. This assumption
may be justified in certain brain areas, e.g. deep in the cortex [20]. On the other hand,
neurons in the early visual system, for example from the retina to the LGN, can
deliver reproducible spike trains, whose trial-to-trial variability is clearly lower than
the one predicted from the simple firing rate approach [21]. To predict individual
spikes, spike patterns with higher timing accuracy and also to account for the sto-
chastic variability of these responses other approaches have to be considered. A first
experimental work comparing the performance of these models has been recently
published [22].
The wireless radio frequency (RF) link must provide both power and bidirec-
tional data transmission between the outside and the implant. While the visual neu-
roprosthesis requires a few tenths of milliwatts of power, the actual power provided
from the outside must be somewhat higher, in order to account for the coupling
26 Visual Cortical Neuroprosthesis: A System Approach
Digital
Camera
Neuromorphic
Encoder
Power
Data
Secondary coil
Electrode
Stimulator
RF
link
Primary coil
Figure 2.1 Cortical visual neuroprosthesis concept. From [37] with permission, © IEEE 2005.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-45-320.jpg)
![losses. The most common solutions proposed in literature for the RF link are Ampli-
tude Shift Keying (FSK) modulation [23–26], FSK [23, 27] and Binary Phase Shift
Keying (BPSK) modulation [23, 28]. The ASK signal is usually demodulated in a
noncoherent fashion, using a very simple receiver. However, the performance of the
ASK receiver is highly dependent on the amplitude of the received signal, which is
unknown and depends on the relative position between the implant and the outside
unit. Therefore, an ASK solution requires high-efficient gain-monitoring and level-
controlling devices. This is not the case with either FSK or BPSK, which are constant
amplitude modulations. Within reasonable limits, the FSK and BPSK receivers are
insensitive to the amplitude of the received signal, making these circuits more
robust with respect to the high variability of the RF channel. Demodulation of FSK
and BPSK is usually done coherently, thus requiring more complex and power-
consuming receivers.
After careful analysis of the different modulation characteristics, FSK was cho-
sen as the modulation to use in the forward link. For monitoring purposes a reverse
data link has also been implemented. It uses BPSK, which is implemented with a very
simple transmitter. BPSK was not selected for the forward link because the receiver
(which is based on a Costas Loop demodulator) is more complex than the FSK
receiver.
This chapter is organized as follows. In Section 2.2 the main components of the
system are specified and an architecture is proposed to fulfill those specifications.
Section 2.3 presents the prosthesis external body (primary) unit, which includes the
neuromorphic encoder and the wireless communication link. Section 2.4 presents
some circuits of the body implantable (secondary) unit. Experimental results of the
system prototype are reported in Section 2.5. Section 2.6 concludes the chapter and
summarizes the main results achieved.
2.2 System Architecture
The system architecture of the proposed visual neuroprosthesis is represented in Fig-
ure 2.2. It is physically divided in two units: a primary unit located outside the body
and a secondary unit consisting of an implant located inside the body. The units are
connected by means of a low-coupling two-coil transformer, which establishes a
magnetic RF link between the two devices. The purpose of this RF link is twofold:
(1) to remotely power the secondary unit, a mandatory requirement to avoid the use
of batteries in the implant and (2) to allow bidirectional data communication
between the units. The primary unit interfaces with a miniature digital video camera
2.2 System Architecture 27
Early
layers
Forward
transmitter
Neuromorphic
pulse order
Control Backward
receiver
Camera
Neuromorphic coder
Primary unit Secondary unit
RF link
Forward
receiver
Backward
transmitter
Electrodes
stimulator
and sensing
Figure 2.2 Prosthesis system architecture. From [37] with permission, © IEEE 2005.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-46-320.jpg)
![and with a personal computer (PC) used for system configuration, patient visual
training, and prosthesis performance analysis purposes.
The Neuromorphic Encoder translates the visual signal captured in the miniature
digital camera into a sequence of electrical pulses, a spike train, capable of being
recognized by the brain. It is composed of two main modules connected in series. The
Early Layers are responsible for processing the visual signal and for its conversion
into a spike rate. This rate is then taken as input by the Neuromorphic Pulse Coding
module and is translated into the actual spike events by using a simplified version
of the integrate-and-fire spiking neuron [29]. The access to the RF link is then arbi-
trated by the latest module using a First-In First-Out (FIFO) buffer to store the events
until the link is able to send more spike events. In the visual neuroprosthesis presented
in this chapter, the Neuromorphic Encoder is required to process visual images at a
rate of 30 frames per second (fps), generating spikes at a rate up to 100 Hz and stim-
ulating a number of microelectrodes equivalent to an array with up to 32 × 32.
The Forward Transmitter receives the multiplexed spike data from the Neuro-
morphic Pulse Coding in a synchronous serial bit stream format at a rate of ¶b =
1 Mbps. This data is modulated using FSK modulation with a center frequency of
¶c = 10 MHz and a frequency deviation D¶ = ±323 kHz. On the secondary unit,
power is extracted from the received signal by a power supply generator circuit
(considered to be part of the Forward Receiver in Figure 2.2) which will be described
later in Section 2.4. Because the integrity of brain tissue does not allow the use of
high-power circuitry, the secondary unit is required to operate with only tenth’s of
milliwatts of remotely delivered power. The spike data is recovered by the Forward
Receiver, which consists of a FSK demodulator, bit synchronizer, and frame disas-
sembly circuit. The recovered data and clock are then forwarded to the microelec-
trodes stimulator circuit.
To accomplish implant monitoring (e.g. electrode impedance measurement and
calibration) a reverse data link has been developed. In the secondary unit, mainte-
nance data is modulated and transmitted using BPSK at a data rate of ¶b =
156.25 kbps using low amplitude (≈1 V) and a carrier frequency ¶c = 5 MHz. The main
objective of the Electrode Stimulators and Sensing module is to stimulate the primary
visual cortex and to measure the connectivity between the electrodes and cortex.
Extensive experiments have shown that in order to safely induce phosphenes a cur-
rent of 20mA is required. Electrode sensing is achieved by injecting a fixed current
value to a microelectrode and then measuring the induced voltage value. This
allows for measuring the connectivity between the microelectrode and the visual
cortex cells.
The Electrode Stimulators and Sensing module is composed of a set of Digital
to Analog Converters (DACs) [30], which are used to stimulate up to 32 × 32 micro-
electrodes in the visual cortex with the spike events received from the Neuromorphic
Encoder. Each DAC has a current-steering type architecture, using scaled currents
added at an output node, in order to ensure the desired linear DAC operation. The
main difference with respect to the common current-steering DAC is that it allows
for the removal of the charge from the brain: it can inject current (positive sign) or
remove current (negative sign) from the electrode. The DAC reference current is
around 29mA and the overall power consumption for stimulating and sensing the
1024 electrodes is expected to be under 50 mW. The amplitude and duration of the
28 Visual Cortical Neuroprosthesis: A System Approach](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-47-320.jpg)
![stimulus is pre-recorded in dedicated registers on the Electrodes Stimulator and
Sensing module, which can be accessed by means of the RF link for both reading and
writing.
The overall system is presently under development in VLSI technology. The Elec-
trode Stimulator and Sensing block is to be implemented in a modular way in AMS
CMOS 0.35mm technology: each module (except for the power supply generator)
drives a 100-microelectrode array, which will be attached directly to the VLSI chip
(flip chip technology) [30]. The Forward and backward emitters and receivers are
also being developed using AMS CMOS 0.35mm technology. Moreover, in order to
evaluate the circuit requirements when implementing the in-deep sub-micron tech-
nology, the Neuromorphic Encoder is now being synthesized using the UMC 0.13mm
CMOS technology process [31]. The UMC L130E SG-HS 1P8M process is a single
poly, 8 metal layer with an operating voltage of 1.2 V.
However, to rapidly prove the concepts involved in the RF link, a scaled-
frequency prototype operating 10 times slower was built using conventional inte-
grated circuits and discrete components: the forward data rate is 100 kbps with a
carrier frequency of 1 MHz; the backward data rate is 15.625 kbps with a carrier fre-
quency of 500 kHz. Also a neuromorphic encoder was developed using FPGA tech-
nology. The visual neuroprothesis system was planned to support the driving of 1024
electrodes. However, the stimulator chip that is being developed will be flipped
directly over the back of one microelectrodes array (100 microelectrodes).
2.3 Prosthesis Exterior Body Unit and Wireless Link
2.3.1 Neuromorphic Encoder
The block diagram of the Neuromorphic Encoder in Figure 2.3 includes the spatio-
temporal receptive fields of the retina ganglion cells. The neuromorphic encoder is
organized in three main blocks: (1) Early Layers that perform both spatial and tem-
poral processing of the visual signal, (2) Neuromorphic Pulse Coder, responsible for
converting the pre-processed visual information to a sequence of pulses that can be
interpreted by the brain, and (3) Spike Multiplexing that applies Address Event Rep-
resentation (AER) [32] to convey information about the pulses through a serial link,
without timestamps, to the microelectrode stimulator. The Neuromorphic Encoder
translates a visual stimulus s(r,t) described by the intensity of each of the three basic
(R)ed, (G)reen and (B)lue color components, as a function of space r = [x y]T
and time
t, into a sequence of pulses. This encoder was designed to allow a blind individual to
recognize patterns up to 32 × 32 points, corresponding to 1024 microelectrodes.
2.3 Prosthesis Exterior Body Unit and Wireless Link 29
Digital
camera
Early layers Neuromorphic
pulse coding
Spike
multiplexing
Serial link
Bio-inspired processing module of the artificial retina
Figure 2.3 Neuromorphic encoder.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-48-320.jpg)
![2.3.1.1 Early Layers
The Early Layers block represented in Figure 2.4 is responsible for spatio-temporal
filtering. This block is an extension to the chromatic domain, by considering inde-
pendent filters for each basic color component. The first filtering element of the Early
Layers is an edge detector implemented by a two-dimensional Difference-of-
Gaussians (DOG) per color channel (see Figure 2.4). As it is well known, DOG func-
tions can be used for edge detection when the gains of the two Gaussians have
opposite signs and different standard deviations.
The output of the edge detection modules, corresponding to the different color
components, are integrated by applying the desired relative weights (* represents the
convolution operator):
(2.1)
The m(r,t) signal is then convolved with the impulse response of a first order high-
pass filter hHP with the pole at –a rad/s to perform motion detection. The resulting
activation function u(r,t) = m(r,t)*hHP(r,t) is then modulated by the Contrast Gain
Controller (CGC) that models the strong modulation effect exerted by stimulus
contrast. The CGC non-linear approach is also used in order to model the motion
anticipation effect [33]: the CGC output w(r,t) is convolved with the impulse
response of a lowpass temporal filter hLP with a single pole at –g rad/s; the resulting
signal v(r,t) = y(r,t)*hLP(r,t) is then processed by the non-linear function:
(2.2)
before being applied to modulate the amplitude of the CGC input signal (H(◊) rep-
resents the Heaviside step function). Finally, the last processing step of the Early Lay-
ers block is a rectifier operation represented in Figure 2.4. It yields the firing rate ¶(r,t)
of the ganglion cells response to the input stimuli:
¶(r,t) = Ψ ◊ H(y(r,t) + q) ◊[y(r,t) + q] (2.3)
where Ψ and q define the scale and baseline values of the firing rate.
The bilinear approximation was used in order to implement the temporal fil-
ters, resulting in first-order Infinite Impulse Response (IIR) digital filters. Also, to
reduce the amount of memory needed, the temporal filters were implemented in a
transposed form where the output is calculated by adding the input x[n] to a stored
value l[n] that is computed in the previous cycle.
The diagram of the visual encoder computational architecture is depicted in Fig-
ure 2.5 (the notation x[q,n] stands for the discrete space/time equivalent of the sig-
nal x(r,t)).
Folding techniques were applied to the architecture directly derived from the
Signal Flow Graph (SFG), in order to comply with restrictions, such as low power
consumption and area circuit. The complete Early Layers circuit was folded 1024
times and the firing rate for each microelectrode is computed in series. Moreover,
g v r t
v r t H v r t
( , ) =
1
1 ( , ) ( , )
4
( )
+ ⋅ ( )
⎡
⎣
⎤
⎦
m r t s r t
i R G B
i i i
( , )= ( , )*
= , ,
∑ ( )
α DOG
30 Visual Cortical Neuroprosthesis: A System Approach](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-49-320.jpg)
![assuming a Gaussian kernel of 7 ¥ 7, edge detection requires a total of 98 multipli-
cations and 98 additions. The folding technique has been applied to the Gaussian
filters by a factor equal to the kernel size. Therefore, as shown in Figure 2.5, only one
multiply-and-accumulate (MAC) unit is needed to compute each Gaussian filter.
The non-linear processing modules, namely the non-linear function applied in the
CGC and the rectifier, were implemented by means of a look-up table and a com-
parator, respectively.
2.3.1.2 Neuromorphic Pulse Coding
The Neuromorphic Pulse Coding (NPC) block performs two operations: (1) con-
verts the continuous time-varying representation of the signal produced in the Early
Layers of the retina into a neural pulse representation, and (2) arbitrates the access
of the generated spikes to the serial bus at the input of the Forward Emitter. We have
considered a representation in which the signal provides information only when a new
pulse begins. This block then stores the information about spike events and sends
them to the implant at the maximum rate allowed by the channel. The model adopted
for the Spike Generation is a simplified version of an integrate-and-fire spiking neu-
ron [29]: the neuron accumulates input values from the respective receptive field (out-
put firing rate determined by the Early Layers) until it reaches a threshold f; then it
fires a pulse and discharges the accumulated value; a leakage term is included to force
the accumulated value to diminish for low or null input values.
2.3 Prosthesis Exterior Body Unit and Wireless Link 31
Visual
Stimulus
High Pass Non Linear Low Pass
Contrast
Gain
Control
Space filtering Time filtering
DOG
m(r,t) u(r,t)
g(r,t)
v(r,t)
y(r,t)
f(r,t)
αB
αG
αR
Figure 2.4 Early layers block.
Figure 2.5 Diagram of the visual encoder computational architecture. From [37] with
permission, © IEEE 2005.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-50-320.jpg)
![The implementation of the pulse generation circuit operates in a two-stage
pipeline: in the first stage the input firing rate is added to the accumulated value; in
the second stage, the leakage value is subtracted and, if the result is higher than a
threshold f, a pulse is fired and the accumulator returns to zero. This block is con-
nected to the Early Layers by means of a dual-port memory bank, as represented in
Figure 2.5. This allows for the Early Layers block to write data onto one port while
the Neuromorphic Pulse Coding block reads data from the other port. The Spike
Multiplexing block uses a first-in first-out (FIFO) buffer to arbitrate the access of
the spikes generated in the Spike Generating block to the RF link (see Figure 2.5).
When a spike is generated, it is stored in the buffer until the channel becomes avail-
able. The buffer allows the system to respond well to short periods in which the spike
rate is high.
2.3.1.3 Model Evaluation
To evaluate the performance of this model, an experimental analysis was made by
using real experimental data from salamander retinal responses [22]. This work has
compared the performance of the presented model to the one of a recently pub-
lished stochastic model, which attempts to predict the temporal occurrence of
spikes and spike patterns [20]. Model performance was assessed based on the mean
squared error (MSE) of the firing rate. The MSE for the firing rate of the presented
model is about 1.11, while for the stochastic model is 1.13 [22]. These results show
that by using a deterministic model, it is possible to approximate the real neural
retina response with an accuracy similar to that of the stochastic model. However,
deterministic models are less demanding in terms of computational capacity, thus
making them a more suitable approach for developing a visual neuroprosthesis.
2.3.2 External Body Unit (Primary RF Unit)
The RF link block diagram is shown in Figure 2.6. The RF link circuitry can be
divided into three parts: the primary RF unit (located outside the body), the second-
ary RF unit (located inside the body, but not necessarily inside the head), and the
transformer, which establishes inductive coupling between the two previously men-
tioned units (one coil is external and another is internal). A bidirectional RF link is
established: the primary (forward) link and the secondary (backward) link. In the
32 Visual Cortical Neuroprosthesis: A System Approach
Figure 2.6 RF link circuitry diagram. From [37] with permission, © IEEE 2005.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-51-320.jpg)
![main link, the data bit rate is up to 1 Mbps, and a power/data signal is transmitted
using FSK modulation with a 10 MHz frequency carrier. In the secondary link, the
data bit rate is up to 156.25 kbps (which is enough for maintenance and initial con-
figuration purposes) and data is transmitted using BPSK modulation with a 5 MHz
frequency carrier. Initially, in order to implement a very compact low-power wireless
communication link, some integrated circuits were designed using AMS CMOS
0.8 mm technology. However, new circuits currently in development use AMS
CMOS 0.35 mm technology [30].
The transmitter is shown in Figure 2.7(a) and includes a FSK modulator (imple-
mented by means of a counter, driven by an oscillator ¶CLK) and a signal amplifier.
The data is modulated with frequencies (data bit ‘0’) and (data bit ‘1’).
This signal feeds a class E switching-mode tuned power amplifier, as shown in Fig-
ure 2.7(a), whose configuration was chosen to optimize the efficiency at the trans-
mitter [34].
The primary RF unit receiver is a Costas-Loop [23] BPSK coherent demodulator.
This receiver is placed after a 6th
order bandpass filter and a RF Automatic Gain
Control (AGC) circuit.
2.3.3 RF Transformer
The coupling transformer is of major importance in the RF link since it has a strong
influence on the overall performance of the internal unit. Its design must allow proper
system operation regardless of the intercoil distance (within reasonable limits, say
1 to 2 cm). It must be noticed that the real transformer, at the desired operation fre-
quencies, exhibits a distributed parameter behavior (as represented in the model in
fCLK
15
fCLK
16
2.3 Prosthesis Exterior Body Unit and Wireless Link 33
(b)
(a)
Figure 2.7 RF unit: (a) transmitter; (b) coupling transformer model. From [37] with permission,
© IEEE 2005.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-52-320.jpg)
![Figure 2.7(b)). Due to the coil separation, there is a high magnetic flux dispersion
(not connected with the secondary coil), which makes the coupling weak and a signif-
icant amount of energy is lost. To maximize the efficiency, it is important to perform
an appropriate design of the coils. In order to compensate the equivalent inductances
relative to the primary and secondary magnetic flux dispersions, capacitors C1 and
C2 are connected in series with the respective coil, resonating at the 10 MHz car-
rier frequency. As a consequence, the RF transformer behaves like a double-tuned
bandpass filter. Both circular coils have a cylindrical powerful neodymium magnet
inside, used for coil self-attracting and fixing purposes [35, 36].
Experiments confirmed the importance of taking into account the distributed
capacitance and the skin effect in the transformer. In fact, the absence of an iron core
makes it impossible to have a strong magnetic coupling: the measured coupling fac-
tor was 0.3 for an intercoil distance of 1 cm using carefully designed planar coils of
Litz wire with about 3 cm of diameter. Figure 2.8 illustrates the transmission of an
unmodulated carrier before and after the transformer for a 16 times lower frequency-
scaled prototype. As one can see, some attenuation is introduced by the transformer,
as the result of the very weak magnetic coupling. Nevertheless, the signal delivered
to the receiver still allows satisfactory power and data recovery.
