r ,

Central File
Account ~Gc.A{1J)f/Jc
Advanced Neural Implants
DARPA Bio:lnfo:Micro Annual PI Meeting
San Francisco, CA
November 5-6, 2003

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 ·The Grand Challenge

External Device Micro Implantable Biological

and Environment Device System

Exploit synergy at interface ofBiology, Information Science

and Microelectronics Technology to realize revolutionary
advances in high capacity and reliable
brain - external world interfaces
Minimal Invasiveness Strategy

Minimum number of neural signals for reliable system

operatton
 Part 1:
Signal/Data Acquisition

Advanced Polymer Neural Interface

.Design, Fabrication and Testing
 Neural Interface Team
Design and Fabrication Visualization
• Jiping He, BE • Greg Nielson, CSE
• Bruce Kim, EE • Gerald Farin, CSE
• Jit Muthuswamy, BE • Anshuman Razdan, CSE
• Amarjit Singh, BE • Jiuxiang Hu, CSE
• Kee-Keun Lee, EE • Dave Capco, LS
• Jing Hu, EE
• Greg Raupp, CME Data Acquisition
• Steve Helms-Tillery, BE
Biocompatibility • Byron Olson, BE
• Steve Massia, BE
• Alyssa Panitch, BE
• Gholam Ehteshami, BE
• Lijiang Wang, CME
 Advanced Polymer Interfaces:
Objectives and Approach
Polymer-based Long-term stable high S/N
flexible micro-devices neural implants

I
I
I
I
I
I
I

• Bulk polymer substitution I modification to enhance device stability

• Flexibility compliance with brain tissue
• Coatings to enhance biocompatibility
• Embedded neurotrophic factors to promote neural interfacing
Bio:lnfo:Micro/Nano Technology Fusion

Advanced micro-device
Cellular and biochemical biomaterials and designs
(810, MICRO)

Imaging /30 visualization of

sensor-tissue dynamics
{810, INFO)
 Principal Technical Advances
• New material for flexible neural implants
~ Microfabrication process developed
~ Flexible I implantable design developed and proven
~ Biocompatibility verified
• Advanced design elements incorporated
~Integrated flexible headstage and op amp buffer circuitry
~ Dual function action potential/ field potential ""butterfly" design
~ Microfluidic channels for controlled biologic delivery
• Demonstrated HA-based bioactive gels promoted neurite
extension and stability
• Surgical implantation and neural recording
 In Search of New Materials:
Principal Technical Requirements
+ Biocompatibility
• toxicity
• immune response
+ Long-term stability
• water uptake I moisture barrier properties
• chemical stability
+ Electronic and mechanical properties M
•
• dielectric constant, dissipation factor I
• bulk and tensile moduli, stiffness, CTE
c
+ Processing and materials integration pro.perties r
• process flow complexity/simplicity and reliability
• thermal stability 0
• thin film adhesion properties
• external connectivity
Photoimageable DVS-BCB vs. Polyimide
Property BCB Polyimide

Water uptake (wto/o) < 0.2% 4-6o/o

Dielectric constant 2.65 3.4 - 3.8

Cure time minutes hours

Cure byproducts none H2 0

Metal barrier none TilTiN

 Tailored Mechanical Design
• Flexible to comply with brain tissue mechanical properties
• Flexible to accommodate micromotion
• Reinforced tip for surgical handling

Bottom view
 .
Process Flow on Thinned SOl Substrates

Etch SOl Si
backbone
Ds;a , Deposit and
pattern upper
BCB layer

layer

Deposit and
pattern base
' BCB layer Backside
Si etch

Deposit and
pattern gold e::£ I Electrode
release:

u u etch buried
Si02
 Si Backbone Strength Enhancement
Young's Modulus (GPa) Rat pia penetration
BCB 2.8 No
BCB + 2 J.lm Si 10 No
BCB + 5 J.lm Si 32 Yes
BCB + 10 J.lm Si 58 Yes
Si 110 Yes
X·Y AUQNMENT

