(1992) Chronic Electrode Implantation [Kennedy]

8/13/2019 (1992) Chronic Electrode Implantation [Kennedy]

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Neuroseienee Letters, 142 (1992) 89 94 89,~ 1992 Elsevier Scientific Publi shers Ireland L td. All rights reserved 0304-3940/92/ 05.00

NSL 08801

T h e c o n e e l e c t r o d e : u l t r a s t r u c t u r a l s t u d i e s f o l l o w i n g l o n g t e r m r e c o r d i n gin r at a n d m o n k e y c o r te x

P h i li p R . K e n n e d y a, S u z a n n e S M i r r a b a n d R o y A E B a k a y cGeorgia Insti tute of Technology and Yerke s Regional Primate Research Center, Emo O, Universio~, Atlanta, GA 30322 ( USA ), ~Department of

Pathology and Labora too, M edicine. VA Medical Center and Emo o' UniversiO' School of Medicine, Atlanta, GA 30322 ( USA ) and 'Dep artm ent g['Neurosurgeo', Em o O' University School of Medicine and V A Medical Center, Athm ta, G A 30322 (U S,4)

(Received 20 December 1991; Revised version received 14 April 1992: Accepted 30 April 1992)K e y w o r&: Cone electrode: Rat: Monkey; Elect ron microscopy; Neurite

The achievement of long-term recording of neural signals from the central nervous system has potenti al clinical and investigative application. Tofacilitate long-term recording, a novel cone electrode composed of an insulated gold wire within a hollow glass cone had been developed. Coneelectrodes containi ng sciatic nerve or neurot rophi c medium were implanted into cerebral cortex in rats and monkeys. Electrophysio logic recordingshad been previously obtained from c one tissue for as long as 15 months following implantat ion and this tissue contained silver-positive processes. Wenow extend these observat ions to ch aracterize the fine structural features of the tissue within these long-term implants. Electron microscopy revealedcentral myelinated axons, dendrites, synaptic profiles, blood vessels, and glia; peripheral nerve was not found in the cones in which sciatic nerve hadbeen placed. These observations further suggest ingrowth of cortical neurites and elements into the hollow glass tip of the cone and support thefeasibility of long-term recordi ng using this electrode.

T h e c o n e e l e c t r o d e , a d e v i c e d e v e l o p e d t o a c h i e v el o n g - t e r m r e c o r d i n g f r o m n e u r a l t i ss u e , c o n si s ts o f a 1 - 2m m l e n g t h o f c o n i c a l h o l l o w g l a s s t u b i n g , 0 .1 0 . 3 m m i nd i a m e t e r , g l u e d t o t h e e n d o f a f le x i b l e r e c o r d i n g w i r e . I na p r e v i o u s s t u d y , n e u r o t r o p h i c t i ss u e o r m e d i u m w a s i n -s e r t e d i n t o t h e c o n e , w h i c h w a s t h e n i n s e r t e d i n t o t h es u p e r f i c ia l c e r e b r a l c o r t e x o f r a ts [9 ] a n d m o n k e y s [ 10 ].I n t h e o r i g i n a l s t u d y , c o n n e c t i v i t y o f c o n e t i ss u e a n d c o r -t ic a l n e u r o n s w a s s u g g e s t e d b y t h e f o l l o w i n g o b s e r v a -t i o n s : ( 1 C o n e e l e c t r o d e s i n w h i c h s c i a t i c n e r v e s e g m e n t sw e r e i n i t i a l l y i n s e r t e d c o n t a i n e d s i l v e r p o s i t i v e f i b e r sm a n y m o n t h s f o l l o w i n g i m p l a n t a t i o n . ( 2) R e t r o g r a d et r a c i n g s t u d i e s w i t h f l u o r o g o l d p l a c e d w i t h i n t h e c o r t i c o -s p i n a l t r a c t a t t h e u p p e r c e r v i c a l l e v e l r e v e a l e d f l u o r e s -c e n t d y e i n n e u r o n a l c e l l b o d i e s a s w e l l a s i n a d j a c e n tc o n e t i ss u e c o n t a i n i n g o n l y p r o c e s s e s . ( 3 ) F i n a l l y , e le c t r i-c a l a c ti v i t y w a s r e c o r d e d w i t h i n t h e c o n e s .