2.4 Body Implantable Unit
The body implantable unit is shown in Figure 2.6 and includes the secondary RF
unit. The power recovery circuit is comprised of a half-wave rectifier, protection cir-
cuits, and a series regulator. It recovers the required power from the received signal,
with a power efficiency of about 30% for an intercoil distance of 1 cm.
The binary FSK Demodulator is based on a Phase Locked Loop (PLL) circuit
and a comparator and provides a stream of Non-Return-to-Zero (NRZ) data. This
bit stream is fed to the Bit Synchronizer, which provides a synchronized clock and
retimed data to the Data Processing and Control unit. The Data Processing and
Control unit performs bit and frame synchronization and frame disassembly. Finally,
the formatted data is forwarded to the Electrode Stimulator and Sensing block.
34 Visual Cortical Neuroprosthesis: A System Approach
Figure 2.8 Transmitted signal for an intercoil distance of 1 cm: (a) before the transformer;
(b) after the transformer.
(a) (b)](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-53-320.jpg)
![The master clock recovery task is accomplished in the Master Clock Recovery
block (see Figure 2.6), which is implemented by means of a narrow-band PLL
designed to produce a 10 MHz reference clock from the received signal.
2.4.1 Bit Synchronizer
The signal received from the primary system is used to extract the system master
clock, with frequency where Mbit/s is the raw bit-
rate and N = 10 (corresponding to a RF carrier frequency of 10 MHz). Since the mas-
ter clock is derived from the transmitted signal, it follows that the data stream is fre-
quency synchronized (i.e., frequency-locked) with the master clock; a data clock
could therefore be obtained by suitable division (by a factor N) of ¶CLK. This is
because there is no frequency offset between transmitter and receiver in this system.
However, the (lead or lag) phase difference between the positive-going clock transi-
tions and the optimum time epoch for sampling the data, which is the middle time of
the data bit, is unknown and varies significantly. In fact, even small disturbances in
the relative position of both coils lead to important phase offsets which have to be
properly estimated and compensated by the bit synchronizer. The task performed by
the bit synchronizer is thus of fundamental importance to establish a proper time ref-
erence in the receiver. The positive-going transitions in this reference clock should
accurately signal the optimum instants to sample and detect the received data bits.
The bit synchronizer and its interaction with the receiver is shown in Figure 2.9(a).
The bit synchronizer has a feed-forward structure that avoids the annoying loop
behavior known as hang-up [36,37]. This phenomenon is typical in feedback syn-
chronizer operation and manifests itself has an unacceptably long synchronizer acqui-
sition period, compromising receiver operation. Suppose that we have a binary
counter being driven with the master clock frequency ¶CLK; then, it will advance N
states within each bit period. If, at time t0, the counter is in state i then, at time
, it will have advanced and be in state (on aver-
age); this is the time epoch at which the recovered clock should have a positive tran-
sition, marking the middle of the data bit. This reasoning justifies the bit synchronizer
block diagram represented in Figure 2.9(b): the positive-going transition on the
raw, unsynchronized data signal latches the counter state i, at reference time t0,
and marks the start of a bit. When the counter reaches the state , then
and the comparator will signal this event to the
final processing block, which in turn samples the raw data and produces a clock pulse
synchronized with the master clock. Note that after a positive-going transition of the
raw data, the synchronizer operates in a free-running fashion. The phase offset, which
eventually accumulates after this event is corrected when the next positive-going tran-
sition occurs. Thus the raw data should not have long sequences of equal bits. This is
guaranteed by the use of self-synchronizing scrambler and descrambler circuits. The
developed bit synchronizer has the following desirable properties, namely (1) due to
S
N
N i N N i
+
⎛
⎝
⎜
⎞
⎠
⎟ +
2
=( ) =
mod mod
S i
N
=
2
+
i
N
+
2
T
T
f
R
N
b
CLK
CLK
b
2
=
2
=
2
× ⋅
t
Tb
0
2
+
R
T
b
b
=
1
=1
f
T
N R
CLK
CLK
b
=
1
= ×
2.4 Body Implantable Unit 35](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-54-320.jpg)
![[155]
“You’re using Mrs. Jones’ rifle!” Red accused, refusing to
be checked.
“Why not? She never touched it. A rifle was meant to be
used not left to rust.”
“Mrs. Jones thinks you’ve been taking things from her.”
“That’s a black lie!”
“Cord wood for instance.”
“What would I steal wood for, when I have to keep
chopping more to replace it?” Jack shouted furiously.
“Use your head, or haven’t you got one?”
At this point, Mr. Hatfield warned Red to drop the
argument.
“Sorry,” the boy mumbled.
Jack however, was not willing to allow the matter to
pass.
“What else did Mrs. Jones say I took?” he demanded.
“I don’t recall that she accused you,” Mr. Hatfield
answered. “She merely was disturbed because of the
wood and a few other trifles.”
“Someone else had been taking that wood. What else
did she say was missing?”
“A black dress,” Dan answered. “One with jet buttons.”
“Of course we don’t think you’d have any use for a
woman’s dress,” Dan went on, watching the boy
intently.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-56-320.jpg)
![[156]
Jack made no reply. After a long while, he said:
“I didn’t take that dress. If I were a mind to though, I
could tell you something about it!”
“Suppose you do just that,” Mr. Hatfield encouraged
him.
Jack smiled in a superior, insolent way. The wave of
friendliness which he briefly had displayed, now was
entirely gone. Once more he seemed the arrogant,
defiant runaway.
“Why should I tell you anything?”
“Because it’s the right thing to do, Jack. We have a
particular reason for being interested in what became of
that black silk dress.”
“You’ve accused me of being a thief.”
“No, Jack. The Cubs were a bit abrupt perhaps. They
believe in being square and honest. Naturally it made
them sore to think you might have taken the biscuits.”
“I told you, I don’t know nothin’ about ’em!”
“And we accept your word, Jack.”
“Then you said I took wood and the Widow’s black
dress.”
“No, Jack, we merely were telling you what she said.
Unfortunately, when one has a past record, it’s apt to
plague one unjustly.”
“Sure, I’m a bad kid! I know!” Jack said, his eyes
flashing. “Okay! Send me to an industrial school! But try](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-57-320.jpg)
![[157]
to keep me there! I’ll run away a thousand times!”
“You’re talking wildly now, Jack. No one wants to send
you away. Quite the opposite. Mrs. Jones likes you.
She’s willing to overlook a lot to keep you with her.”
“She’s been pretty decent to me,” Jack admitted,
softening again. “I did take food out of the ice box
without asking her. Not very much though. Just enough
so I could get along out here in the woods.”
“She’s worried about you now, Jack. She asked me to
send you home, if I saw you.”
“Oh, I’ll go,” Jack sighed. “I’d intended to anyhow as
soon as this rabbit finishes cooking. It’s done now, I
guess.”
The boy removed the rabbit from the spit, and salted it,
using a shaker which the Cubs were certain had come
from Mrs. Jones’ home.
“Have some?” he invited the Cubs.
They declined.
“Well, I’m hungry,” Jack announced.
Dismembering the rabbit, he gnawed at the tough meat.
Now and then as he ate, he glanced at the Cubs.
Having finished his meal, he put out the fire and
cleaned away the debris. The Cubs noted that he was
efficient at it, leaving not a spark which could set off a
forest fire.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-58-320.jpg)
![[158]
“I’ll go back to Mrs. Jones’ place now and chop more
wood,” Jack said finally, picking up the rifle. “I’ll chop
and chop until my hands bleed!”
“I hardly think Mrs. Jones will require that,” Mr. Hatfield
said, smiling. “By the way, Jack, who do you figure may
be taking that wood?”
The boy gave him a quick, knowing look.
“I don’t stay up nights watching!”
“But you have a fairly good idea where it is going?”
“Maybe. Maybe not.”
“Jack, if you wanted to cooperate, you could be very
helpful.”
“I mind my own business. That’s more than I can say
about some folks.”
His resentment returning, Jack glared at the Cubs.
“You guys think you’re so smart and know so much
about camping out and the like!” he scoffed. “Why,
you’re babes in the woods! If you weren’t so dumb, you
wouldn’t have to ask so many stupid questions. You’d
see for yourselves what’s going on around here.”
“Why, you conceited—” Red began, but Dan checked
him with a hard kick in the ankle.
“Maybe we are sort of dumb,” Brad said, falling in with
Jack’s mood. “You’re probably right, we don’t know
what’s going on around here. That’s because we’re not
on the scene much of the time. You’re roaming the](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-59-320.jpg)
![[159]
[160]
woods and the marsh every day. I suppose you’ve seen
things we haven’t.”
“You’re darn right I have,” Jack boasted. “I could tell
you something about that black dress, if I had a mind
to! What’s more, I could tell you about the money box
—”
The boy broke off, suddenly aware that he was talking
entirely too much.
“What about the money box?” Mr. Hatfield asked quietly.
Jack, however, started off through the woods.
“Wait!” Dan called after him.
Jack turned around, but his eyes were unfriendly and
defiant.
“You won’t get anything out of me!” he taunted the
Cubs. “I could tell you a lot if I wanted to. But I won’t!
I’m not forgetting that it was the Cubs who took me
back to the Child Study Institute!”](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-60-320.jpg)
![[161]
CHAPTER 16
Inside the Log
Jack Phillip’s hint that he was in possession of vital
information relative to the missing money box amazed
the Cubs.
Even Mr. Hatfield was so taken by surprise that for the
moment he made no attempt to detain the boy.
“Say, are we going to let him get away again?” Brad
demanded. “He knows what became of that money
box!”
“He took it himself, that’s why!” muttered Chips. “Who
does he think he is, anyhow? Someone that doesn’t
have to obey the law?”
“Jack does have a few things to explain,” Mr. Hatfield
said quietly. “Now, take it easy, boys. He’ll not elude us.”
“He’s heading for the road now!” Red said excitedly. “If
we don’t stop him quick, he’ll slip away and we may
never see him again!”
“We’ll head him off,” the Cub leader replied,
undisturbed. “Brad, you and Dan and Midge start](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-61-320.jpg)
![[162]
through the hollow which is shorter than the path he’s
taken. The rest of us will come up from the rear.”
“Sure!” Brad said eagerly. “We’ll get him!”
“Just circle in and don’t use any force. In fact, don’t try
to hold him until I get there. He has a rifle, you know. It
may or may not be loaded, but we’re taking no
chances.”
“We’ll be careful,” Brad promised, already starting off
with Midge and Dan.
At a fast lope, the three boys followed the low ground.
For a considerable distance they were unable to see the
boy they pursued.
However, as they came presently to a rise of ground,
they glimpsed him off to the right not far from the main
road.
“He’s taking it easy,” Brad said in relief. “I guess he
doesn’t suspect we’re following him.”
“Shall we show ourselves?” Dan demanded.
“No need to yet, Dan. The minute we do, he’ll either
defy us or start to run. We’ll just keep him in sight until
Mr. Hatfield catches up.”
“Sure, that’s what he told us to do,” Midge said
nervously. “No telling how the kid may react.”
Without glancing around, Jack made his way directly to
the road. Once he paused to stare at the crotch of a
tree which had been split by lightning.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-62-320.jpg)
![[163]
Another time, hearing the crackle of a stick, he looked
quickly over his shoulder. Brad, Dan and Midge froze in
their positions and the boy did not see them.
“He’s heading for the road all right,” Brad observed.
“We’ve got to beat him to it.”
Dropping back into the hollow, the three Cubs hastened
on. Presently, they emerged at a point where they had
calculated Jack would come out of the woods.
Nor were they mistaken. In a moment, before they fully
had caught their breath, they saw him coming.
Jack was whistling a slightly off-key tune. Seeing the
three boys in front of him, he broke off and stopped
dead in his tracks.
The moment was a tense one for the three Cubs. They
were relieved though that Jack made no attempt to
draw his rifle.
“What’s the idea?” he demanded, trying to shove past
them.
The Cubs stood their ground.
“Mr. Hatfield wants to talk to you,” Brad said pleasantly.
“You raised a few points.”
“You’ll learn nothing more from me!” Jack retorted. “I
told you that! Let me past!”
Brad, Dan and Midge refused to move. Jack glared at
them, and then whirled, evidently intending to run.
However, he found retreat also blocked.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-63-320.jpg)
![[164]
During the brief conversation, Mr. Hatfield, his son,
Fred, Chips, Red and Babe quietly had come up from
the rear.
“What’s the big idea?” Jack repeated furiously. “You got
nothing on me!”
At a signal from Mr. Hatfield, the Cubs closed about the
boy in a tight circle.
“Hand over the rifle, Jack,” the Cub leader ordered. “You
handle it very well for a boy of your age, but you
shouldn’t have taken it from Mrs. Jones without her
permission.”
“Aw, she never used it.”
“Nevertheless, it was her property. The rifle, Jack.”
The boy seemed on the verge of defying the Cub leader.
Then, he thought through the matter, and with a
gesture of contempt, extended the weapon.
“It ain’t loaded,” the boy muttered. “You got nothing to
worry about.”
Mr. Hatfield checked the rifle for himself, finding that
Jack had spoken the truth. Evidently he had used his
last shot on the rabbit.
“What d’you aim to do? Turn me over to the cops
again?”
“That depends on what you tell us, Jack. From the start,
we’ve tried to give you the benefit of every doubt. Your
remarks about the tin box, however, were disturbing.”](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-64-320.jpg)
![[165]
“I didn’t take the money!”
“No one has accused you, Jack. It’s clear though, that
you know plenty about the matter.”
“I read about it in the paper.”
“I think you know more than the facts you have read,
Jack. Why don’t you come clean?”
“You turned me in!”
“We’re law abiding citizens, Jack,” Mr. Hatfield argued.
“What else could we do?”
“I help only my friends.”
“We are your friends,” the Cub leader insisted. “At least
we want to be. Sit down, Jack, and let’s talk this over.”
Mr. Hatfield brushed off a hollow log which had fallen
near the fence, and made room for Jack. The other boys
gathered around close enough so the Institute lad could
not hope to make a break for freedom.
“Jack, can’t you realize that we’re trying to help, not
make things hard for you,” Mr. Hatfield attempted to
reason with him. “You must return to Mrs. Jones’ home.”
“I was going there anyhow,” the boy muttered, his gaze
on the ground.
“You weren’t running away again?”
“'Course not,” Jack said irritably. “I wouldn’t go away
and take her rifle. I’m not a thief. She’s been good to
me in her way—better than anyone else.”](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-65-320.jpg)
![[166]
“I’m glad to hear that!” Mr. Hatfield exclaimed. “I knew
you had good stuff if you’d just give it a chance to come
out. Now about the money box—”
“I don’t know anything about it.”
“But you hinted—”
“I was just blowing,” Jack said, avoiding Mr. Hatfield’s
direct gaze. “All I know is what I read in the
newspaper.”
The Cubs were disgusted. But Jack, they knew, did not
abide by their standards of honor and fair play.
“Let me go now,” Jack muttered, getting up from the
log. “You got no right to keep me.”
“Do we have your word that you’ll return to Mrs. Jones’
house?” the Cub leader asked.
“I told you I would, didn’t I?”
“I’ll accept your word, Jack. And here’s the rifle. When
you return it to Mrs. Jones, why not ask her if you may
borrow it now and then? She’d likely give her consent
and you wouldn’t feel low and sneaking about it.
Furthermore, in season you probably could help out by
bringing in game for the table.”
“Maybe she would let me take it,” Jack said. “Sure, I’ll
ask her next time. I promise.”
Mr. Hatfield smiled and reached out to shake the boy’s
hand.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-66-320.jpg)
![[167]
“Good luck, Jack,” he said. “You’ll do all right. I’m
confident of it. I—”
An odd expression came over the Cub leader’s face.
Without finishing what he had started to say, he
stooped down to examine one end of the hollow log.
The Cubs then saw what had attracted their leader’s
attention. A bit of water-soaked cloth protruded from
the end of the log.
“What’s this?” Mr. Hatfield murmured.
As the boys watched in amazement, he removed a
wadded-up garment. The Cub leader shook it out,
revealing a woman’s black dress trimmed in diamond-
shaped jet buttons.
“Why, that must be the costume stolen from Mrs. Jones’
place!” exclaimed Brad as Mr. Hatfield spread the
garment over the log.
“Sure, the same one maybe that was worn by the thief
who made off with the money box!” added Dan,
becoming highly excited.
Mr. Hatfield carefully examined the diamond-shaped
buttons.
“Aren’t they the same as the one police found in your
desk?” Dan demanded.
“They certainly look the same,” the Cub leader
admitted. “I wonder how this dress came to be in the
log?”](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-67-320.jpg)
![[168]
“Someone must have stuffed it in here just to be rid of
it,” Brad ventured.
His gaze fastened upon Jack Phillips. The boy leaned on
his rifle, staring at the dress with a fixed, almost frozen
expression.
Observing the odd look of his eyes, the Cubs could not
fail to wonder what he knew of the matter.
“Jack,” said Mr. Hatfield, without mincing words, “have
you ever seen this dress before?”
“Have I seen it?” the boy echoed indignantly.
“That’s what I asked, Jack.”
“No, I never saw the dress before!” the boy answered
sullenly. “What’s more I didn’t put it in this old log! I
had nothing to do with stealing your money box!”
“Finding this dress here gave me a bad moment,” Mr.
Hatfield said. “Frankly, it’s something of a shock.”
“Well, blame me! I always get accused of everything
whether I did it or not!”
“No one has accused you of anything, Jack. We only
want to get at the truth of the matter. I have a deep-
seated feeling that you might help us, if only you
would.”
Jack remained silent.
Mr. Hatfield examined the dress and then wrapped it
into a tight roll.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-68-320.jpg)
![[169]
[170]
“Jack, we’ll walk along with you to Mrs. Jones’ place,” he
said. “I think this is the dress that disappeared from her
shed. I want to find out for certain.”
“I didn’t take it,” Jack denied. “What would I want with
a woman’s dress? If you go back and tell the widow,
she’ll think I stole it! She’ll send me back to the
Institute!”
“Not if you tell a straight story, Jack,” Mr. Hatfield
reassured him. “Come along, boys. We’re wasting
valuable time.”
Jack did not openly defy Mr. Hatfield or the Cubs, but he
made it evident by glances he directed at them that he
resented their interference.
As the group approached the old farmhouse, Mrs. Jones
saw the boys from afar. She was waiting at the door
when they came up.
“Well, I see you caught the rascal!” she commented
grimly.
“We found him,” Mr. Hatfield corrected. “Jack wasn’t
running away though. He said he intended to come
back.”
“Jack, why do you do it?” the widow asked, taking the
rifle from him. “Haven’t I been good to you?”
“Yes’m,” the boy responded, his eyes on the ground.
“I’ll fix you some victuals. You must be hungry.”
“I’ve had enough to eat. I’m sorry about taking so much
from the refrigerator.”](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-69-320.jpg)
![[171]
The tight lines around Mrs. Jones’ mouth relaxed.
“There! I reckon boys are all alike,” she remarked. “I
had three of my own once. I never could break ’em of
taking cookies from the jar.”
The widow cordially invited the Cubs into the kitchen.
Mr. Hatfield declined the invitation for them.
“Mrs. Jones, here is something we wish to show you,”
he said, exposing the rolled-up black gown to her gaze.
“Did you ever see this dress before?”
“Land sakes! It’s the dress that disappeared from the
shed!”
“You’re certain it’s the same one?”
“Of course I’m certain. Didn’t I wear that dress for six
years? Where did you find it?”