8 ---- - - - -- -- - ---,
I
-~
(G
6'
I
-
"J 4 I

-
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f
00
2

0
0 0.00005 0.0001 0.00015 0.0002 0.00025 SPECIMEN

Strain (mm/mm)
Micro-Force Thermo-Mechanical Test

------
 Surgical Insertion Test

Video clip ofBCB neural interface

penetrating rat pia
 Recording Site Impedance

Channel 1 2 3 4 5 6
Z (KQ) 210 206 290 295 240 255
. 90 -63 -64 -58 -62 -63 -61

Impedance at 1KHz for 20 tJm x 20tJm gold recording sites

measured in 0.9% saline solution at room temperature
In vitro Biocompatibility Test
Morphology of adherent 3T3
cells on BCB electrode shank
and surrounding wafer surface

Cell area coverage on Tissue

Culture Plastic and BCB Electrode
100

~
en 80
l!
~

~ 60
(..)
(G

~ 40
-cu
u
';;li!. 20

0
Tissue Culture BCB Electrode
Plastic
BCB I GFAP Confocal Microscopy Image Analysis
GFN> Volume va. Distance

I~ 120000
I ~1~~--~~--~~+-~--------~
•
~ ~~~------~~~~----------
0
~ ~~----~~--~~~~~--~~
...
~

Cl40000+-------------.....-=:-------=---~------l

3 6 9 12 15 18 21 24 'D 30
Ollila nee to z•O plan (um)

GFAP Volurre va. Dlst.nc:e

3 s s a u • ~ ~ v ~ ~ ~ ~ ~ ~ ~
DilllaRU to aleccrocS. (um)
Cell Attachment and Scarring

Cell Attachment

Electrode
GFAP Scar Size: Electrode Size
substrate
BCB 0.25
Silicon 0.74
 Bioactive Coating and Bioactive Gel
Improve Biocompatibility

Bare Wwire Dextran Coated Dextran + P20

 Principal Technical Advances
•

• Advanced design elements incorporated

~Integrated flexible headstage and op amp buffer circuitry
~ Dual function action potential/ field pc;>tential ""butterfly" design
)> Microfluidic channels for controlled biologic delivery
•
•
 BCB Neural Interface with Flexible
Headstage and Integrated Buffers
~1Dit~-m Buffen(1.4mm. by L4mm)

lOmm

Flenble Cable Stiff fluible Part

(Connect to coDDec:tor) (Skull) (Skull, bendable)
Butterfly N~ural Interface Design

Flex cable

Integ rated buffers

Field potential
recording sites
Action potential
recording sites
 Microfluidic Channels Fa·bricated in BCB

Sibackbone
layer
-
Microfluidic
channel
BCB Interface with Microfluidic Channel

..
...
...
••
•• ..
•• .
••
...
•
•

Inlet Outlet
Tri-shank BCB Interface with Microfluidic Channel
Microfluidic Channel Liquid Flow Test

101Jm dia
tube
 Neurite Outgrowth Quantified

:= H y a lu ron lc A c ld
F lbrln
Mean
enhancement
=65o/o
1 .5 ........ .. . ..... . .

.I
!.5I
•
::z:

*p<0.02, **p<0.0005, ***p<0.002

 Principal Technical Advances
•

• Demonstrated HA-based bioactive gels promoted neurite

extension and stability
•
 Hyaluronic Acid
• Non-sulfated, unbranched glycosaminoglycan (GAG)
comprised of repeating disaccharides ( D-glucuronic
acid(~ 1-3)N-acetyi-D-glucosamine(~ 1-4) )
• Ubiquitously present in connective tissue -- forms loose
hydrated matrices for cell division and migration during
embryonic development
• Plays a role in intracellular signaling
HA Enhances Neurite Outgrowth and Stability
Fibrin Hyaluronic Acid

48 hours

60 hours
HA Provides Long-term Structural Stability

192 hours
 Principal Technical Advances
••

•
• Surgical implantation and neural recording
Surgical Implantation and Neural Recording

Stimulus

Single shaft BCB neural Stimuli were delivered by

interface inserted into right manually brushing a ~mall
rat barrel cortex rod over the left whisker
patch at different rates
Neural Recording Responses Modulated in
Proportion to Stimulus Rate
100.
Stit ulation (Hz)
none

-100.
34.37
l .. l 36.37 1
100.