“In a hollow log not far from here.”
“Well, of all places! How did it get there?”
“That’s what I’d like to know myself. Dan tells me that
someone in a black dress was seen leaving my place on
the day the money box disappeared.”
“A jet button exactly like those on the dress was found
by police in Mr. Hatfield’s study,” Brad contributed.
“My stars! Then you think the money was taken by
someone who wore my dress?”
“Naturally, one wonders,” Mr. Hatfield replied.
Mrs. Jones gazed searchingly at Jack.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-70-320.jpg)
![[172]
“I didn’t do it!” he said, almost fiercely. “Quit lookin’ at
me like that! I always get the blame for everything.”
“I’m sure Jack didn’t take the dress,” Mr. Hatfield
declared. “As I recall, Mrs. Jones, I believe you said it
disappeared some time ago.”
“That’s so! Before Jack came here! Land sakes, I guess
we get so in the habit of blaming a boy, that we don’t
give him the benefit of any doubt.”
In a gesture of kindness, she reached out and drew the
boy to her. He resisted, but as her arm remained firm,
finally allowed it to remain thrown around his shoulders.
“I’m fairly convinced Jack didn’t take the dress,” Mr.
Hatfield resumed. “Unfortunately, I’m afraid I can’t say I
think he isn’t hiding vital information. I believe Jack
knows more about the affair than he is willing to tell.”
Mrs. Jones’ arm fell from the boy’s shoulder. Sternly, she
regarded him.
“Jack, is that the truth?”
“Maybe!” The boy regarded her defiantly.
“Then you just tell Mr. Hatfield everything you know!”
“Wild horses can’t drag it from me! I’m no snitcher. I
don’t help anyone who made it hard for me!”
“You little ninny!” Mrs. Jones exclaimed, losing patience.
“I declare, I wonder if you have an ounce of sense. Now
march into the house.”
“Yes’m,” Jack muttered.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-71-320.jpg)
![[173]
“Everyone come in,” Mrs. Jones invited. “We’ll thrash
this out right here and now. If there’s one thing I can’t
stand it’s nonsense!”
The Cubs trooped into the warm kitchen, fairly
overflowing the tiny room. Mr. Hatfield, Babe, Chips and
Fred found chairs. Dan perched himself on the corner of
the wood box by the stove. The others stood.
“Jack, I’d try to switch a little sense into you, but I know
now it doesn’t do a mite of good,” Mrs. Jones sighed.
“Now what’s wrong with you anyhow?”
“Nothin’.”
“Then why don’t you speak up and tell Mr. Hatfield and
the Cubs what they want to know?”
“They turned me in!”
“I reckon it was mighty inconsiderate of ’em to give you
another chance,” the widow said, her brittle voice edged
with sarcasm. “You’ve had a hard lot here. I’ve kept you
chopping wood every day and helping with the
housework. At night you’ve had to do your lessons.”
“The work wasn’t so hard,” Jack muttered.
“You’ve been chained to the house—never could go
away—”
“Aw, quit rubbin’ it in,” Jack pleaded. “I’ve liked it here.
I’m willing to stay.”
The widow regarded him steadily.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-72-320.jpg)
![[174]
“You may be willing,” she said, “but I don’t want you
any more.”
Jack drew in his breath and for a moment could not
reply.
“You—you’re sending me back?” he finally stammered.
“Just as fast as I can send for Mr. Wentworth. I did the
best I could for you, Jack. I needed a boy I could
depend on that would help me with the work, and act
like my own son. Well, you let me down. So I’ll go on
living here alone.”
The words cut deep into Jack. “I’ll do better,” he
promised. “Please don’t send me back to the Institute.
I’ll cut all the wood you want me to—honest I will. I
won’t take things out of the ice box again or run off so
often. Only just once in a long while, when I get to
feeling tight and mean inside. And I’ll tell you ahead
that I’m going—I promise!”
“You’re promising a heap, Jack,” the widow returned
dryly. “Only trouble is, you’ve made a lot of ’em before
you never kept.”
“I never made any to you.”
“Well, that’s a fact. You have kept your word such as
you’ve given.”
“Then let me have another chance. Just one more!”
“Not unless you tell the truth about that black dress of
mine.”](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-73-320.jpg)
![[175]
“I never took it!” Jack said desperately. “Believe me, I
never did!”
“But you know how it came to be in the hollow log?”
“Not for sure,” Jack hedged.
“You could make a pretty shrewd guess.”
“Maybe.”
“Then suppose you come clean and tell the Cubs
everything you know.”
“Help ’em after they turned me in?”
“Did they really do you such a bad turn seeing to it that
you were sent out here to my place?”
“No’m,” Jack murmured. “I’m all mixed up. I don’t know
what to do—”
“I want you to stay with me always, Jack. You’re a fine
boy.”
“You mean that? You ain’t just handing me a line so’s I’ll
do what you want?”
“I really mean it, Jack. You should know by this time
that when I give my word I keep it.”
Jack debated with himself only a moment longer. Then
he arrived at his decision.
“I want to stay here,” he said earnestly. “I’ll do whatever
you tell me to—and I ain’t crossin’ my fingers when I
say it, either! You can switch me whenever you want to
and I won’t try to take the switch away from you.”](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-74-320.jpg)
![[176]
[177]
“Now that’s right considerate of you, Jack,” Mrs. Jones
smiled. “We’ll get along fine from now on. And we won’t
need that switch again.”
“I’ll fill the woodbox,” Jack offered eagerly. “You’re most
out of kindling.”
Mrs. Jones hauled him up short. “That job can wait,
Jack. You got something else more important to do.”
“Tell us everything you know about the tin box,” Mr.
Hatfield urged. “You’ll be doing the Cubs a real service,
Jack. You see, not only myself but the entire
organization has been under a cloud since the money
disappeared.”
“I ain’t sure what became of it, but I may know,” Jack
admitted.
“Then suppose you tell us,” the Cub leader urged.
“I’ll show you instead,” Jack offered. “Follow me to the
woods, and you may see something kinda interesting!”](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-75-320.jpg)
![[178]
CHAPTER 17
Through the Window
Skirting the marsh, Jack led the Cubs deep into the
shadowy woods. Apparently he had gone that way
often, for he seldom hesitated in choosing the trail.
“Where do you think he’s taking us?” Dan speculated,
bringing up the rear with Brad.
“It has me guessing, Dan. He seems to know where’s
he’s going though. I have a hunch he may show us
something that will have an important bearing.”
After a brisk five-minute hike through the woods, Jack
abruptly halted.
“If you want to see anything, you got to be quiet from
here on,” he warned.
All conversation ceased. Still led by Jack, the Cubs
moved on at a slower pace. Carefully they trod, taking
care not to step on sticks or dry leaves.
Presently Jack again halted. This time he did not speak.
However, the Cubs, gathering close about, saw that
they had neared their destination.](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-76-320.jpg)
![[179]
Directly ahead, in a tiny clearing close to the stream,
stood a crude shack. Side walls were badly built from
odd-shaped lumber which the Cubs guessed had been
taken from near-by construction jobs.
The flat roof was made of tar paper. Some of it had torn
loose and flapped in the light breeze.
“You didn’t build the shack?” Mr. Hatfield whispered to
Jack. He had noted a tiny curl of smoke rising lazily
from a tin pipe cut through the roof.
Jack shook his head. Motioning for the Cubs to follow,
he moved in a little closer.
“Who lives there?” Brad whispered, impatient for
information.
“Wait,” Jack said. “We’ll get in close, and maybe you can
see for yourselves.”
“If we all move in, we’ll likely be seen,” Mr. Hatfield
insisted.
It was decided that Jack, Mr. Hatfield, Brad and Dan
should go on ahead, leaving the others in the shelter of
the trees.
Moving softly over the uneven ground, the trio crept
close to the shack. Keeping close to the wall, they
reached a broken pane of glass which served as the
only window.
Jack pressed his face against it and nodded in
satisfaction.
“He’s in there! Have a look!”](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-77-320.jpg)
![[180]
Jack moved back to allow Dan to take his place.
The boy peered into the dark interior of the shack. At
first he caught only an impression of an empty room
with an old box which served as a table.
Then gradually he made out a balsam-bough bed on the
floor, covered with an army blanket. Sprawled on the
bed, fully clothed was a man with a stubbly beard.
“It’s that same fellow who looked in the church
window!” Dan murmured, startled to recognize him.
“Careful, Dan!” Mr. Hatfield warned, for in his
excitement, the boy very nearly had spoken aloud. “Let
me have a look.”
Dan moved aside so that both the Cub leader and Brad
might peer at the stranger.
“It’s the same man all right,” Brad confirmed Dan’s
identification. “He’s dead to the world!”
Mr. Hatfield had turned to Jack. “This is all very
interesting,” he whispered. “But you promised to show
us something that might explain about the missing
money box.”
“I can’t show you while he’s in there. But he’s got it.”
“Not the money?”
“Sure.” Jack thoroughly enjoyed his knowledge.
“How do you know this, Jack? Did you see the box?”
“Right from this very window. I was wandering through
the woods late one afternoon when I came onto this](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-78-320.jpg)
![[181]
shack. I was curious, so I sneaked up and looked in.”
“And this same tramp was living in there?” Dan asked.
“When was that?”
“Oh, I didn’t find the shack until a couple of days ago. I
don’t know how long it’s been here.”
“Tell us about the money box,” Mr. Hatfield urged.
“Well, as I looked through the window, I saw that tramp
take it out from under his bed. While I watched, he
counted the money. I saw a lot of bills in neat stacks.”
“Jeepers!” Dan whispered. “It must be the money we
found in the church!”
“That hunk of baloney saw us through the window, and
probably found out that the box was taken to Mr.
Hatfield’s house,” Brad reasoned. “But how did he get it
from there?”
“Remember Mrs. Jones’ black dress!” Dan reminded
him.
“Sure, I get it. He must have stolen it from her place
and wore the garment when he slipped into the house.”
“That’s why the milkman reported seeing a woman
leave the place,” Dan nodded, peering again through
the window. “The dope still is sleeping hard.”
“After stealing the money, it’s odd he didn’t try to get
away from here,” Mr. Hatfield thought aloud. “Well, let’s
get back and report to the Cubs. It’s risky standing here
in the open.”](https://image.slidesharecdn.com/823083-250527050648-dd1cfde3/85/Vlsi-Circuits-For-Biomedical-Applications-1st-Edition-Krzysztof-Iniewski-79-320.jpg)
Vlsi Circuits For Biomedical Applications 1st Edition Krzysztof Iniewski
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- 9. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the U.S. Library of Congress. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library. ISBN 13: 978-1-59693-317-0 Cover design by Igor Valdman © 2008 ARTECH HOUSE, INC. 685 Canton Street Norwood, MA 02062 All rights reserved. Printed and bound in the United States of America. No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without permission in writing from the publisher. All terms mentioned in this book that are known to be trademarks or service marks have been appropriately capitalized. Artech House cannot attest to the accuracy of this information. Use of a term in this book should not be regarded as affecting the validity of any trademark or service mark. 10 9 8 7 6 5 4 3 2 1
- 10. Contents Preface xiii CHAPTER 1 Wireless Integrated Neurochemical and Neuropotential Sensing 1 1.1 Introduction 1 1.2 Neurochemical Sensing 1 1.2.1 A Review of Neurotransmitters 1 1.2.2 Electrochemical Analysis and Instrumentation 2 1.2.3 VLSI Multichannel Potentiostat 4 1.3 Neuropotential Sensing 6 1.3.1 Physiological Basis of EEG/ECoG 7 1.3.2 Interface Circuitry 8 1.4 RF Telemetry and Power Harvesting in Implanted Devices 10 1.4.1 Introduction to Inductive Coupling 11 1.4.2 Telemetry System Architecture and VLSI Design 13 1.4.3 Alternative Encoding and Transmission Schemes 17 1.5 Multimodal Electrical and Chemical Sensing 18 1.6 Summary 21 CHAPTER 2 Visual Cortical Neuroprosthesis: A System Approach 25 2.1 Introduction 25 2.2 System Architecture 27 2.3 Prosthesis Exterior Body Unit and Wireless Link 29 2.3.1 Neuromorphic Encoder 29 2.3.2 External Body Unit (Primary RF Unit) 32 2.3.3 RF Transformer 33 2.4 Body Implantable Unit 34 2.4.1 Bit Synchronizer 35 2.4.2 Reverse Link 36 2.4.3 Communication Protocol 37 2.5 System Prototype 37 2.6 Conclusions 40 v
- 11. CHAPTER 3 CMOS Circuits for Biomedical Implantable Devices 45 3.1 Introduction 45 3.2 Inductive Link to Deliver Power to Implants 46 3.2.1 Inductive Link Fundamentals 47 3.2.2 The Power Efficiency 48 3.2.3 Power Recovery and Voltage Regulation 50 3.3 High Data Rate Transmission Through Inductive Links 51 3.3.1 The BPSK Demodulator 53 3.3.2 The QPSK Demodulator 53 3.3.3 Validation of the Demodulator Architecture 56 3.4 Energy and Bandwidth Issues in Multi-Channel Biopotential Recording: Case Study 56 3.4.1 Micropower Low-Noise Bioamplifier 57 3.4.2 Real-Time Data Reduction and Compression 62 3.5 Summary 70 CHAPTER 4 Toward Self-Powered Sensors and Circuits for Biomechanical Implants 75 4.1 Introduction 75 4.2 Stress, Strain and Fatigue Prediction 76 4.3 In Vivo Strain Measurement and Motivation for Self-Powered Sensing 78 4.4 Fundamentals of Piezoelectric Transduction and Power Delivery 81 4.4.1 Piezoelectric Basics 81 4.4.2 Piezoelectric Modeling 83 4.4.3 Orthopaedic Applications 84 4.5 Sub-Microwatt Piezo-Powered VLSI Circuits 86 4.5.1 Floating-Gate Transistors 87 4.5.2 Floating-Gate Injector and Its Mathematical Model 90 4.5.3 CMOS Current References 94 4.5.4 Floating-Gate Current References 95 4.6 Design and Calibration of a Complete Floating-Gate Sensor Array 96 4.7 Conclusions 106 CHAPTER 5 CMOS Circuits for Wireless Medical Applications 111 5.1 Introduction 111 5.2 Spectrum Regulations for Medical Use 112 5.3 Integrated Receiver Architectures 113 5.4 Integrated Transmit Architectures 116 5.5 Radio Architecture Selection 118 5.6 System Budget Calculations 120 vi Contents
- 12. 5.7 Low Noise Amplifiers 121 5.8 Mixers 123 5.9 Polyphase Filter 125 5.10 Power Amplifier (PA) 126 5.11 Phase Locked Loop (PLL) 129 5.12 Conclusions 130 CHAPTER 6 Error-Correcting Codes for In Vivo RF Wireless Links 133 6.1 Introduction 133 6.2 In Vivo Human Body Channel Modeling 135 6.3 Power Dissipation Model for the RF Link with Error-Correcting Codes 137 6.4 Encoder Implementations and Power Savings for ECC 139 6.5 Conclusions 141 Acknowledgments 142 CHAPTER 7 Microneedles: A Solid-State Interface with the Human Body 145 7.1 Introduction 145 7.1.1 The Structure of the Skin 145 7.1.2 Categories of Microneedles and Probes 146 7.2 Fabrication Methods for Hollow Out-of-Plane Microneedles 148 7.2.1 Fabrication of Metal Microneedles 148 7.2.2 Fabrication of Silicon Microneedles 150 7.2.3 Fabrication of Polymer Microneedles 152 7.2.4 Further Fabrication Methods for Microneedles 156 7.3 Applications for Microneedles 156 7.3.1 Drug Delivery Through Microneedles 156 7.3.2 Biosensing Using Microneedles 158 7.4 Conclusions and Outlook 159 7.4.1 The State of the Art of Microneedle Research 159 7.4.2 Future Research Directions 159 CHAPTER 8 Integrated Circuits for Neural Interfacing: Neuroelectrical Recording 165 8.1 Introduction To Neural Recording 165 8.2 The Nature of Neural Signals 166 8.3 Neural Signal Amplification 168 8.3.1 Design Requirements 168 8.3.2 Circuit Architecture and Design Techniques 170 8.3.3 Noise vs. Layout Area 174 Contents vii
- 13. CHAPTER 9 Integrated Circuits for Neural Interfacing: Neurochemical Recording 179 9.1 Introduction to Neurochemical Recording 179 9.2 Chemical Monitoring 179 9.3 Sensor and Circuit Technologies 182 9.3.1 Neurochemical Sensing Probes 182 9.3.2 Neurochemical Sensing Interface Circuitry 183 CHAPTER 10 Integrated Circuits for Neural Interfacing: Neural Stimulation 191 10.1 Introduction to Neural Stimulation 191 10.2 Electrode Configuration and Tissue Volume Conductor 192 10.3 Electrode-Electrolyte Interface 193 10.4 Efficacy of Neural Stimulation 194 10.5 Stimulus Generator Architecture 198 10.6 Stimulation Front-End Circuits 199 CHAPTER 11 Circuits for Implantable Neural Recording and Stimulation 207 11.1 Introduction 207 11.2 Neurophysiology and the Action Potential 208 11.3 Electrodes 211 11.4 The Tripolar Cuff Model and Tripolar Amplifier Configurations 213 11.5 Bioamplifier Circuits 216 11.5.1 Clock-Based Techniques 216 11.5.2 Continuous-Time Techniques 219 11.6 Stimulation and Circuits 222 11.6.1 Modes of Stimulation 223 11.6.2 Types of Stimulation Waveforms 224 11.6.3 Stimulator Failure Protection Techniques 224 11.6.4 Stimulator Output Stage Configurations Utilizing Blocking Capacitors 227 11.6.5 Method to Reduce the Blocking Capacitor Value 228 11.6.6 Stimulator Current Generator Circuits 231 11.7 Conclusion 236 CHAPTER 12 Neuromimetic Integrated Circuits 241 12.1 Introduction and Application Domain 241 12.2 Neuron Models for Different Computation Levels of SNNs 242 12.2.1 Cell Level 242 12.2.2 Network Level 244 viii Contents
- 14. 12.3 State of the Art of Hardware-Based SNN 245 12.3.1 System Constraints and Computation Distribution 245 12.3.2 Existing Solutions 245 12.4 Criteria for Design Strategies of Neuromimetic ICs 247 12.4.1 Specific or Generic Mathematical Operators 247 12.4.2 Monosynapses or Multisynapses 248 12.4.3 IC Flexibility vs. Network Specifications 249 12.4.4 CMOS or BICMOS Technology 249 12.4.5 IP-Based Design 250 12.5 Neuromimetic ICs: Example of a Series of ASICs 252 12.5.1 A Subthreshold CMOS ASIC with Fixed Model Parameters 253 12.5.2 A BICMOS ASIC with Fixed Model Parameters 255 12.5.3 A BICMOS ASIC with Tunable Model Parameters 257 12.5.4 A BICMOS ASIC with Tunable Model Parameters and Multisynapses 259 12.6 Conclusion and Perspectives 262 CHAPTER 13 Circuits for Amperometric Electrochemical Sensors 265 13.1 Introduction 265 13.2 Electrochemical Sensors 265 13.2.1 Electrochemistry and the Electrode Process 265 13.2.2 Electrochemical Cell 267 13.2.3 Electrochemical Sensors 268 13.2.4 Three-Electrode Measurement System 269 13.3 Potentiostat 270 13.3.1 Potential Control Configurations 270 13.3.2 Current Measurement Approaches 272 13.4 Design Issues in Advanced CMOS Processes 275 13.4.1 Generating the Input Drive Voltage 277 13.5 Electrical Equivalent Circuit Modeling 279 13.5.1 Mathematical Circuit Modeling 279 13.5.2 Numerical Modeling 282 13.5 Conclusions 283 CHAPTER 14 ADC Circuits for Biomedical Applications 287 14.1 Introduction 287 14.2 A Second-Order ΣΔ Modulator (ΣΔM) with 80 dB SNDR and 83 dB DR Operating Down to 0.9 V 290 14.2.1 Introduction 290 14.2.2 Second-Order Sigma-Delta Architecture 290 14.2.3 Circuit Implementation 291 Contents ix
- 15. 14.2.4 Integrated Prototypes and Measured Results 296 14.3 A Calibration-Free Low-power and Low-Area 1.2 V 14-b Resolution and 80 kHz BW Two-Stage Algorithmic ADC 298 14.3.1 Introduction 298 14.3.2 Architecture Description and Timing 299 14.3.3 OTA and Comparators 302 14.3.4 The Mismatch-Insensitive Multiplying-DAC 303 14.3.5 Circuit Implementation and Simulation Results 305 14.4 Conclusions 306 CHAPTER 15 CMOS Circuit Design for Label-Free Medical Diagnostics 309 15.1 Introduction 309 15.1 Label-Free Molecular Detection with Electrochemical Capacitors 311 15.2.1 The Ideal-Capacitance Model 311 15.2.2 The Constant Phase Element Model 312 15.3 Electrodes Bio-Functionalization 313 15.3.1 DNA Probe Immobilization 313 15.3.2 DNA Target Hybridization 313 15.3.3 DNA Detection 314 15.4 Chip Design for Capacitance Measurements 314 15.4.1 Charge-Based Capacitance Measurements 314 15.4.2 Frequency to Capacitance Measurements Technique 318 15.5 Biochip Application to DNA 321 15.6 Discussion on Results: Analysis and Future Perspectives 324 15.6.1 Frequency Analysis of Electrical Measurements 324 15.6.2 Discussion on Biochemical Issues 325 15.7 Conclusions and Perspectives 326 CHAPTER 16 Silicon-Based Microfluidic Systems for Nucleic Acid Analysis 331 16.1 From Tubes to Chips 331 16.2 Nucleic Acid Extraction 332 16.3 Nucleic Acid Amplification 337 16.4 Nucleic Acid Detection 342 16.5 Discussion 348 16.6 Conclusion 349 CHAPTER 17 Architectural Optimizations for Digital Microfluidic Biochips 355 17.1 Introduction 355 17.2 Challenges 358 17.3 Testing and Reconfiguration Strategies 359 x Contents
- 16. 17.3.1 Testing Technique Based on Partitioning the Grid for Multiple Sources and Sinks 360 17.3.2 Reconfiguration Techniques for Fault Isolation 366 17.4 Scheduling and Resource Allocation for Pin-Constrained Biochips 369 17.4.1 EWOD Droplet Constraints 370 17.4.2 Additional Constraints Due to Cross Referencing 371 17.4.3 Optimization 373 17.5 Integrated Testing, Scheduling, and Resource Allocation 381 17.5.1 Off-Line Testing 381 17.5.2 On-Line Testing 383 17.5.3 Comparisons between Off-Line and On-Line Testing and Limitations 386 17.6 Future Trends 388 CHAPTER 18 Magnetotactic Bacteria as Functional Components in CMOS Microelectronic Systems 391 18.1 Introduction 391 18.2 Selecting the Type of Magnetotactic Bacteria 393 18.3 Bacterial Flagellated Nanomotors 394 18.4 Thrust Force and Terminal Velocity 395 18.5 Controlling the Swimming Direction of MTB Through Magnetotaxis 396 18.6 Controlling the Velocity of Bacterial Carriers by Modifying Viscosity and/or Temperature 402 18.7 Loading the Bacterial Carriers 404 18.8 Integrating MTB-Based Carrier Detection and Tracking in CMOS Circuits 406 18.9 Sensing Microelectrodes 409 18.10 Conclusion and Summary 414 List of Contributors 417 About the Editor 421 Index 423 Contents xi
- 18. Preface Human beings historically had a short life span caused by infectious diseases, wars, and natural disasters. Considerable progress in the last century was made due to improvements in hygiene, medicine and nutrition. The longer life span, however, has led to a dramatic increase in health costs and increased efforts to deal with chronic diseases. Further progress in medicine and the confinement of exploding healthcare costs can be only expected with advances in technology, electronics in particular. This book addresses the-state-of-the-art in integrated circuit design in the context of new technologies for biomedical applications. New and exciting opportunities in interfacing to the human body, medical implants, on-chip DNA analysis, and molecular biology are discussed. Emerging circuit design techniques, new materials, and innovative system approaches are explored. This book is a must for anyone seri- ous about electronic design for future technologies in the healthcare sector. Krzysztof (Kris) Iniewski Editor Vancouver, Canada June 2008 xiii
- 20. C H A P T E R 1 Wireless Integrated Neurochemical and Neuropotential Sensing Mohsen Mollazadeh, Kartikeya Murari, Christian Sauer, Nitish Thakor, Milutin Stanacevic, and Gert Cauwenberghs 1.1 Introduction Since the first use of multisite electroencephalography experiments by W. Grey Wal- ter in the 1930s [1], instrumentation for monitoring the physiological state of the brain has undergone tremendous advances. Instrumentation, electrodes, and analysis tools are continually being developed for the basic research as well as clinical applications. Today, among several other stellar achievements, it is possible to locate the focal origin of epilepsy with millimetric precision [2] and to control prosthetic devices with thought alone [3]. Most of the advances made both in the clinical and research fields have been based on analyzing the electrical activity of the brain. While the majority of information flow in the nervous system is electrical, neural processing and trans- mission also have a chemical aspect, mediated by neurotransmitters [4]. These crucial chemical messengers are an integral part of the nervous system. Deficits and imbal- ances in this system have serious neurological consequences such as Parkinson’s dis- ease, epilepsy, and so on. General principles in the design of VLSI circuits for biomedical instrumentation are extensively covered elsewhere in this edited volume. This chapter describes com- ponents for a multimodal wireless monitoring system and their integration into a system capable of recording and telemetering both electrical and neurochemical activity from multiple sites. 1.2 Neurochemical Sensing 1.2.1 A Review of Neurotransmitters Neurotransmitters are chemical messengers that conduct signals along the electrically insulating parts of nervous pathways [5] i.e. from one neuron to another, across gaps called synapses. Neurotransmitters may be either excitatory or inhibitory. That is, they may be of a type that fosters the initiation of a nerve impulse in the receiving neuron, or they may inhibit such an impulse. Within the cells, neurotransmitter molecules are packaged in vesicles and released by rapid exocytosis upon the arrival of a nerve impulse. Then they diffuse across the synaptic gap to bind neurotransmit- ter receptors or other ligand gated ion channels and stimulate or inhibit the firing of the postsynaptic neuron. Figure 1.1 shows a schematic of a synapse and shows how the electrical and chemical signals are related. 1
- 21. Neurotransmitters are crucial in ensuring the proper functioning of neural path- ways. Imbalances or malfunctions of neurotransmitters leads to several debilitating nervous disorders like Parkinson’s disease (due to lack of Dopamine [6]), bipolar depression (due to Serotonin imbalance [7]), and so on. The study of neurotransmit- ters is paramount in understanding the mechanism of neural pathways and diseases. Numerous methods like optical [8] (detecting light emitted by reactions), immuno- chemical [9] (detecting tracer compounds attached to neurotransmitters), liquid chromatography [10] (chemical separation of neurotransmitters) are used to detect and measure neurotransmitter activity. Electrochemical sensing of certain electroac- tive neurotransmitters (e.g. nitric oxide, dopamine) is very attractive due to high sensitivity, rapidity, and the ability to perform distributed measurements [11, 12]. 1.2.2 Electrochemical Analysis and Instrumentation Among the first applications of electrochemical analysis in biological sensing was the Clark oxygen sensor [13] patented in 1956. Electrochemical detection makes use of chemical redox reactions characterized by a transfer of electrons among the reacting species [14]. The reaction occurs at an electrode (the working electrode) surface that is held at some voltage (VREDOX) with respect to a reference electrode. Usually the sys- tem requires a third electrode, a counter electrode, to maintain the voltage difference in the presence of potential drops across the solution being monitored. The transferred electrons constitute a current that is proportional to the concentration of the species 2 Wireless Integrated Neurochemical and Neuropotential Sensing 1 2 3 4 5 6 Figure 1.1 Schematic of a synapse showing the interplay between electrical and chemical signaling. Electrical signals (1), cause neurotransmitter containing vesicles to dock (2) and release the messengers (3). These bind to receptors (4) that cause downstream changes (5) in ion channels that initiate electrical signaling.
- 22. being analyzed and the surface area of the electrode. Typically, in electrochemical analysis VREDOX is the independent variable and the redox current is measured. There are several modes of analyses [14], two of the major kinds being cyclic voltammetry and chronoamperometry. In the former, VREDOX is swept periodically over a given voltage interval while the redox current is measured. This results in an I-V signature of the species and is useful to obtain the potential difference at which the redox reac- tion is maximal. In chronoamperometry, or more simply, amperometry, current is measured as a function of time while the voltage difference is held constant at the opti- mal redox potential for maximum sensitivity obtained by cyclic voltammetry. This is the preferred mode of analysis for monitoring concentrations over time. The instrumentation used for electrochemical analysis is called a potentiostat. There are various methods used, namely voltametry amperometry, cyclic voltametry and amperometry. As the name signifies, in the voltametric method the VREDOX is held at a specified value (or waveform) while simultaneously measuring the current. The schematic of a basic potentiostat is shown in Figure 1.2. The reaction occurs between the working and the reference electrodes so the drop VRE-WE is the potential of interest. The output voltage of an opamp of gain A is given by: eOUT = A (e+ – e–) (1.1) Let VCELL denote the drop between the counter and working electrodes and the subscripts CE, WE and RE denote the counter working, and the reference electrodes, respectively. Since WE is grounded, single ended potentials are referred to it. Thus, e+ = VREDOX, e– = VRE-WE and eOUT = VCE-WE = VCELL. Substituting in Eqn. (1.1), VCELL = A (VREDOX – VRE-WE) (1.2) VRE-WE = VREDOX – VCELL / A (1.3) VRE-WE ~ VREDOX as A → ∞ (1.4) Thus, the potential drop between the reference and the working electrodes is forced to the preset value VREDOX, which appears across the reaction media, and the redox current being forced through the counter electrode is measured. 1.2 Neurochemical Sensing 3 Counter electrode + − + − Working electrode Reference electrode VREDOX Figure 1.2 Schematic of a basic three-terminal potentiostat for neurochemical sensing by measurement of neurotransmitter-activated redox currents.
- 23. 1.2.3 VLSI Multichannel Potentiostat Typically utilized benchtop potentiostats are used for electroanalytical biosensing that offer a poor match in terms of footprint, power consumption, sensitivity, paral- lel scalability, etc. CMOS VLSI potentiostats having one or a few channels have been developed in the past to record from electrochemical sensors [15–19]. Custom potentiostats for biosensing applications can be reduced to a two-terminal setup, with just the working and reference electrodes. The counter electrode is not needed since the expected redox currents are very small due to very low physiological con- centrations of analytes leading to negligible voltage drops across the solution. The system diagram for one channel of a multichannel VLSI potentiostat [20] is shown in Figure 1.3. Each channel essentially integrates the redox current for a certain conversion period and then digitizes the result. The circuit consists of a charge-mode incremen- tal delta-sigma analog-to-digital converter [21] with time-multiplexing digital gain modulation to extend the dynamic range that is needed for physiological monitor- ing. Figure 1.4 shows the implementation and the timing diagram for the front end. The redox current is integrated on the capacitor C1. C1 can be digitally set to 100fF or 1.1pF to accommodate a wide range of redox currents while maintaining reason- able conversion times. The capacitor C2 provides a low input impedance virtual ground node that is charged to VREDOX at the beginning of a conversion period. The single bit digital to analog converter is implemented using switched current sources realized by the transistors M1 and M2. These transistors are always turned on to decrease the effects of charge injection noise. Transistors M3, M4, M5, and M6 are minimum size switches that direct the reference current into either the integrator or the reference voltage source. The high gain amplifier is a cascoded inverter operat- ing in the subthreshold region. In a standard ΔΣ modulator, the reference current Iref is either added to or subtracted from the input current Iin and Iin ± Iref is integrated during the entire time. This forces the input and reference currents to be of the same magnitude. To allow for a wider range of input currents, a programmable gain of the input current is introduced by controlling the integration time of the reference cur- rent using a clock, dsClk, that has a programmable duty cycle. The reference current is integrated only when dsClk is high, while the input current is integrated through 4 Wireless Integrated Neurochemical and Neuropotential Sensing Counter Shifter From previous channel To next channel Time modulation feedback { 1,0} ± { 1} ± { ,0} ±INF 1 bit D/A dsClk + + − − VMID IIN Figure 1.3 Block diagram of a single channel of the VLSI potentiostat showing the ΔΣ modulator with the time modulation feedback. From [18] with permission, © IEEE 2007.
- 24. the whole period of the clock dsClk. The duty cycle of dsClk represents the gain of input current with respect to the reference current, enabling multiple scales with the same reference current. In Figure 1.4, this digital gain is represented by the logic gates feeding into the transistors M3 and M4 and M5 and M6. The integration period and the rate of sampling the input current are set by the clock intClk. The clocks intClk1 and intClk2 are non-overlapping clocks derived from intClk. intClk1e is a copy of intClk1 with the rising edge following and the falling edge preceding those of intClk1. The ratio of periods of the clocks dsClk and intClk represents the oversampling ratio (OSR) of the ΔΣ modulator. The decimator is implemented as the simple accumulate and dump circuit. The number of active (logic one) output bits of the ΔΣ modulator are counted using a 16-bit counter during one conversion period. The conversion period is programmable and is represented by the period of the pro- grammable clock intClk. At the end of each conversion cycle, the counter value is written to the output parallel-in serial-out shift register and a new conversion cycle begins with the cleared counter. The registers for all the channels are daisy-chained to obtain a single output bit stream. The register is read out asynchronously at any time during the conversion cycle. Figure 1.5 (a) shows the normalized digital outputs of the chip for input currents over six orders of magnitude. An illustrative example of the operation of one channel of the chip is shown in Figure 1.5 (b). In vitro monitoring of the neurotransmitter dopamine was performed using commercially 1.2 Neurochemical Sensing 5 Vp Vn D dsClk dsClk D VDD VREDOX Vmid Vint scale intClk 1 intClk 2 intClk 1e Iin VREDOX intClk 1e VREDOX Ca C1 −A Cb C1 C2 scale M1 M2 M3 M4 M5 M6 Figure 1.4 Implementation level diagram of the ΔΣ modulator. From [18] with permission, © IEEE 2007.
- 25. available electrochemical sensors (CF30-250, WPI, FL). Different concentrations of dopamine were added to a stirred phosphate buffered saline (PBS) solution and the chip output was observed after equilibrating. 1.3 Neuropotential Sensing While synapses transfer information locally in insulating gaps through electrochem- ical signaling as described in the previous section, information is transmitted over a longer range in the form of electrical action potentials traveling across the central nervous system. The electrical activity of the brain can be recorded from within the brain (spike or local field potentials), the surface of the brain (electrocorticogram or ECoG), or from the scalp (electroencephalogram or EEG). These signals encode infor- mation about the state of the brain which potentially can be extracted by signal pro- cessing methods. Thus, electrophysiology-based recording systems can be used to understand the mechanism underlying brain function as well as help paralyzed patients using a brain-computer interface [3]. Another common application area is 6 Wireless Integrated Neurochemical and Neuropotential Sensing −14 −12 −10 −8 −6 −5 −4 −3 −2 −1 0 log(Iin(A)) Normalized digital output Iin>0 Iin<0 Figure 1.5 Measured results from the potentiostat chip: (a) characterization data for input currents over six orders of magnitude and (b) calibration curve obtained for monitoring micromolar dopamine concentration in vitro. From [18] with permission, © IEEE 2007. (a) 0 5 10 15 20 0 100 200 300 400 Dopamine (mM) Current (pA) Measured Linear fit (b)
- 26. the recording of electrocorticograms in clinical investigation of neurological disorders such as epilepsy. However, due to the large-scale instrumentation needed to imple- ment EEG recording systems, these systems are currently mostly used inside hospi- tals. In all these applications, miniaturized recording systems are required so that they can be integrated into the daily lives for those who need it. In this section, we limit the discussion to ECoG and EEG signals, and present VLSI interface circuitry for these signals. Discussion on spike signals and associated circuitry can be found in the following chapters. 1.3.1 Physiological Basis of EEG/ECoG The brain is an extremely complex system, constantly carrying out information transfer and processing. The neural system works through the interactions between large assemblies of neurons in the central nervous system (CNS) and the peripheral neural system. At the cellular level, neurons transfer and process the information via the action potentials and neural firing (also known as spikes). When this kind of electrical activity transfers to the surface of the cortex and to the surface of the scalp, it can be recorded and processed to reveal the information contained in the signal. EEG/ECoG is the prevailing method to record the dynamics of the brain’s larger- scale electrical activity. While the origin of the activities recorded by scalp electrodes lie in the action potentials of cortical neurons, it is generally agreed that the ECoG and EEG signals are generated by excitatory postsynaptic potentials (EPSP) [22]. Yet, the origins of the generated rhythms in these electrical signals are not fully under- stood. The recorded electrical signals are the result of aggregation of excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) across large volumes of neural tissue that undergo volume conduction before they reach the cortical surface for ECoG recording, and that undergo further spatial signal smearing through bone and tissue conduction before reaching the scalp for EEG recording. The effect of volume conduction is that of both spatial and temporal filtering, removing high- frequency components and masking individual spike waveforms. The effect of this signal aggregation also reveals patterns of synchronous activ- ity that are indicative of mental states and hence are useful in brain state monitoring. Electrical recordings from the surface of the brain demonstrate continuous oscilla- tory activity with different intensities and patterns. The intensities of the ECoG can be as large as 10 mV while EEG recordings are usually around 100 mV due to the attenuation through the skull and skin. The frequencies of these waves range from 0.5 to 100 Hz and their character is highly dependent on the degree of activity in the cerebral cortex. For example, brain waves change markedly between states of wake- fulness and sleep. Depending on brain state and mental activity, brain waves could be irregular without discernable patterns, or distinct spatiotemporal patterns could manifest. Some of these are characteristics of specific abnormalities of the brain such as epilepsy. Others occur under normal healthy conditions and can be typically classified as belonging to one of four major wave groups, based on their frequency content: Delta (0.5–4 Hz), Theta (4–8 Hz), Alpha (8–12 Hz), Beta (12–30 Hz), and Gamma (>40 Hz) [23]. 1.3 Neuropotential Sensing 7
- 27. 1.3.2 Interface Circuitry EEG/ECoG signals have very low amplitudes in the mV voltage range that require amplification before any signal processing. The inputs to the amplifier can be con- nected in three different methods: between each two electrodes (bipolar), between one monopolar lead and a distant reference electrode (usually attached to one or both ear lobes), or between one electrode and the average of all. In the last method, the system reference is formed by connecting all scalp recording locations through equal high resistances to a common point [23]. The application requirements call for the following specifications on the instrumentation amplifier: low input-referred voltage noise (< 2 mVrms), low leakage current (< 1 pA), high common mode rejection ratio (CMRR > 80 dB), high input impedance (> 1 MΩ), high power supply rejection ratio (PSRR > 90 dB), and high iso- lation mode rejection ratio (IMRR > 120 dB). For digitized electrophysiology record- ing systems, control over quantization error in analog-to-digital conversion (ADC), sensitivity, and filter cutoff frequency should also be considered [24]. The amplified EEG/ECoG signals need to be filtered to remove noise and out- of-band frequency signals. EEG spectra typically span a 0–125 Hz signal band- width, whereas ECoG spectra extend to higher frequencies (500 Hz or larger) and require larger bandwidth filters. Routine EEG should be acquired at least at a sam- ple rate of 250 Hz, to accommodate the 0–125 Hz signal band. Higher sampling rates are often used to account for finite roll-off of anti-alias filtering and for improved noise suppression. Further filtering may be required to remove power line artifacts (50 or 60 Hz). Accounting for the different frequency bands of interest (Alpha, Beta, Gamma, Theta) in EEG, band selection filters are typically provided by the EEG recording system. While some systems include band-selection analog filters in the recording unit, others provide digital filtering in their accompanying utility software. In light of these considerations, we describe efficient VLSI implementation of EEG/ECoG electrophysiology recording systems for micropower implantable use. Figure 1.6 shows the functional block diagram for one channel of a multi-channel 8 Wireless Integrated Neurochemical and Neuropotential Sensing C1 C1 C2 C2 M1 M1 Vin+ Vin− vhpf vhpf Time modulation feedback Adaptive offset cancellation Counter Shifter From previous channel To next channel Continuous-time g − ΔΣ C m + + + − − − Figure 1.6 Block functional diagram for one channel of the biopotential sensing chip.