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IN
-1Hz

:::::'
as
+=i
-100.
~_,• t - -
~ 100.
.....
0
0.. IJV -2Hz

-100.
8~~ 1~

Time [seconds]
 Immediate Future Goals
• Long term {>6 months) BCB neural interface
evaluation
', Recording stability
,. Neural cell responses to
• Establish procedures for routine integrated
processing of bioactive coatings with neural
interfaces
• Develop and implement integrated controlled
bioactive gel release systems
 2003-04 Publications
"An Ex Vivo Method for Evaluating the Biocompatibility of Neural Electrodes in Rat Brain Slice Cultures", B. A. Koeneman,
K-K. Lee, A. Singh, J . He, G. B. Raupp, A. Panitch, D.G. Capco, submitted to Journal of Neuroscience Methods.

"Glial Cell and Fibroblast Cytotoxicity Study on 4026-Cyclotene Photosensitive Benzocyclobutene (BCB) Polymer Films",
G. Ehteshami, A. Singh, G. Coryell, S. Massia, J . He and G. B. Raupp, accepted for publication in Journal of Biomaterials
Research - Polymers. ·

"Benzocyclobutene (BCB) Based lntracortical Neurallmplanr, A. Singh, K.-K. Lee, J . He, G. Ehteshami, S. Massia and
G. B. Raupp, submitted to Proc. IEEE Engineering in Medicine and Biology Society.

"Glial Cell and Fibroblast Cytotoxicity Study on Plasma-deposited Diamond-like Carbon Coatings", A. Singh, G .
Ehteshami, S. Massia, J . He, R. G. Storer and G. B. Raupp, accepted for publication in Journal of Biomaterials Research
-Polymers.

"Polyimide-based lntracortical Neural Implant with Improved Structural Stiffness", K.-K. Lee, J. He, A. Singh, S. Massia,
G. Ehteshami, B. Kim and G. B. Raupp, Journal of Micromechanics and Microengineering 14, 32-37 (2004).
 Part II:
Decoding/Modeling/Application

Neuronal Interactions
Brain-controlled Neuroprosthetic Arm
Brain-controlled Autonomous Robot
 Principal Technical Advances
• Plasticity and adaptability of neural networks in
motor and sensory cortices
• Brain control feasibility demonstrated
Motor and Sensory Cortical Interactions during
Learning and Adaptation in Primates

Dr. Narayanan Krishnamurthi

Dr. Doug Weber
Prof. Jiping He
Prof. Leon lasemidis

Brain Dynamics Lab

Neuro-Mechanical Control and Rehabilitation Research Lab
 Neural Control Team
Applications Visualization
• Jiping He, BE • Greg Nielson, CSE
• Steve Helms-Tillery, BE • Gerald Farin, CSE
• Byron Olson, BE · • Anshuman Razdan, CSE
• Chris Jennings, BE • Wei Chen, CSE
• Matt Holecko, BE

Analysis
• Jennie Si
• Narayanan Krishnamu.rthi
• Doug Weber
• Leon lasemidis
• Frank Hoppensteadt
Motor and Sensory Cortical Interactions during
Learning and Adaptation in Primates

1. Is plasticity observed in neuronal interactions?

Identify/quantify existence of significant changes of interaction
between and within motor and sensory cortices during learning and
adaptation

2. What is the underlying mechanism of observed

plasticity?
Individual vs. Spatial Patterns of neuronal firing rates over time

3. Are the neuronal interactions global or local?

Identify set of neurons responsible for a particular learning and
behavioral pattern
 Experimental Design
4 7

Experimental
Phases
• Training (2-8 weeks)
• Normal reaching in 3D
space (1 week)
Perturbation
• Short duration pulling
Force Vectors
force perturbation
force (1-1.5 weeks)

Neural Recording
• Four 16-channel microwire arrays
• Simultaneous spike train recordings from sensory, motor, and
pre-motor regions
 SPIKE TRAINS
Trial 1 Trial 2 Trial N
N1 Ill II I ... 1111 II 111111 IIIII ... II Ill IIIII II ... II
N2 IIIII 1111 ... II Ill I 1111 ... II I 1111 Ill ...
. . . . . . . . . . . . . . ... . . . .. . .
..• .•. ... ... ... ... ..
. ... ..• ..
.
..
.
..
. ... ... ...
..
.
.. .. .. ..
. .. . ..
.
Nn II I Ill ... IIIII 1111 II Ill . . . II I 1111 ... I