- 28. VLSI biopotential interface chip. Each channel integrates a dedicated ADC to relax the precision requirements on signal transmission over a wireless link and thus min- imize the net power consumption. The channel comprises a bandpass filtering ampli- fier, Gm-C incremental ΔΣ analog-to-digital converter, decimating counter, and daisy-chained parallel-to-serial output register. Amplifier The front-end amplifier used is a fully differential version of the design presented in [25]. The amplifier midband gain is set to 40 dB by ratio of capacitors (C1 = 20pF and C2 = 200fF). The PMOS transistors M1 and M2 provide large resistance in the GΩ range for sub-Hz cutoff highpass filtering and AC coupling of the input [25]. Transistor sizing of the fully differential, two-stage amplifier is optimized for low input-referred noise. The gate bias Vhpf controls the highpass cutoff frequency, rang- ing from 0.2 Hz to 95 Hz. The lowpass cutoff frequency ranges from 120 Hz to 8.2 kHz, and is gm1/2pACc set by the transconductance of the first stage gm1 propor- tional to bias current Ibiasp, midband gain of the amplifier A, and by the compensa- tion capacitance Cc between first and second stage [26]. Analog-to-Digital Converter The choice of ADC topology in the design is determined by several factors that include the nature of the signal and system level considerations in the interface. One could choose to provide a single ADC for the entire system, which requires multi- plexing the output of the amplifiers at high rate. This increases the power require- ments of the amplifier, which needs to drive a large load because of the high switching rate. A more energy-efficient alternative choice is to include one ADC per channel as shown in Figure 1.6. High efficiency requires the design of the ADC to be optimized for high density of integration, and for accuracy rather than speed in the conver- sion. Algorithmic and ΔΣ ADCs are suitable for this design, and offer a further advantage of adjustable resolution through global control of clocking waveforms. The functional diagram of a Gm-C incremental ΔΣ implementing variable-resolution ADC is shown also in Figure 1.6. The core of the ΔΣ ADC is identical to the one implemented in the potentiostat for neurochemical sensing presented in the previ- ous section [20], offering also the benefit of a digitally selectable gain using time- modulation feedback. A transconductance element, implemented with an nMOS differential pair OTA and current mirror, converts the differential output of the EEG preamplifier to a current Iin, which is continuously integrated by the ΔΣ input stage. The continuous integration in the Gm-C ΔΣ avoids the need for sampling and for anti-alias filtering. A second nMOS OTA provides an offset current Ioffset that adaptively compensates for OTA and current feedback mismatch in the ADC. The MSB from the decimator adjusts the direction of Ioffset through an integrator imple- mented by a charge pump, one update per conversion cycle. Larger or more frequent updates in Ioffset make it possible to further filter 1/f noise outside the signal band. The digital output of all the channels can then be decimated and shifted out in a daisy-chain fashion for a serial readout. To characterize the accuracy in the overall response including front-end ampli- fication/filtering and ADC quantization, Figure 1.7 shows the power spectrum of 1.3 Neuropotential Sensing 9
- 29. the recorded digital output with a 1mVpp 70 Hz sine wave presented to the front- end amplifier input. The data indicate a THD of 0.3%, and an input-referred noise of 3.7 mVrms over the 0.1 Hz to 1 kHz range. Lower quantization noise levels can be attained by a higher gain setting for smaller signal amplitudes. 1.4 RF Telemetry and Power Harvesting in Implanted Devices While the previous two sections describe the sensor interface circuitry for multi- modal sensing, telemetry of the recorded data as well as powering the VLSI interface circuitry is a major performance-limiting factor in implanted devices. Recording from unrestrained animals requires wireless, untethered operation. Batteries are not avail- able, since they increase the size of the device and limit implant locations. Energy harvesting makes use of the external environment as a source of energy (temperature, gradient, wind, etc.), but most of these factors are unavailable for powering an implantable system. Radio Frequency (RF) power harvesting through inductive cou- pling is an alternate solution to power the system. The same link can also be used to 10 Wireless Integrated Neurochemical and Neuropotential Sensing Figure 1.7 Normalized power spectrum of digital output for 1 mVpp 70 Hz sine input to the front-end amplifier. Vhpf = 3.3 V, Iamp = 12.2 mA, resolution = 10 bits, G = 4, fs = 4 MHz (1 kS/s).
- 30. transmit data to and from the implantable system. In this section, we will review the basics of power harvesting through magnetic coupling and give circuit designs for telemetry and powering in CMOS. 1.4.1 Introduction to Inductive Coupling The operational frequency of the telemetry system and its impact on tissue absorption in the body are important design considerations. The human body comprises differ- ent layers of tissue with variable conductivity and permeability. High-frequency energy is absorbed by the body while low-frequency energy is reflected [27]. In a frequency region between 1 and 20 MHz, maximum energy passes through the body. Therefore, the design of the telemetry system is constrained to operation frequencies in this range. As a special case of interest, assume an operation frequency of 4 MHz. The corresponding wavelength is 75 meters, precluding the use of antennas that require much larger apertures than practically possible in an implant. Power and information can however be transmitted through inductive coupling between two coils that are placed relatively close to one another. These coils can be sized signif- icantly smaller than the wavelength since transmission of data and power is mediated through coupling in magnetic field, rather than through electromagnetic radiation and wave propagation. In two inductively coupled coils, a current generated in the primary coil induces a current in the secondary coil, proportional to the first current. The proportion of power that is transferred is quantified by the coupling factor, k, which ranges between 0 and 1 (100%) depending on geometrical factors and material properties of the coupling medium (air, tissue, bone, hair, etc.). Typical coupling factors in trans- formers with optimized coupling are usually around 0.5 (50%), with parasitic cou- pling and absorption in surrounding media contributing to the power losses in transmission. For telemetric power and data transfer between implant and reader/ host coils, the coupling is relatively weak, resulting in much lower coupling factors. In order to understand the effect of design parameters on coupling efficiency in power transfer, we need to quantify the magnetic field strength induced and carried between the two coils. The magnetic field produced by a primary circular coil of radius R1 at distance x along the perpendicular axis is: where N is the number of windings, and I is the current supplied through the coil. For a secondary coil placed parallel to the primary coil and centered along the same axis at distance x, the induced current can be derived from estimating the magnetic flux through the secondary coil, resulting in an approximate expression for the cou- pling factor [28]: k R R R R R x = + 1 2 2 2 1 2 1 2 2 3 ( ) H NIR R x = + 1 2 1 2 2 3 2 ( ) 1.4 RF Telemetry and Power Harvesting in Implanted Devices 11
- 31. where R2 is the radius of the secondary coil. Maximizing the power transfer efficiency amounts directly to maximizing the coupling factor k. The optimal coil radius for the primary coil, maximizing k, is thus directly given by the distance between coils: R1 = x In an implantable system, the distance x between outside coil and implant is approximately 2.5 cm, which constrains the reader coil to a radius R1 = 2.5 cm. The coupling factor is further maximized by maximizing the radius R2 of the implant coil, subject to physical size constraints of the implant typically in the mm range. The weak inductive coupling results in relatively low coupling efficiency k, approxi- mately 5%. Figure 1.8 (a) shows a simplified circuit model of an inductively coupled system. The left side of this model represents the outside reader coil, while the right coil rep- resents the implanted system. We can model the inductive link as a weakly coupled transformer as shown in Figure 1.8 (b). The induced voltage across the load RL can be written as: Because of the low coupling efficiency (5%), very large values of V1 around 100 V are required to generate sufficiently large V2 for operating the implant circuits. A tuned LC circuit is required to generate such a large voltage from low source voltage at the generator; V1 = Q2Vdd/p. Hence for a Vdd of at most 5 V in submicron CMOS V V j L R R j C p L 2 1 2 1 1 1 = + + + ( )( ) ω ω 12 Wireless Integrated Neurochemical and Neuropotential Sensing Ideal 1:n i1 i2 k2 L2 (1 k − 2 )L2 (a) 1:n i1 low k R1 C1 RL u2 (b) 1:n i1 low k R1 C1 R L u2 R D Data (c) Figure 1.8 (a) Simplified model of the inductively coupled system. (b) Common model of a weakly coupled transformer. (c) System schematic with attached load modulation resistor and switch. The switch is controlled by the data sent through the system.
- 32. processes, Q should be around 100. This on the other hand limits the bandwidth of the system since wb = wc /Q, so for a center frequency of 4 MHz, the maximum bandwidth is 40 kHz. This is acceptable because of the slow sensing application targeted here. Also, note that the high voltage levels generated in the primary coil are safe for use and do not pose a danger to the subject or others handling the sys- tem because the high impedance of the high-Q telemetry system carries relatively lit- tle power. As presented, the coupling between coils provides for inductive power transfer from the reader coil to the implant coil. Different methods for data transmission from the interface circuitry at the implant to the reader coil are available. Here, we con- sider ohmic load modulation, using the same inductive link to transmit the acquired data upstream as used to transmit power downstream. Other methods such as capac- itive load modulation and active transmission can be used, although each has its own drawbacks. Data transmission using ohmic load modulation in an inductively coupled system is accomplished simply by changing the load resistance of the implant. Generally, this is achieved by switching a second resistor loading the implant coil, in addition to the resistive load of the implant interface circuits, as shown in Figure 1.8 (c). The switched insertion of the resistor changes the current in the implanted coil, which in turn changes the impedance and hence the current in the reader coil. This current is sensed using transimpedance circuits at the reader, and this simple ASK data transmission scheme is further decoded. 1.4.2 Telemetry System Architecture and VLSI Design The VLSI power harvesting and telemetry system at the minimum should include these subunits: rectifier, regulator, clock and data recovery, and data encoder. Figure 1.9 shows the block diagram of such a system. The transmitter coil can be driven by a high-efficiency class-E transmitter. A full wave rectifier followed by a low-pass circuit recovers a dc voltage. Figure 1.10 (a) shows an example of a rectifier circuit implemented in a AMI 0.5 mm CMOS process [29]. When voltage on side A of the coil is higher than that of side B, M2, and M3 are shut off while M1 and M4 are turned on. This ties the low voltage side of the coil to ground while passing the high voltage. The situation is reversed when B is higher than A. The use of pMOS transistors prevents latch-up inducing collector currents from occurring and removes the necessity of using additional components. This voltage is dependent on the load and not suitable for driving the active circuitry. A regulated supply voltage is required to ensure proper operation of the circuitry. Fig- ure 1.10 (b) shows an example circuit diagram of a regulator. The output voltage is stabilized proportional to voltage reference through a negative feedback. The ref- erence voltage can be generated from rectified voltage by a supply independent ref- erence circuit made out of CMOS devices only. Note that this topology requires a minimum current to be drawn from the output for proper operation of the circuitry. Since most implantable systems are mixed-signal systems, it is preferred to have two regulators on the chip to separate analog from digital supply and minimize the switch- ing noise in the analog part. 1.4 RF Telemetry and Power Harvesting in Implanted Devices 13
- 33. 14 Wireless Integrated Neurochemical and Neuropotential Sensing Data recovery Power transmitter Data recovery Data encoding Modulation Command generation Data Power Data Power supply Clock Control Clock recovery Rectification Voltage regulation Figure 1.9 Block diagram of the RF power harvesting and telemetry system. From [29] with permission, © IEEE 2005. Vrectified M1 M2 M4 Coil M3 B A C (a) (b) – + Vrectified Vref Vdd M1 C Figure 1.10 (a) Rectifier and (b) regulator circuit diagram. From [29] with permission, © IEEE 2005.
- 34. In order to test the coupling and determine the maximum power transfer, the transmitter and receiver coils were placed close together and moved apart. As shown in Figure 1.11, distances between 10 mm and 100 mm were tested. The chip was loaded such that it would produce 0.7 mA when the voltage was enough to operate the regulator. With this load the chip was able to provide the desired regulated volt- age with a distance of up to 3 cm between the two coils. The RMS voltage on the coil, the rectified voltage, and the regulated voltage were recorded. At low current draw the rectified voltage follows the coil RMS voltage fairly closely. The two val- ues diverge when more current is drawn from the regulator. When the rectified volt- age drops to the regulated value, the PMOS controlling current is completely on. This ties the regulated voltage to the rectified, while affecting the coil voltage slightly less. The next step is to recover the digital clock and commands from the induced signals. A square wave clock can be extracted from the sinusoidal signal by a chain of inverters. Slower clocks can also be obtained by dividing the main clock. Figure 1.12 shows the actual measurement of the above circuitry during operation. The largest voltage (Ch2) is the rectified voltage, followed by the regulated (Ch1) and than the reference (Ch3) voltages. The recovered 4 MHz clock (Ch4) is shown at the bottom of the trace. Data demodulation circuitry depends on the type of modulation implemented in the base station. For an ASK scheme, an envelope detector followed by an RC fil- ter is sufficient. Figure 1.13 shows a circuit diagram of such a circuitry. A filter cir- cuit (C1, R1) reduces the amplitude of this signal to workable levels. The envelope recovery is performed with 2 NMOS devices (M1, M2), a transconductance ampli- fier (I1), and several filter circuits (C2, R2, R3) [30]. These serve to remove the car- rier waveform and leave only the data signal. A high-pass filter (C3, R4) removes any 1.4 RF Telemetry and Power Harvesting in Implanted Devices 15 Coil voltage (RMS) Rectified voltage ( , dc) Vrectified Regulated voltage ( , dc) Vdd Distance (mm) Measured voltage (V) 0 1 2 3 4 5 6 7 20 30 40 50 60 70 80 90 100 Figure 1.11 Air coupling at different distances. From [29] with permission, © IEEE 2005.
- 35. DC component remaining in this signal and biases the voltage around a level for sub- sequent Schmitt triggering. The Schmitt trigger (I2) recovers the digital signal while suppressing noise present due to low signal amplitude or excessive noise on the enve- lope signal. A finite state machine at the next level decodes this data and determines the parameters for system operation (e.g. number of channels, channel selection, and A/D resolution). Data are accepted from the sensor in non-return to zero (NRZ) format. The data are encoded in a modified Miller encoding scheme. For every logical one in the NRZ data stream a pulse is generated. The pulse width is controlled by gating the 16 Wireless Integrated Neurochemical and Neuropotential Sensing Figure 1.13 Oscilloscope trace of the microchip analog waveforms. − + Vdd Vdd C1 R1 C2 R2 R3 C3 R4 M1 M2 I1 I2 Data out Signal in Vth Figure 1.12 Data recovery circuitry (ASK demodulation).
- 36. 1.4 RF Telemetry and Power Harvesting in Implanted Devices 17 input clock for ease of implementation. This clock could also be supplied by clocks internally generated on chip. This encoding format transmits two signal transitions for every “one” datum, and none for a “zero” datum. The transmission of the two- level NRZ signal is accomplished by turning on an NMOS transistor that connects a resistor between the coil and ground. This modulates the impedance of the coil, a change that can be read out on the transmission coil. With the Modified Miller encoding scheme, the active time of the switched resistor load is minimized, thus reducing the power consumption. This scheme is also more tolerant to noise. It does not depend on the duration of a high pulse, but rather the occurrence of such a pulse. 1.4.3 Alternative Encoding and Transmission Schemes Digitized data can also be transmitted via different modulation techniques for higher performance at the expense of higher complexity, where desired. As mentioned, one limitation of the simple scheme using the same coil both for power transmission as well as data telemetry, is the limited data bandwidth wb = wc/Q, which is 40 kbps in the design described. Higher rates can be achieved (where desired, e.g. for multi- channel ECoG measurement) by using a dedicated reader coil in addition to the power delivery coil at the receiver end. To achieve these higher data rates further requires implementation of alternative encoding schemes to the simple ASK scheme (switching a resistor on and off across the coil), again at the expense of increased complexity and power consumption. Improvements in either data rate or error rate can also be obtained by optimizing the decoder performance at the receiver, where power consumption and complexity are less noticeable as constraining factors. Alter- natives to the envelope detection scheme for ASK demodulation described above, such as synchronous detection, should be considered. To illustrate the effect of encoding and decoding strategy on the quality of data transmission in the above system, 10 seconds of data were sent and recorded at sev- eral data rates ranging from 1 to 10 kbps. The highest theoretical data rate possible on this link is 40 kbps, as primarily determined by the quality factor of the trans- mitter coil (with a carrier frequency of 4 MHz). This can be lowered at the cost of increased power to operate the system over the same distance. Figure 1.14 shows data recovered by the envelope detector after modified Miller encoding and transmis- sion at several data rates. At higher data transmission rates the signal is smaller and harder to detect. At the highest frequency (10 kbps) errors occur in both data formats (NRZ and modified Miller) with more errors in the NRZ data. This is likely due to the increased complexity of decoding such data. A more robust scheme of ASK demodulation is coherent demodulation. This requires a phase locked copy of the carrier signal that is multiplied with the received signal and low pass filtered to remove the carrier. In order to reduce complexity and making use of the fact that in the time domain, the square of a digital bitstream is equivalent to the bitstream itself, a coherent demodulator was implemented using a four quadrant Gilbert multiplier. The received signal was squared and then filtered with a low-pass filter at 400 kHz to extract the data from the carrier. The data rate of the system could be pushed to 20 kbps without errors for both NRZ and modi- fied Miller data using this demodulating scheme.
- 37. 1.5 Multimodal Electrical and Chemical Sensing Simultaneous detection and sensing of neurochemicals and electrophysiological field potentials are very useful when studying the interaction between the chemical synaptic and electrical neuronal activity, both in the healthy and the diseased brain. The capability to monitor the close interaction between electrical and chemical activ- ity in vivo is crucial, as in vitro experimentation is deficient in studying network aspects and environmental factors in awake and behaving animals. Implantable multi-channel instrumentation with this multi-model capability could provide impor- tant information regarding neurological conditions where there is an imbalance between the chemical and electrical activity as in epilepsy [31]. The previous three sections have described the individual VLSI components that when properly com- bined comprise a multimodal amperometric/voltametric sensing system. This sec- tion describes the combination of the three systems and the protocol under which they co-operate. Figure 1.15 shows the schematic diagram of the system in an implantable scenario [32]. The principle is to (a) have the power harvesting chip supply power and clocks to both the potentiostat and the EEG processor; and (b) utilize the telemetry link to 18 Wireless Integrated Neurochemical and Neuropotential Sensing 0 1 2 3 4 5 6 7 8 9 10 −40 −20 0 20 0 1 2 3 4 5 6 7 8 9 10 −20 −10 0 10 0 1 2 3 4 5 6 7 8 9 10 −10 0 10 0 1 2 3 4 5 6 7 8 9 10 0 500 1000 Bit number Amplitude (mV) Figure 1.14 Comparison of data envelopes at frequencies tested for the Miller encoded data stream ‘1 101 001 010’. From the top, data at 1 kbps, data at 5 kbps, data at 10 kbps, and the ideal output Miller encoded data.
- 38. transmit the digitized neurochemical and electrophysiological data to a base station. This involves transmitting two simultaneous data streams over a single link, requir- ing additional interface circuitry. The interface circuitry serves to interleave and buffer the two data streams, equalized for a constant data rate over the telemetry link. The bandwidth assignment takes into account the sampling requirements of both signals. Neurochemical changes are generally on a much slower time scale (on the order of several hundreds of milliseconds to seconds) than EEG signals (on the order of a few tens of milliseconds), and hence are assigned proportionally lower bandwidth in data transmission. The net bandwidth in the assignment is limited by that of the telemetry module, which utilizes the same link for power and data transmission. As described above, the constraint on telemetry bandwidth is the Q-factor of the coils used for transmission. A high Q-factor benefits range of transmission, but also curtails the bandwidth of the data transmission subsystem. Both the potentiostat and the EEG processor produce bit-serial output at variable rate and precision, as controlled by system clock, digital gain, and OSR, as described above. With a system clock of 2 MHz and a digital gain of 32, the potentiostat chip digitizes 16 channels of transduced neurotransmitter concentrations to 16 bits per sample at a sampling rate of 1Hz. The chip serially outputs the digitized data at a burst rate of Rrx = 64 kHz. For the EEG processor, a system clock of 4 MHz, a digi- tal gain of 4- and 12-bit digitization over 4 channels produces EEG data sampled at 250 Hz, and output serially at the same burst rate as the neurochemical data. To com- bine and equalize the two data streams compatible with the constant rate bit-serial transmission by the telemetry system, the digital data from both sources is multi- plexed and written in a buffer memory. Read and write operations are performed asynchronously for uninterrupted continuous data transfer. An example recording illustrating the operation of the multimodal neurosensing system is shown in Figure 1.16. Real-time neurochemical data was obtained in vitro by monitoring the solution of phosphate buffered saline to which dopamine was added at timed intervals. The system shown in Figure 1.15 was set up with the power 1.5 Multimodal Electrical and Chemical Sensing 19 Potentiostat data sampled at FS pot ( ) Field potential data sampled at FS fp ( ) Power/ clocks Power at 4 MHz LSK modulated transmission at RTX Power/ clocks S fp ( ) Data at at R F RX Data at at R F RX S pot ( ) Logic and FIFO Figure 1.15 System diagram of the wireless multimodal recording system including micrographs of the constituent chips.
- 39. 20 Wireless Integrated Neurochemical and Neuropotential Sensing (a) 0 125 250 375 500 625 750 875 1000 −1 −0.5 0 0.5 1 1.5 Time (ms) Normalized FP Received Original (b) (c) −20 0 20 40 60 Current (nA) 0 100 Time(s) 200 300 400 500 Figure 1.16 (a) Scope plot showing the timing scheme. The top trace shows potentiostat data bursts. Lower trace shows the transmission of the multiplexed potentiostat and field potential data. (b) Original and demultiplexed field potential (FP) data shown for a 1-second window. (c) Demultiplexed output of one potentiostat channel showing response to the addition of the neurotransmitter dopamine to the test solution. harvesting chip supplying the power and system clock to the potentiostat. Discrete logic was used to implement the interface and memory. This was powered independ- ently. The received data were demodulated using a coherent detector, read into a computer using a DAQ card and demultiplexed. Figure 1.16 (b) shows the original and received electrophysiological data. Figure 1.16 (c) shows the received data from the simultaneous in vitro neurochemical monitoring.
- 40. 1.6 Summary In this chapter we framed the challenges inherent in wireless monitoring of multi- modal electrochemical neural activity, and presented a design methodology for an integrated solution capable of recording and telemetering both electrical and neu- rochemical activity from multiple sites. The following observations summarize the message of this chapter: 1. Wireless monitoring of in vivo neural activity using implanted passive telemetry poses stringent constraints on the available power for sensor acquisition, signal processing, and transmission of recorded neural activity. Without on-chip signal compression, signal bandwidth scales with available power. Transmitted power scales approximately inversely with the square of the distance between implant and reader, and also depends on coil geom- etry and coding/decoding schemes. Larger peak activity (but same average sustained activity) can be supported by including a rechargeable battery with the implant. 2. Both electrical (neuropotential) and chemical (neurotransmitter) activity are simultaneously monitored by combining voltage and current measure- ment with properly designed electrodes and properly controlled biasing and waveform generation. Redox currents in cyclic voltametry using a potentio- stat register concentrations of cation-sensitive neurotransmitters selected by electrode coating and further identified by redox potential. Scalp and intracranial electrical recording identify EEG and ECoG neuropotentials at various spatial and temporal scales, from single-neuron spikes in extra- cellular electrode recording to brain waves extending across the cerebral cortex. Simultaneous monitoring of these signals at various spatial and tem- poral scales are important in detection of pathological neural/brain states such as epilepsy and in the study of Alzheimer’s and other neurodegenera- tive diseases. 3. A mixed-signal VLSI circuit methodology, with analog front-end acquisi- tion, amplification and filtering, and with digital bit-serial coding of the quantized signals, offers low noise acquisition, high fidelity transmission, and low power operation. By multiplexing and interleaving of bit-serial data streams, the available wireless transmission bandwidth can be traded between a lower number of higher bandwidth signals (such as ECoG), or a larger number of lower bandwidth signals (such as low-frequency EEG, or distributed neurochemical activity). References [1] P. F. Bladin, “W. Grey Walter, pioneer in the electroencephalogram, robortics, cybernet- ics, artificial intelligence,” Journal of Clinical Neuroscience, vol. 13, pp. 170–177, 2006. [2] C. Plummer, A. S. Harvey, and M. Cook, “EEG source localization in focal epilepsy: Where are we now?,” Epilepsia, 2007. 1.6 Summary 21
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- 42. [25] R. Harrison and C. Charles, “A low-power low-noise CMOS amplifier for neural record- ing applications,” IEEE Journal of Solid-State Circuits, vol. 38, pp. 958–965, 2003. [26] D. A. Johns, Analog integrated circuit design: John Wiley & Sons, 1997. [27] P. Vaillancourt, A. Djemouai, J. Harvey, and M. Sawan, “EM radiation behavior upon biological tissues in a radio-frequency power transfer link for a cortical implant,” in IEEE Eng. in Medicine & Biology, 1997, pp. 2499–2503. [28] K. Finkenzeller, RFID Handbook. London, U.K.: Wiley, 2003. [29] C. Sauer, M. Stanacevic, G. Cauwenberghs, and N. V. Thakor, “Power harvesting and telemetry in CMOS for implanted devices,” IEEE Trans. Circuits and Systems I: Funda- mental theory and applications, vol. 52, pp. 2605–2613, 2005. [30] D. Su and W. McFarland, “An IC for linearizing RF power amplifiers using envelope elim- ination and restoration,” IEEE Journal of Solid-State Circuits, vol. 33, pp. 2252–2258, 1998. [31] I. Fried, C. L. Wilson, N. T. Maidment, J. J. Engel, E. Behnke, T. A. Fields, K. A. MacDon- ald, J. W. Morrow, and L. Ackerson, “Cerebral microdialysis combined with single-neuron and electroencephalographic recording in neurosurgical patients. Technical note,” Journal of Neurosurgery, vol. 91, pp. 697–705, 1999. [32] M. Mollazadeh, K. Murari, C. Sauer, M. Stanacevic, N. V. Thakor, and G. Cauwenberghs, “Wireless integrated voltametric and amperometric biosensing,” in Life Science Systems and Applications Workshop, Bethesda, MD, 2006. 1.6 Summary 23
- 44. C H A P T E R 2 Visual Cortical Neuroprosthesis: A System Approach Moisés Piedade, José Gerald, Leonel Sousa, and Gonçalo Tavares 2.1 Introduction In the last few years there has been a huge effort to develop implantable integrated stimulators for biomedical applications. Most of these stimulators are in the area of muscular stimulation (for instance, for heart or limb diseases) [1–5] and in the area of cortical or nerve stimulations (e.g., for blind/partially blind people or hear- ing diseases) [6–12]. In all these stimulators, information has to be coded in a format somewhat similar to the way stimulation is performed prior to the development of each of the particular diseases. Moreover, with the exception of a few applications (e.g., pacemakers), long-time performance of the implanted stimulator implies the power to be provided by the outside unit. It avoids future operations to replace old batteries, reduces the risk of infections and therefore improves the patient health level. This poses the need for wireless remote delivery of power and data [10–12]. Microelectronic prostheses that interact with the remaining healthy retina have been developed to restore some vision to those who suffer from eye diseases, such as Retinitis Pigmentosa. This type of prosthesis can use sub-retinal devices [13] (to replace the photoreceptors) or more complex epiretinal devices [14] (for capturing and processing images that are transmitted to the ganglion cells through an electrode array) but requires that output neurons of the eye and the optical nerves are in a healthy state. When this is not the case, these microelectronic prostheses are not useful and the stimulation has to be performed in the primary visual cortex, directly to the neurons in higher visual regions of the brain. This is a challenge, because visual information has to be encoded in a format somewhat similar to the way stimulation was done prior to the development of total blindness. It is expected that neurons will adapt to the stimulus in a way that a blind individual will be able to extract from it information on the physical world [15]. Brindley [16] and Dobelle [17] showed that simultaneous stimulation of multiple electrodes allowed blind volunteers to recognize simple patterns. This research, how- ever, also showed that a cortical prosthesis based on a relatively large number of superficial implanted electrodes requires high currents to produce phosphenes (more than 1 mA), which leads to problems such as epileptic seizures. To avoid this, deep intracortical neuro-stimulation should be used, exciting the neurons at a depth 25
- 45. between 1 mm and 2 mm, which corresponds to the cortical layers 4 (namely, Ca and Cb), where signals from the Lateral Geniculate Nucleus (LGN) arrive. This chapter presents a cortical visual neuroprosthesis for profoundly blind peo- ple which has been developed within the scope of the CORTIVIS project and sup- ported by the European Commission [18] and by the Portuguese Foundation for Science and Technology (FCT) [19]. Figure 2.1 illustrates the basic components of our Cortical Visual Neuroprosthe- sis approach. The whole system uses a bioinspired visual processing front-end, the Neuromorphic Encoder, which generates the electrical signals that are transferred to inside the skull through a RF link, for stimulating an array of penetrating electrodes implanted into the primary visual cortex. Power to operate the stimulating circuitry is also provided from the outside through the RF link. This visual neuroprosthesis is expected to recreate a limited, but useful visual sense in blind individuals, by apply- ing the electrical signals up to 1024 microelectrodes. In what concerns the neuro- morphic encoder, the simplest models assume that the neural coding can be reduced to predicting the firing rate as a function of the sensory stimulus. This assumption may be justified in certain brain areas, e.g. deep in the cortex [20]. On the other hand, neurons in the early visual system, for example from the retina to the LGN, can deliver reproducible spike trains, whose trial-to-trial variability is clearly lower than the one predicted from the simple firing rate approach [21]. To predict individual spikes, spike patterns with higher timing accuracy and also to account for the sto- chastic variability of these responses other approaches have to be considered. A first experimental work comparing the performance of these models has been recently published [22]. The wireless radio frequency (RF) link must provide both power and bidirec- tional data transmission between the outside and the implant. While the visual neu- roprosthesis requires a few tenths of milliwatts of power, the actual power provided from the outside must be somewhat higher, in order to account for the coupling 26 Visual Cortical Neuroprosthesis: A System Approach Digital Camera Neuromorphic Encoder Power Data Secondary coil Electrode Stimulator RF link Primary coil Figure 2.1 Cortical visual neuroprosthesis concept. From [37] with permission, © IEEE 2005.
- 46. losses. The most common solutions proposed in literature for the RF link are Ampli- tude Shift Keying (FSK) modulation [23–26], FSK [23, 27] and Binary Phase Shift Keying (BPSK) modulation [23, 28]. The ASK signal is usually demodulated in a noncoherent fashion, using a very simple receiver. However, the performance of the ASK receiver is highly dependent on the amplitude of the received signal, which is unknown and depends on the relative position between the implant and the outside unit. Therefore, an ASK solution requires high-efficient gain-monitoring and level- controlling devices. This is not the case with either FSK or BPSK, which are constant amplitude modulations. Within reasonable limits, the FSK and BPSK receivers are insensitive to the amplitude of the received signal, making these circuits more robust with respect to the high variability of the RF channel. Demodulation of FSK and BPSK is usually done coherently, thus requiring more complex and power- consuming receivers. After careful analysis of the different modulation characteristics, FSK was cho- sen as the modulation to use in the forward link. For monitoring purposes a reverse data link has also been implemented. It uses BPSK, which is implemented with a very simple transmitter. BPSK was not selected for the forward link because the receiver (which is based on a Costas Loop demodulator) is more complex than the FSK receiver. This chapter is organized as follows. In Section 2.2 the main components of the system are specified and an architecture is proposed to fulfill those specifications. Section 2.3 presents the prosthesis external body (primary) unit, which includes the neuromorphic encoder and the wireless communication link. Section 2.4 presents some circuits of the body implantable (secondary) unit. Experimental results of the system prototype are reported in Section 2.5. Section 2.6 concludes the chapter and summarizes the main results achieved. 2.2 System Architecture The system architecture of the proposed visual neuroprosthesis is represented in Fig- ure 2.2. It is physically divided in two units: a primary unit located outside the body and a secondary unit consisting of an implant located inside the body. The units are connected by means of a low-coupling two-coil transformer, which establishes a magnetic RF link between the two devices. The purpose of this RF link is twofold: (1) to remotely power the secondary unit, a mandatory requirement to avoid the use of batteries in the implant and (2) to allow bidirectional data communication between the units. The primary unit interfaces with a miniature digital video camera 2.2 System Architecture 27 Early layers Forward transmitter Neuromorphic pulse order Control Backward receiver Camera Neuromorphic coder Primary unit Secondary unit RF link Forward receiver Backward transmitter Electrodes stimulator and sensing Figure 2.2 Prosthesis system architecture. From [37] with permission, © IEEE 2005.
- 47. and with a personal computer (PC) used for system configuration, patient visual training, and prosthesis performance analysis purposes. The Neuromorphic Encoder translates the visual signal captured in the miniature digital camera into a sequence of electrical pulses, a spike train, capable of being recognized by the brain. It is composed of two main modules connected in series. The Early Layers are responsible for processing the visual signal and for its conversion into a spike rate. This rate is then taken as input by the Neuromorphic Pulse Coding module and is translated into the actual spike events by using a simplified version of the integrate-and-fire spiking neuron [29]. The access to the RF link is then arbi- trated by the latest module using a First-In First-Out (FIFO) buffer to store the events until the link is able to send more spike events. In the visual neuroprosthesis presented in this chapter, the Neuromorphic Encoder is required to process visual images at a rate of 30 frames per second (fps), generating spikes at a rate up to 100 Hz and stim- ulating a number of microelectrodes equivalent to an array with up to 32 × 32. The Forward Transmitter receives the multiplexed spike data from the Neuro- morphic Pulse Coding in a synchronous serial bit stream format at a rate of ¶b = 1 Mbps. This data is modulated using FSK modulation with a center frequency of ¶c = 10 MHz and a frequency deviation D¶ = ±323 kHz. On the secondary unit, power is extracted from the received signal by a power supply generator circuit (considered to be part of the Forward Receiver in Figure 2.2) which will be described later in Section 2.4. Because the integrity of brain tissue does not allow the use of high-power circuitry, the secondary unit is required to operate with only tenth’s of milliwatts of remotely delivered power. The spike data is recovered by the Forward Receiver, which consists of a FSK demodulator, bit synchronizer, and frame disas- sembly circuit. The recovered data and clock are then forwarded to the microelec- trodes stimulator circuit. To accomplish implant monitoring (e.g. electrode impedance measurement and calibration) a reverse data link has been developed. In the secondary unit, mainte- nance data is modulated and transmitted using BPSK at a data rate of ¶b = 156.25 kbps using low amplitude (≈1 V) and a carrier frequency ¶c = 5 MHz. The main objective of the Electrode Stimulators and Sensing module is to stimulate the primary visual cortex and to measure the connectivity between the electrodes and cortex. Extensive experiments have shown that in order to safely induce phosphenes a cur- rent of 20mA is required. Electrode sensing is achieved by injecting a fixed current value to a microelectrode and then measuring the induced voltage value. This allows for measuring the connectivity between the microelectrode and the visual cortex cells. The Electrode Stimulators and Sensing module is composed of a set of Digital to Analog Converters (DACs) [30], which are used to stimulate up to 32 × 32 micro- electrodes in the visual cortex with the spike events received from the Neuromorphic Encoder. Each DAC has a current-steering type architecture, using scaled currents added at an output node, in order to ensure the desired linear DAC operation. The main difference with respect to the common current-steering DAC is that it allows for the removal of the charge from the brain: it can inject current (positive sign) or remove current (negative sign) from the electrode. The DAC reference current is around 29mA and the overall power consumption for stimulating and sensing the 1024 electrodes is expected to be under 50 mW. The amplitude and duration of the 28 Visual Cortical Neuroprosthesis: A System Approach
- 48. stimulus is pre-recorded in dedicated registers on the Electrodes Stimulator and Sensing module, which can be accessed by means of the RF link for both reading and writing. The overall system is presently under development in VLSI technology. The Elec- trode Stimulator and Sensing block is to be implemented in a modular way in AMS CMOS 0.35mm technology: each module (except for the power supply generator) drives a 100-microelectrode array, which will be attached directly to the VLSI chip (flip chip technology) [30]. The Forward and backward emitters and receivers are also being developed using AMS CMOS 0.35mm technology. Moreover, in order to evaluate the circuit requirements when implementing the in-deep sub-micron tech- nology, the Neuromorphic Encoder is now being synthesized using the UMC 0.13mm CMOS technology process [31]. The UMC L130E SG-HS 1P8M process is a single poly, 8 metal layer with an operating voltage of 1.2 V. However, to rapidly prove the concepts involved in the RF link, a scaled- frequency prototype operating 10 times slower was built using conventional inte- grated circuits and discrete components: the forward data rate is 100 kbps with a carrier frequency of 1 MHz; the backward data rate is 15.625 kbps with a carrier fre- quency of 500 kHz. Also a neuromorphic encoder was developed using FPGA tech- nology. The visual neuroprothesis system was planned to support the driving of 1024 electrodes. However, the stimulator chip that is being developed will be flipped directly over the back of one microelectrodes array (100 microelectrodes). 2.3 Prosthesis Exterior Body Unit and Wireless Link 2.3.1 Neuromorphic Encoder The block diagram of the Neuromorphic Encoder in Figure 2.3 includes the spatio- temporal receptive fields of the retina ganglion cells. The neuromorphic encoder is organized in three main blocks: (1) Early Layers that perform both spatial and tem- poral processing of the visual signal, (2) Neuromorphic Pulse Coder, responsible for converting the pre-processed visual information to a sequence of pulses that can be interpreted by the brain, and (3) Spike Multiplexing that applies Address Event Rep- resentation (AER) [32] to convey information about the pulses through a serial link, without timestamps, to the microelectrode stimulator. The Neuromorphic Encoder translates a visual stimulus s(r,t) described by the intensity of each of the three basic (R)ed, (G)reen and (B)lue color components, as a function of space r = [x y]T and time t, into a sequence of pulses. This encoder was designed to allow a blind individual to recognize patterns up to 32 × 32 points, corresponding to 1024 microelectrodes. 2.3 Prosthesis Exterior Body Unit and Wireless Link 29 Digital camera Early layers Neuromorphic pulse coding Spike multiplexing Serial link Bio-inspired processing module of the artificial retina Figure 2.3 Neuromorphic encoder.