SPIKE COUNT
N1 3 2 1 ... 4 2 6 5 ... 2 3 5 2 .. . 2
N2 0 5 4 . . . 2 3 1 4 ... 2 1 4 3 .. . 0
.
... .. ... ... ... ... ... .. .. .. .. .. .. .. .. .. .. ... ... .. ..
. . . .. . . .. .. .. .. .. .. .. .. .. .. .. .. ..
Nn 2 1 3 ... 5 4 2 3 .. • 0 2 1 4 ... 1
 . - ·- ... ----------~~

Mutual Information (MI) Methodology

• Non parametric measure of statistical similarity between two
systems--
Information gained (or reduction ofuncertainty, i.e., entropy) about the
unknown state ofone ofthe systems by observing the state of the other system

• Ml is estimated on the basis of individual and joint system

entropies, which in turn are estimated through their corresponding
individual and joint probabilities

M M M
- LP( N;m}/og2 ( P(N;m }} - L L P( Ni m'N jm }fog 2( P( N im,N jm}}
m=l m = l m =l
 Mutual Information Measures
Average Mutual Information {AMI) between cortices A and B
1 NA - 1 NB-1
AMI( A,B)= L LMI(Ni,Nj)
(NA -1)(Ns -1) i=1 J=1
For i =F- j

Number of distinct neurons

Optimai .Average Mutual Information (OAMI)

Averaged over top a.% of all possible neuronal interactions

Normalized Optimal Average Mutual Information (NOAMI)

 Monkey 1 - [8 MC(M), 8MC(M)]
110

Observed
1 00
Success Rate
to
~
sI 80

8:I
II) 'TO

fO

500 2

Normalized Optimal AMI Optimal Average Firing Rate

~--~--~--~--~--~~--~--~~
25

~20
j 15
~ 10
5

~~~--~--~--~--~~--~---
Dor• •
150F . .
Doyo

30
25
l Post-Perturbation Post-Perturbation

~ 20 · !100
~ 15
~ 10
Ja sor
5 ~ 0~
•o~~--~--~--~~~~~~-
D•r•
Doyo
 Monkey 2- [HSC(L), HSC(L)]
110 ,------,.------.---,..------,- r - ---.-- -
Observed 105

Success Rate 100

95
~
Q>
to
~
i8 u

~ eo
1$

Target4
70

- -J.- - ~ _ __..
Target7
•
-~
150 1 2 4 5 • 7
Days

Normalized Optimal AMI Optimal Average Firing Rate

20 -. --,-- -.,---~ r-
120 Pre-Perturbation Pre -Perturbatlon
-100
!.
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i
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~

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40
~ 5
20

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0111
5
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Daya

12t ,----,- 20 ----~--~--~----~

Poat-Perturbatlon Poat·Perturbatlon
100

leo
I 10

40

~~-~-~-~,~--~
4----~
, --~~--~--~
Day•
 Monkey 3- [8 MC(L), 8MC(L)]
120

Observed 110

Success Rate 100

eo
! ao .
•
1ii
a: 70
Iuu 10
i
50

40 .
Target4
so
Target 7
zo, 2 3 4 5 6
Days
7
• • 10 11 12 13

Normalized Optimal AMI Optimal Average Firing Rate

1~ ,---~----~----r---~----~----~---. 15
Pre-Perturbation Pre-Perturbation
'1110
l1oo ~

! s
.J
5
i so !'
: 0

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• ... • 10 12 14 -5
0
.
2 4 10 12
Day a

1~ 20
Post-Perturbation Post-.P erturbatlon
'1115
l100 ~
• 10
I !
I? s
i 50
s...
•
o, 14 40 2 ,-----·----1~
0 ----~
12----~
14
dip Day a
 Total Optimal Average Mutual Information (OAMI)
if Between All Pairs of Cortices
:a - - ,
- 6 1 - - T - - 1

5 Monkey 1

- - L-._· - --'- - - - ....~_ __ _ _ _J _

'i 3 4 5 6 7 8
E
,g 2.5
c
0
Monkey 2
:; 2

....5s1.5
1
Ci
:i.a 0.51 2 3 4 5 6 7
G)
Cia 4 --,--- ----,-- , - ---,.- - ,---.---.----.,
l!
G) (c) Monkey 3
~ 3 -

.
"i
E
a.
2

...
0
0
1

E 01 2 3 4 5 6 7 8 9 10 11 12
:I
(/) Days
Pre-perturbation
·Post-perturbation
 ..

Cortical pair~ that show plasticity via NOAMI

~
-- ~
- --
~1
~

1·~- .'::~
.~
llankay2 MaUqY
Pan ofCOitiGM Pan of cediGea p. . of corllces
pre-ps post-ps pre-ps post-p.J - pre-ps pon-ps
[ 5MC(M),5 MC(M)I
- 1' 1' [AMC(L),AMC(L)] -1 -1 [MC{M),MC(M)] -1 -1
(5 MC(M),SC(L)] Jl 1' [AMC(L),"SC(L)] -1 -1 [MC(M),PMC(L)] -1 -1
(5MC(M),5 SC(M)J I' 1' [AMC(L),SC(M)] -1 -1 [MC(M),5MC(L)] -1 -1
[SMC(M),"MC(L)] 0 - 0 [AMC(L),sMC(M)] -1 -1 [MC(M),MC(M)] -1 -1
(SC(L),SC(L)] Jd 0 f"SC(L), "SC(L)) i' J' [PMC(L),PMC(L)] -1 -1
[SC(L), 5 SC(M)J 0 -1 ["SC(L),SC(M)] -1 -1 [PMC(L),5MC(L)] -1 -1
(SC(L), "MC(L)] 1d -1 ["SC(L),8 MC(M)] 0 0 [PMC(L),MC(M)] -1 -1
[ 5SC{M), 5SC(M)J 0 0 [SC(M),SC(M)] -1 -1 15MC(L),5MC(L)] Jl 1~

[ 8 SC(M), "MC(L)] 0 -1 [SC(M),8 MC(M)] -1 -1 [ 8 MC(L),MC(M)] 0 0

["MC(L), "MC(L)] 0 -1 ( 5MC(M),5MC(M)] Jd Jd [MC(M),MC(M)] -1 -1

1i - statistically significant increasing trend

1d -statistically significant decreasing trend
 Neuron·al Interactions -- Conclusions
• Neuronal plasticity across days was observed between particular
areas of motor and sensory cortices in all (3) monkeys
• The estimated NOAMI trends corresponded with observed
success rate
• The Normalized Optimal Average Mutual Information (NOAMI)
between neuronal firing rates progressively increases or
decreases over days at specific cortical areas of the monkeys'
brain, denoting strengthening I weakening of particular
interactions between cortical sensori-motor areas
• The sum of NOAMI did not exhibit any particular trend over days;
Individual neuronal firing rates did not show plasticity over days
• Implication -- spatial synchronization of neuron firing rates is the
cause of strengthening I weakening of interactions that
eventually leads to cortical plasticity ·
 Future Goals
• Validate preliminary results
• Design new experiments and develop complementary methods
with better temporal and spatial resolution (at the level of
neurons versus cortical areas) to further investigate the
observed plasticity trends
• Identify main neurons and interactions in the motor and sensory
cortices that are responsible for motor learning and adaptation
• Apply results to motor control
 2003-2004 Publications
• "Analysis of neuronal interactions during adaptation and learning in motor control of primates: A model independent
approach using information theory", K. Narayanan, D.J. Weber, J. He, A. Prasad & L.D. lasemidis, IEEE Engineering
in Medicine and Biology Society, Annual Meeting, Houston, Texas, pp. 2552-2553,2002.

• "Learning and Adaptation in the Cortex of Primates: Information Analysis of Motor Control Tasks", K. Narayanan, D.J.
Weber, Jiping He and L.D. lasemidis, submitted to the Journal of Neuroscience, 2003.
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