- 49. 2.3.1.1 Early Layers The Early Layers block represented in Figure 2.4 is responsible for spatio-temporal filtering. This block is an extension to the chromatic domain, by considering inde- pendent filters for each basic color component. The first filtering element of the Early Layers is an edge detector implemented by a two-dimensional Difference-of- Gaussians (DOG) per color channel (see Figure 2.4). As it is well known, DOG func- tions can be used for edge detection when the gains of the two Gaussians have opposite signs and different standard deviations. The output of the edge detection modules, corresponding to the different color components, are integrated by applying the desired relative weights (* represents the convolution operator): (2.1) The m(r,t) signal is then convolved with the impulse response of a first order high- pass filter hHP with the pole at –a rad/s to perform motion detection. The resulting activation function u(r,t) = m(r,t)*hHP(r,t) is then modulated by the Contrast Gain Controller (CGC) that models the strong modulation effect exerted by stimulus contrast. The CGC non-linear approach is also used in order to model the motion anticipation effect [33]: the CGC output w(r,t) is convolved with the impulse response of a lowpass temporal filter hLP with a single pole at –g rad/s; the resulting signal v(r,t) = y(r,t)*hLP(r,t) is then processed by the non-linear function: (2.2) before being applied to modulate the amplitude of the CGC input signal (H(◊) rep- resents the Heaviside step function). Finally, the last processing step of the Early Lay- ers block is a rectifier operation represented in Figure 2.4. It yields the firing rate ¶(r,t) of the ganglion cells response to the input stimuli: ¶(r,t) = Ψ ◊ H(y(r,t) + q) ◊[y(r,t) + q] (2.3) where Ψ and q define the scale and baseline values of the firing rate. The bilinear approximation was used in order to implement the temporal fil- ters, resulting in first-order Infinite Impulse Response (IIR) digital filters. Also, to reduce the amount of memory needed, the temporal filters were implemented in a transposed form where the output is calculated by adding the input x[n] to a stored value l[n] that is computed in the previous cycle. The diagram of the visual encoder computational architecture is depicted in Fig- ure 2.5 (the notation x[q,n] stands for the discrete space/time equivalent of the sig- nal x(r,t)). Folding techniques were applied to the architecture directly derived from the Signal Flow Graph (SFG), in order to comply with restrictions, such as low power consumption and area circuit. The complete Early Layers circuit was folded 1024 times and the firing rate for each microelectrode is computed in series. Moreover, g v r t v r t H v r t ( , ) = 1 1 ( , ) ( , ) 4 ( ) + ⋅ ( ) ⎡ ⎣ ⎤ ⎦ m r t s r t i R G B i i i ( , )= ( , )* = , , ∑ ( ) α DOG 30 Visual Cortical Neuroprosthesis: A System Approach
- 50. assuming a Gaussian kernel of 7 ¥ 7, edge detection requires a total of 98 multipli- cations and 98 additions. The folding technique has been applied to the Gaussian filters by a factor equal to the kernel size. Therefore, as shown in Figure 2.5, only one multiply-and-accumulate (MAC) unit is needed to compute each Gaussian filter. The non-linear processing modules, namely the non-linear function applied in the CGC and the rectifier, were implemented by means of a look-up table and a com- parator, respectively. 2.3.1.2 Neuromorphic Pulse Coding The Neuromorphic Pulse Coding (NPC) block performs two operations: (1) con- verts the continuous time-varying representation of the signal produced in the Early Layers of the retina into a neural pulse representation, and (2) arbitrates the access of the generated spikes to the serial bus at the input of the Forward Emitter. We have considered a representation in which the signal provides information only when a new pulse begins. This block then stores the information about spike events and sends them to the implant at the maximum rate allowed by the channel. The model adopted for the Spike Generation is a simplified version of an integrate-and-fire spiking neu- ron [29]: the neuron accumulates input values from the respective receptive field (out- put firing rate determined by the Early Layers) until it reaches a threshold f; then it fires a pulse and discharges the accumulated value; a leakage term is included to force the accumulated value to diminish for low or null input values. 2.3 Prosthesis Exterior Body Unit and Wireless Link 31 Visual Stimulus High Pass Non Linear Low Pass Contrast Gain Control Space filtering Time filtering DOG m(r,t) u(r,t) g(r,t) v(r,t) y(r,t) f(r,t) αB αG αR Figure 2.4 Early layers block. Figure 2.5 Diagram of the visual encoder computational architecture. From [37] with permission, © IEEE 2005.
- 51. The implementation of the pulse generation circuit operates in a two-stage pipeline: in the first stage the input firing rate is added to the accumulated value; in the second stage, the leakage value is subtracted and, if the result is higher than a threshold f, a pulse is fired and the accumulator returns to zero. This block is con- nected to the Early Layers by means of a dual-port memory bank, as represented in Figure 2.5. This allows for the Early Layers block to write data onto one port while the Neuromorphic Pulse Coding block reads data from the other port. The Spike Multiplexing block uses a first-in first-out (FIFO) buffer to arbitrate the access of the spikes generated in the Spike Generating block to the RF link (see Figure 2.5). When a spike is generated, it is stored in the buffer until the channel becomes avail- able. The buffer allows the system to respond well to short periods in which the spike rate is high. 2.3.1.3 Model Evaluation To evaluate the performance of this model, an experimental analysis was made by using real experimental data from salamander retinal responses [22]. This work has compared the performance of the presented model to the one of a recently pub- lished stochastic model, which attempts to predict the temporal occurrence of spikes and spike patterns [20]. Model performance was assessed based on the mean squared error (MSE) of the firing rate. The MSE for the firing rate of the presented model is about 1.11, while for the stochastic model is 1.13 [22]. These results show that by using a deterministic model, it is possible to approximate the real neural retina response with an accuracy similar to that of the stochastic model. However, deterministic models are less demanding in terms of computational capacity, thus making them a more suitable approach for developing a visual neuroprosthesis. 2.3.2 External Body Unit (Primary RF Unit) The RF link block diagram is shown in Figure 2.6. The RF link circuitry can be divided into three parts: the primary RF unit (located outside the body), the second- ary RF unit (located inside the body, but not necessarily inside the head), and the transformer, which establishes inductive coupling between the two previously men- tioned units (one coil is external and another is internal). A bidirectional RF link is established: the primary (forward) link and the secondary (backward) link. In the 32 Visual Cortical Neuroprosthesis: A System Approach Figure 2.6 RF link circuitry diagram. From [37] with permission, © IEEE 2005.
- 52. main link, the data bit rate is up to 1 Mbps, and a power/data signal is transmitted using FSK modulation with a 10 MHz frequency carrier. In the secondary link, the data bit rate is up to 156.25 kbps (which is enough for maintenance and initial con- figuration purposes) and data is transmitted using BPSK modulation with a 5 MHz frequency carrier. Initially, in order to implement a very compact low-power wireless communication link, some integrated circuits were designed using AMS CMOS 0.8 mm technology. However, new circuits currently in development use AMS CMOS 0.35 mm technology [30]. The transmitter is shown in Figure 2.7(a) and includes a FSK modulator (imple- mented by means of a counter, driven by an oscillator ¶CLK) and a signal amplifier. The data is modulated with frequencies (data bit ‘0’) and (data bit ‘1’). This signal feeds a class E switching-mode tuned power amplifier, as shown in Fig- ure 2.7(a), whose configuration was chosen to optimize the efficiency at the trans- mitter [34]. The primary RF unit receiver is a Costas-Loop [23] BPSK coherent demodulator. This receiver is placed after a 6th order bandpass filter and a RF Automatic Gain Control (AGC) circuit. 2.3.3 RF Transformer The coupling transformer is of major importance in the RF link since it has a strong influence on the overall performance of the internal unit. Its design must allow proper system operation regardless of the intercoil distance (within reasonable limits, say 1 to 2 cm). It must be noticed that the real transformer, at the desired operation fre- quencies, exhibits a distributed parameter behavior (as represented in the model in fCLK 15 fCLK 16 2.3 Prosthesis Exterior Body Unit and Wireless Link 33 (b) (a) Figure 2.7 RF unit: (a) transmitter; (b) coupling transformer model. From [37] with permission, © IEEE 2005.
- 53. Figure 2.7(b)). Due to the coil separation, there is a high magnetic flux dispersion (not connected with the secondary coil), which makes the coupling weak and a signif- icant amount of energy is lost. To maximize the efficiency, it is important to perform an appropriate design of the coils. In order to compensate the equivalent inductances relative to the primary and secondary magnetic flux dispersions, capacitors C1 and C2 are connected in series with the respective coil, resonating at the 10 MHz car- rier frequency. As a consequence, the RF transformer behaves like a double-tuned bandpass filter. Both circular coils have a cylindrical powerful neodymium magnet inside, used for coil self-attracting and fixing purposes [35, 36]. Experiments confirmed the importance of taking into account the distributed capacitance and the skin effect in the transformer. In fact, the absence of an iron core makes it impossible to have a strong magnetic coupling: the measured coupling fac- tor was 0.3 for an intercoil distance of 1 cm using carefully designed planar coils of Litz wire with about 3 cm of diameter. Figure 2.8 illustrates the transmission of an unmodulated carrier before and after the transformer for a 16 times lower frequency- scaled prototype. As one can see, some attenuation is introduced by the transformer, as the result of the very weak magnetic coupling. Nevertheless, the signal delivered to the receiver still allows satisfactory power and data recovery. 2.4 Body Implantable Unit The body implantable unit is shown in Figure 2.6 and includes the secondary RF unit. The power recovery circuit is comprised of a half-wave rectifier, protection cir- cuits, and a series regulator. It recovers the required power from the received signal, with a power efficiency of about 30% for an intercoil distance of 1 cm. The binary FSK Demodulator is based on a Phase Locked Loop (PLL) circuit and a comparator and provides a stream of Non-Return-to-Zero (NRZ) data. This bit stream is fed to the Bit Synchronizer, which provides a synchronized clock and retimed data to the Data Processing and Control unit. The Data Processing and Control unit performs bit and frame synchronization and frame disassembly. Finally, the formatted data is forwarded to the Electrode Stimulator and Sensing block. 34 Visual Cortical Neuroprosthesis: A System Approach Figure 2.8 Transmitted signal for an intercoil distance of 1 cm: (a) before the transformer; (b) after the transformer. (a) (b)
- 54. The master clock recovery task is accomplished in the Master Clock Recovery block (see Figure 2.6), which is implemented by means of a narrow-band PLL designed to produce a 10 MHz reference clock from the received signal. 2.4.1 Bit Synchronizer The signal received from the primary system is used to extract the system master clock, with frequency where Mbit/s is the raw bit- rate and N = 10 (corresponding to a RF carrier frequency of 10 MHz). Since the mas- ter clock is derived from the transmitted signal, it follows that the data stream is fre- quency synchronized (i.e., frequency-locked) with the master clock; a data clock could therefore be obtained by suitable division (by a factor N) of ¶CLK. This is because there is no frequency offset between transmitter and receiver in this system. However, the (lead or lag) phase difference between the positive-going clock transi- tions and the optimum time epoch for sampling the data, which is the middle time of the data bit, is unknown and varies significantly. In fact, even small disturbances in the relative position of both coils lead to important phase offsets which have to be properly estimated and compensated by the bit synchronizer. The task performed by the bit synchronizer is thus of fundamental importance to establish a proper time ref- erence in the receiver. The positive-going transitions in this reference clock should accurately signal the optimum instants to sample and detect the received data bits. The bit synchronizer and its interaction with the receiver is shown in Figure 2.9(a). The bit synchronizer has a feed-forward structure that avoids the annoying loop behavior known as hang-up [36,37]. This phenomenon is typical in feedback syn- chronizer operation and manifests itself has an unacceptably long synchronizer acqui- sition period, compromising receiver operation. Suppose that we have a binary counter being driven with the master clock frequency ¶CLK; then, it will advance N states within each bit period. If, at time t0, the counter is in state i then, at time , it will have advanced and be in state (on aver- age); this is the time epoch at which the recovered clock should have a positive tran- sition, marking the middle of the data bit. This reasoning justifies the bit synchronizer block diagram represented in Figure 2.9(b): the positive-going transition on the raw, unsynchronized data signal latches the counter state i, at reference time t0, and marks the start of a bit. When the counter reaches the state , then and the comparator will signal this event to the final processing block, which in turn samples the raw data and produces a clock pulse synchronized with the master clock. Note that after a positive-going transition of the raw data, the synchronizer operates in a free-running fashion. The phase offset, which eventually accumulates after this event is corrected when the next positive-going tran- sition occurs. Thus the raw data should not have long sequences of equal bits. This is guaranteed by the use of self-synchronizing scrambler and descrambler circuits. The developed bit synchronizer has the following desirable properties, namely (1) due to S N N i N N i + ⎛ ⎝ ⎜ ⎞ ⎠ ⎟ + 2 =( ) = mod mod S i N = 2 + i N + 2 T T f R N b CLK CLK b 2 = 2 = 2 × ⋅ t Tb 0 2 + R T b b = 1 =1 f T N R CLK CLK b = 1 = × 2.4 Body Implantable Unit 35
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- 56. [155] “You’re using Mrs. Jones’ rifle!” Red accused, refusing to be checked. “Why not? She never touched it. A rifle was meant to be used not left to rust.” “Mrs. Jones thinks you’ve been taking things from her.” “That’s a black lie!” “Cord wood for instance.” “What would I steal wood for, when I have to keep chopping more to replace it?” Jack shouted furiously. “Use your head, or haven’t you got one?” At this point, Mr. Hatfield warned Red to drop the argument. “Sorry,” the boy mumbled. Jack however, was not willing to allow the matter to pass. “What else did Mrs. Jones say I took?” he demanded. “I don’t recall that she accused you,” Mr. Hatfield answered. “She merely was disturbed because of the wood and a few other trifles.” “Someone else had been taking that wood. What else did she say was missing?” “A black dress,” Dan answered. “One with jet buttons.” “Of course we don’t think you’d have any use for a woman’s dress,” Dan went on, watching the boy intently.
- 57. [156] Jack made no reply. After a long while, he said: “I didn’t take that dress. If I were a mind to though, I could tell you something about it!” “Suppose you do just that,” Mr. Hatfield encouraged him. Jack smiled in a superior, insolent way. The wave of friendliness which he briefly had displayed, now was entirely gone. Once more he seemed the arrogant, defiant runaway. “Why should I tell you anything?” “Because it’s the right thing to do, Jack. We have a particular reason for being interested in what became of that black silk dress.” “You’ve accused me of being a thief.” “No, Jack. The Cubs were a bit abrupt perhaps. They believe in being square and honest. Naturally it made them sore to think you might have taken the biscuits.” “I told you, I don’t know nothin’ about ’em!” “And we accept your word, Jack.” “Then you said I took wood and the Widow’s black dress.” “No, Jack, we merely were telling you what she said. Unfortunately, when one has a past record, it’s apt to plague one unjustly.” “Sure, I’m a bad kid! I know!” Jack said, his eyes flashing. “Okay! Send me to an industrial school! But try
- 58. [157] to keep me there! I’ll run away a thousand times!” “You’re talking wildly now, Jack. No one wants to send you away. Quite the opposite. Mrs. Jones likes you. She’s willing to overlook a lot to keep you with her.” “She’s been pretty decent to me,” Jack admitted, softening again. “I did take food out of the ice box without asking her. Not very much though. Just enough so I could get along out here in the woods.” “She’s worried about you now, Jack. She asked me to send you home, if I saw you.” “Oh, I’ll go,” Jack sighed. “I’d intended to anyhow as soon as this rabbit finishes cooking. It’s done now, I guess.” The boy removed the rabbit from the spit, and salted it, using a shaker which the Cubs were certain had come from Mrs. Jones’ home. “Have some?” he invited the Cubs. They declined. “Well, I’m hungry,” Jack announced. Dismembering the rabbit, he gnawed at the tough meat. Now and then as he ate, he glanced at the Cubs. Having finished his meal, he put out the fire and cleaned away the debris. The Cubs noted that he was efficient at it, leaving not a spark which could set off a forest fire.
- 59. [158] “I’ll go back to Mrs. Jones’ place now and chop more wood,” Jack said finally, picking up the rifle. “I’ll chop and chop until my hands bleed!” “I hardly think Mrs. Jones will require that,” Mr. Hatfield said, smiling. “By the way, Jack, who do you figure may be taking that wood?” The boy gave him a quick, knowing look. “I don’t stay up nights watching!” “But you have a fairly good idea where it is going?” “Maybe. Maybe not.” “Jack, if you wanted to cooperate, you could be very helpful.” “I mind my own business. That’s more than I can say about some folks.” His resentment returning, Jack glared at the Cubs. “You guys think you’re so smart and know so much about camping out and the like!” he scoffed. “Why, you’re babes in the woods! If you weren’t so dumb, you wouldn’t have to ask so many stupid questions. You’d see for yourselves what’s going on around here.” “Why, you conceited—” Red began, but Dan checked him with a hard kick in the ankle. “Maybe we are sort of dumb,” Brad said, falling in with Jack’s mood. “You’re probably right, we don’t know what’s going on around here. That’s because we’re not on the scene much of the time. You’re roaming the
- 60. [159] [160] woods and the marsh every day. I suppose you’ve seen things we haven’t.” “You’re darn right I have,” Jack boasted. “I could tell you something about that black dress, if I had a mind to! What’s more, I could tell you about the money box —” The boy broke off, suddenly aware that he was talking entirely too much. “What about the money box?” Mr. Hatfield asked quietly. Jack, however, started off through the woods. “Wait!” Dan called after him. Jack turned around, but his eyes were unfriendly and defiant. “You won’t get anything out of me!” he taunted the Cubs. “I could tell you a lot if I wanted to. But I won’t! I’m not forgetting that it was the Cubs who took me back to the Child Study Institute!”
- 61. [161] CHAPTER 16 Inside the Log Jack Phillip’s hint that he was in possession of vital information relative to the missing money box amazed the Cubs. Even Mr. Hatfield was so taken by surprise that for the moment he made no attempt to detain the boy. “Say, are we going to let him get away again?” Brad demanded. “He knows what became of that money box!” “He took it himself, that’s why!” muttered Chips. “Who does he think he is, anyhow? Someone that doesn’t have to obey the law?” “Jack does have a few things to explain,” Mr. Hatfield said quietly. “Now, take it easy, boys. He’ll not elude us.” “He’s heading for the road now!” Red said excitedly. “If we don’t stop him quick, he’ll slip away and we may never see him again!” “We’ll head him off,” the Cub leader replied, undisturbed. “Brad, you and Dan and Midge start
- 62. [162] through the hollow which is shorter than the path he’s taken. The rest of us will come up from the rear.” “Sure!” Brad said eagerly. “We’ll get him!” “Just circle in and don’t use any force. In fact, don’t try to hold him until I get there. He has a rifle, you know. It may or may not be loaded, but we’re taking no chances.” “We’ll be careful,” Brad promised, already starting off with Midge and Dan. At a fast lope, the three boys followed the low ground. For a considerable distance they were unable to see the boy they pursued. However, as they came presently to a rise of ground, they glimpsed him off to the right not far from the main road. “He’s taking it easy,” Brad said in relief. “I guess he doesn’t suspect we’re following him.” “Shall we show ourselves?” Dan demanded. “No need to yet, Dan. The minute we do, he’ll either defy us or start to run. We’ll just keep him in sight until Mr. Hatfield catches up.” “Sure, that’s what he told us to do,” Midge said nervously. “No telling how the kid may react.” Without glancing around, Jack made his way directly to the road. Once he paused to stare at the crotch of a tree which had been split by lightning.
- 63. [163] Another time, hearing the crackle of a stick, he looked quickly over his shoulder. Brad, Dan and Midge froze in their positions and the boy did not see them. “He’s heading for the road all right,” Brad observed. “We’ve got to beat him to it.” Dropping back into the hollow, the three Cubs hastened on. Presently, they emerged at a point where they had calculated Jack would come out of the woods. Nor were they mistaken. In a moment, before they fully had caught their breath, they saw him coming. Jack was whistling a slightly off-key tune. Seeing the three boys in front of him, he broke off and stopped dead in his tracks. The moment was a tense one for the three Cubs. They were relieved though that Jack made no attempt to draw his rifle. “What’s the idea?” he demanded, trying to shove past them. The Cubs stood their ground. “Mr. Hatfield wants to talk to you,” Brad said pleasantly. “You raised a few points.” “You’ll learn nothing more from me!” Jack retorted. “I told you that! Let me past!” Brad, Dan and Midge refused to move. Jack glared at them, and then whirled, evidently intending to run. However, he found retreat also blocked.
- 64. [164] During the brief conversation, Mr. Hatfield, his son, Fred, Chips, Red and Babe quietly had come up from the rear. “What’s the big idea?” Jack repeated furiously. “You got nothing on me!” At a signal from Mr. Hatfield, the Cubs closed about the boy in a tight circle. “Hand over the rifle, Jack,” the Cub leader ordered. “You handle it very well for a boy of your age, but you shouldn’t have taken it from Mrs. Jones without her permission.” “Aw, she never used it.” “Nevertheless, it was her property. The rifle, Jack.” The boy seemed on the verge of defying the Cub leader. Then, he thought through the matter, and with a gesture of contempt, extended the weapon. “It ain’t loaded,” the boy muttered. “You got nothing to worry about.” Mr. Hatfield checked the rifle for himself, finding that Jack had spoken the truth. Evidently he had used his last shot on the rabbit. “What d’you aim to do? Turn me over to the cops again?” “That depends on what you tell us, Jack. From the start, we’ve tried to give you the benefit of every doubt. Your remarks about the tin box, however, were disturbing.”
- 65. [165] “I didn’t take the money!” “No one has accused you, Jack. It’s clear though, that you know plenty about the matter.” “I read about it in the paper.” “I think you know more than the facts you have read, Jack. Why don’t you come clean?” “You turned me in!” “We’re law abiding citizens, Jack,” Mr. Hatfield argued. “What else could we do?” “I help only my friends.” “We are your friends,” the Cub leader insisted. “At least we want to be. Sit down, Jack, and let’s talk this over.” Mr. Hatfield brushed off a hollow log which had fallen near the fence, and made room for Jack. The other boys gathered around close enough so the Institute lad could not hope to make a break for freedom. “Jack, can’t you realize that we’re trying to help, not make things hard for you,” Mr. Hatfield attempted to reason with him. “You must return to Mrs. Jones’ home.” “I was going there anyhow,” the boy muttered, his gaze on the ground. “You weren’t running away again?” “'Course not,” Jack said irritably. “I wouldn’t go away and take her rifle. I’m not a thief. She’s been good to me in her way—better than anyone else.”
- 66. [166] “I’m glad to hear that!” Mr. Hatfield exclaimed. “I knew you had good stuff if you’d just give it a chance to come out. Now about the money box—” “I don’t know anything about it.” “But you hinted—” “I was just blowing,” Jack said, avoiding Mr. Hatfield’s direct gaze. “All I know is what I read in the newspaper.” The Cubs were disgusted. But Jack, they knew, did not abide by their standards of honor and fair play. “Let me go now,” Jack muttered, getting up from the log. “You got no right to keep me.” “Do we have your word that you’ll return to Mrs. Jones’ house?” the Cub leader asked. “I told you I would, didn’t I?” “I’ll accept your word, Jack. And here’s the rifle. When you return it to Mrs. Jones, why not ask her if you may borrow it now and then? She’d likely give her consent and you wouldn’t feel low and sneaking about it. Furthermore, in season you probably could help out by bringing in game for the table.” “Maybe she would let me take it,” Jack said. “Sure, I’ll ask her next time. I promise.” Mr. Hatfield smiled and reached out to shake the boy’s hand.
- 67. [167] “Good luck, Jack,” he said. “You’ll do all right. I’m confident of it. I—” An odd expression came over the Cub leader’s face. Without finishing what he had started to say, he stooped down to examine one end of the hollow log. The Cubs then saw what had attracted their leader’s attention. A bit of water-soaked cloth protruded from the end of the log. “What’s this?” Mr. Hatfield murmured. As the boys watched in amazement, he removed a wadded-up garment. The Cub leader shook it out, revealing a woman’s black dress trimmed in diamond- shaped jet buttons. “Why, that must be the costume stolen from Mrs. Jones’ place!” exclaimed Brad as Mr. Hatfield spread the garment over the log. “Sure, the same one maybe that was worn by the thief who made off with the money box!” added Dan, becoming highly excited. Mr. Hatfield carefully examined the diamond-shaped buttons. “Aren’t they the same as the one police found in your desk?” Dan demanded. “They certainly look the same,” the Cub leader admitted. “I wonder how this dress came to be in the log?”
- 68. [168] “Someone must have stuffed it in here just to be rid of it,” Brad ventured. His gaze fastened upon Jack Phillips. The boy leaned on his rifle, staring at the dress with a fixed, almost frozen expression. Observing the odd look of his eyes, the Cubs could not fail to wonder what he knew of the matter. “Jack,” said Mr. Hatfield, without mincing words, “have you ever seen this dress before?” “Have I seen it?” the boy echoed indignantly. “That’s what I asked, Jack.” “No, I never saw the dress before!” the boy answered sullenly. “What’s more I didn’t put it in this old log! I had nothing to do with stealing your money box!” “Finding this dress here gave me a bad moment,” Mr. Hatfield said. “Frankly, it’s something of a shock.” “Well, blame me! I always get accused of everything whether I did it or not!” “No one has accused you of anything, Jack. We only want to get at the truth of the matter. I have a deep- seated feeling that you might help us, if only you would.” Jack remained silent. Mr. Hatfield examined the dress and then wrapped it into a tight roll.
- 69. [169] [170] “Jack, we’ll walk along with you to Mrs. Jones’ place,” he said. “I think this is the dress that disappeared from her shed. I want to find out for certain.” “I didn’t take it,” Jack denied. “What would I want with a woman’s dress? If you go back and tell the widow, she’ll think I stole it! She’ll send me back to the Institute!” “Not if you tell a straight story, Jack,” Mr. Hatfield reassured him. “Come along, boys. We’re wasting valuable time.” Jack did not openly defy Mr. Hatfield or the Cubs, but he made it evident by glances he directed at them that he resented their interference. As the group approached the old farmhouse, Mrs. Jones saw the boys from afar. She was waiting at the door when they came up. “Well, I see you caught the rascal!” she commented grimly. “We found him,” Mr. Hatfield corrected. “Jack wasn’t running away though. He said he intended to come back.” “Jack, why do you do it?” the widow asked, taking the rifle from him. “Haven’t I been good to you?” “Yes’m,” the boy responded, his eyes on the ground. “I’ll fix you some victuals. You must be hungry.” “I’ve had enough to eat. I’m sorry about taking so much from the refrigerator.”
- 70. [171] The tight lines around Mrs. Jones’ mouth relaxed. “There! I reckon boys are all alike,” she remarked. “I had three of my own once. I never could break ’em of taking cookies from the jar.” The widow cordially invited the Cubs into the kitchen. Mr. Hatfield declined the invitation for them. “Mrs. Jones, here is something we wish to show you,” he said, exposing the rolled-up black gown to her gaze. “Did you ever see this dress before?” “Land sakes! It’s the dress that disappeared from the shed!” “You’re certain it’s the same one?” “Of course I’m certain. Didn’t I wear that dress for six years? Where did you find it?” “In a hollow log not far from here.” “Well, of all places! How did it get there?” “That’s what I’d like to know myself. Dan tells me that someone in a black dress was seen leaving my place on the day the money box disappeared.” “A jet button exactly like those on the dress was found by police in Mr. Hatfield’s study,” Brad contributed. “My stars! Then you think the money was taken by someone who wore my dress?” “Naturally, one wonders,” Mr. Hatfield replied. Mrs. Jones gazed searchingly at Jack.
- 71. [172] “I didn’t do it!” he said, almost fiercely. “Quit lookin’ at me like that! I always get the blame for everything.” “I’m sure Jack didn’t take the dress,” Mr. Hatfield declared. “As I recall, Mrs. Jones, I believe you said it disappeared some time ago.” “That’s so! Before Jack came here! Land sakes, I guess we get so in the habit of blaming a boy, that we don’t give him the benefit of any doubt.” In a gesture of kindness, she reached out and drew the boy to her. He resisted, but as her arm remained firm, finally allowed it to remain thrown around his shoulders. “I’m fairly convinced Jack didn’t take the dress,” Mr. Hatfield resumed. “Unfortunately, I’m afraid I can’t say I think he isn’t hiding vital information. I believe Jack knows more about the affair than he is willing to tell.” Mrs. Jones’ arm fell from the boy’s shoulder. Sternly, she regarded him. “Jack, is that the truth?” “Maybe!” The boy regarded her defiantly. “Then you just tell Mr. Hatfield everything you know!” “Wild horses can’t drag it from me! I’m no snitcher. I don’t help anyone who made it hard for me!” “You little ninny!” Mrs. Jones exclaimed, losing patience. “I declare, I wonder if you have an ounce of sense. Now march into the house.” “Yes’m,” Jack muttered.
- 72. [173] “Everyone come in,” Mrs. Jones invited. “We’ll thrash this out right here and now. If there’s one thing I can’t stand it’s nonsense!” The Cubs trooped into the warm kitchen, fairly overflowing the tiny room. Mr. Hatfield, Babe, Chips and Fred found chairs. Dan perched himself on the corner of the wood box by the stove. The others stood. “Jack, I’d try to switch a little sense into you, but I know now it doesn’t do a mite of good,” Mrs. Jones sighed. “Now what’s wrong with you anyhow?” “Nothin’.” “Then why don’t you speak up and tell Mr. Hatfield and the Cubs what they want to know?” “They turned me in!” “I reckon it was mighty inconsiderate of ’em to give you another chance,” the widow said, her brittle voice edged with sarcasm. “You’ve had a hard lot here. I’ve kept you chopping wood every day and helping with the housework. At night you’ve had to do your lessons.” “The work wasn’t so hard,” Jack muttered. “You’ve been chained to the house—never could go away—” “Aw, quit rubbin’ it in,” Jack pleaded. “I’ve liked it here. I’m willing to stay.” The widow regarded him steadily.
- 73. [174] “You may be willing,” she said, “but I don’t want you any more.” Jack drew in his breath and for a moment could not reply. “You—you’re sending me back?” he finally stammered. “Just as fast as I can send for Mr. Wentworth. I did the best I could for you, Jack. I needed a boy I could depend on that would help me with the work, and act like my own son. Well, you let me down. So I’ll go on living here alone.” The words cut deep into Jack. “I’ll do better,” he promised. “Please don’t send me back to the Institute. I’ll cut all the wood you want me to—honest I will. I won’t take things out of the ice box again or run off so often. Only just once in a long while, when I get to feeling tight and mean inside. And I’ll tell you ahead that I’m going—I promise!” “You’re promising a heap, Jack,” the widow returned dryly. “Only trouble is, you’ve made a lot of ’em before you never kept.” “I never made any to you.” “Well, that’s a fact. You have kept your word such as you’ve given.” “Then let me have another chance. Just one more!” “Not unless you tell the truth about that black dress of mine.”
- 74. [175] “I never took it!” Jack said desperately. “Believe me, I never did!” “But you know how it came to be in the hollow log?” “Not for sure,” Jack hedged. “You could make a pretty shrewd guess.” “Maybe.” “Then suppose you come clean and tell the Cubs everything you know.” “Help ’em after they turned me in?” “Did they really do you such a bad turn seeing to it that you were sent out here to my place?” “No’m,” Jack murmured. “I’m all mixed up. I don’t know what to do—” “I want you to stay with me always, Jack. You’re a fine boy.” “You mean that? You ain’t just handing me a line so’s I’ll do what you want?” “I really mean it, Jack. You should know by this time that when I give my word I keep it.” Jack debated with himself only a moment longer. Then he arrived at his decision. “I want to stay here,” he said earnestly. “I’ll do whatever you tell me to—and I ain’t crossin’ my fingers when I say it, either! You can switch me whenever you want to and I won’t try to take the switch away from you.”
- 75. [176] [177] “Now that’s right considerate of you, Jack,” Mrs. Jones smiled. “We’ll get along fine from now on. And we won’t need that switch again.” “I’ll fill the woodbox,” Jack offered eagerly. “You’re most out of kindling.” Mrs. Jones hauled him up short. “That job can wait, Jack. You got something else more important to do.” “Tell us everything you know about the tin box,” Mr. Hatfield urged. “You’ll be doing the Cubs a real service, Jack. You see, not only myself but the entire organization has been under a cloud since the money disappeared.” “I ain’t sure what became of it, but I may know,” Jack admitted. “Then suppose you tell us,” the Cub leader urged. “I’ll show you instead,” Jack offered. “Follow me to the woods, and you may see something kinda interesting!”
- 76. [178] CHAPTER 17 Through the Window Skirting the marsh, Jack led the Cubs deep into the shadowy woods. Apparently he had gone that way often, for he seldom hesitated in choosing the trail. “Where do you think he’s taking us?” Dan speculated, bringing up the rear with Brad. “It has me guessing, Dan. He seems to know where’s he’s going though. I have a hunch he may show us something that will have an important bearing.” After a brisk five-minute hike through the woods, Jack abruptly halted. “If you want to see anything, you got to be quiet from here on,” he warned. All conversation ceased. Still led by Jack, the Cubs moved on at a slower pace. Carefully they trod, taking care not to step on sticks or dry leaves. Presently Jack again halted. This time he did not speak. However, the Cubs, gathering close about, saw that they had neared their destination.
- 77. [179] Directly ahead, in a tiny clearing close to the stream, stood a crude shack. Side walls were badly built from odd-shaped lumber which the Cubs guessed had been taken from near-by construction jobs. The flat roof was made of tar paper. Some of it had torn loose and flapped in the light breeze. “You didn’t build the shack?” Mr. Hatfield whispered to Jack. He had noted a tiny curl of smoke rising lazily from a tin pipe cut through the roof. Jack shook his head. Motioning for the Cubs to follow, he moved in a little closer. “Who lives there?” Brad whispered, impatient for information. “Wait,” Jack said. “We’ll get in close, and maybe you can see for yourselves.” “If we all move in, we’ll likely be seen,” Mr. Hatfield insisted. It was decided that Jack, Mr. Hatfield, Brad and Dan should go on ahead, leaving the others in the shelter of the trees. Moving softly over the uneven ground, the trio crept close to the shack. Keeping close to the wall, they reached a broken pane of glass which served as the only window. Jack pressed his face against it and nodded in satisfaction. “He’s in there! Have a look!”
- 78. [180] Jack moved back to allow Dan to take his place. The boy peered into the dark interior of the shack. At first he caught only an impression of an empty room with an old box which served as a table. Then gradually he made out a balsam-bough bed on the floor, covered with an army blanket. Sprawled on the bed, fully clothed was a man with a stubbly beard. “It’s that same fellow who looked in the church window!” Dan murmured, startled to recognize him. “Careful, Dan!” Mr. Hatfield warned, for in his excitement, the boy very nearly had spoken aloud. “Let me have a look.” Dan moved aside so that both the Cub leader and Brad might peer at the stranger. “It’s the same man all right,” Brad confirmed Dan’s identification. “He’s dead to the world!” Mr. Hatfield had turned to Jack. “This is all very interesting,” he whispered. “But you promised to show us something that might explain about the missing money box.” “I can’t show you while he’s in there. But he’s got it.” “Not the money?” “Sure.” Jack thoroughly enjoyed his knowledge. “How do you know this, Jack? Did you see the box?” “Right from this very window. I was wandering through the woods late one afternoon when I came onto this
- 79. [181] shack. I was curious, so I sneaked up and looked in.” “And this same tramp was living in there?” Dan asked. “When was that?” “Oh, I didn’t find the shack until a couple of days ago. I don’t know how long it’s been here.” “Tell us about the money box,” Mr. Hatfield urged. “Well, as I looked through the window, I saw that tramp take it out from under his bed. While I watched, he counted the money. I saw a lot of bills in neat stacks.” “Jeepers!” Dan whispered. “It must be the money we found in the church!” “That hunk of baloney saw us through the window, and probably found out that the box was taken to Mr. Hatfield’s house,” Brad reasoned. “But how did he get it from there?” “Remember Mrs. Jones’ black dress!” Dan reminded him. “Sure, I get it. He must have stolen it from her place and wore the garment when he slipped into the house.” “That’s why the milkman reported seeing a woman leave the place,” Dan nodded, peering again through the window. “The dope still is sleeping hard.” “After stealing the money, it’s odd he didn’t try to get away from here,” Mr. Hatfield thought aloud. “Well, let’s get back and report to the Cubs. It’s risky standing here in the open.”
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