T h e s e e x p e r i m e n t s w e r e l i m i t e d t o s c i a t i c n e r v e c o n ee l e c t ro d e i n s e r ti o n s in r a t a n d m o n k e y s a n d d i d n o t p r o -v i d e d i r e c t c o n f i r m a t i o n o f t h e t is s u e c o n s t i t u e n t s w i t h i nt h e c o n e . T h e c u r r e n t e x p e r i m e n t s e x t e n d t h e u s e o f t h e

Correspondence: P.R. Kennedy, Neuroscience Laboratory, GeorgiaInsti tute of Technology, Roo m 325, CRB, 400 10th Street, Atlan ta, GA30322, USA.

c o n e e l e c t ro d e b y s u b s t it u t in g n e u r o t r o p h i c m e d i u m( M a t r i g e l , C o l l a b o r a t i v e R e s e a r c h I n c . , B e d f o r d , M A[ 6 ] ) f o r s c i a t i c n e r v e i n s e r t s a n d c h a r a c t e r i z e t h e f i n es t r u c tu r a l f e a t u r e s o f t h e c o n e - c o n t a i n e d a n d s u r r o u n d -i ng t i s sue i n bo t h spec i e s .

E l e c t r o d e c o n s t r u c t i o n , i m p l a n t a t i o n , a n d m e t h o d o fr e c o r d i n g o f s i g n a ls h a v e b e e n d e s c r i b e d [ 9 ]. F i g . 1 i ll u s-t r a t e s t h e e l e c t ro d e i m p l a n t e d b e l o w t h e s u r f a c e o f c o r -t e x . T h e s e e l e c t r o d e s w e r e f a b r i c a t e d b y g l u i n g o n e o rt w o r e c o r d i n g w i r e s , 2 o r 3 m il s in d i a m e t e r , i n t o a s m a l lc o n i c a l p ie c e o f gl as s m e a s u r i n g 5 0 - 1 0 0 / a m a t i ts d e e pe n d a n d 2 5 ( ~ 4 0 0 / l m a t it s s u p e r f ic i a l e n d w h e r e t h e w i r e se n t e r . I n t h e p r e s e n t e x p e r i m e n t s , h o w e v e r , g l a s s c o n e sw e r e u s e d w i t h o u t w i r e s fo r t w o M a t r i g e l - i m p l a n t e d r a ts .I m p l a n t a t i o n s w e r e m a d e i n t o th e b a r r e l c o r t e x o f ra t f o rr e c o r d i n g s e n s o r y r e s p o n s e s t o v i b r i s s a e d e f l e c t i o n s , a n di n t o th e m o t o r c o r t e x o f m o n k e y s f o r m o n i t o r i n g s ig n a lsr e l a te d t o a r m a n d h a n d m o v e m e n t s a s d e t e r m i n e d p e r i o -p e r a t iv e l y b y s u r f a c e m i c r o s t i m u l a t i o n .

F o r r e m o v a l o f th e c o n e a n d i t s i n d w e l l i n g t is s u e , r a tsw e r e p e r f u s e d w i t h 2 5 0 m l o f n o r m a l s a l i n e , fo l l o w e d b y2 5 0 m l o f 4 g l u t a r a l d e h y d e . I n m o n k e y s , th e e l e c t ro d et ip , a n d a b o u t 1 c m o f s u r r o u n d i n g t is s ue , w e r e re m o v e de n m a s s e a n d i m m e r s e d in 4 g l u t a r a l d e h y d e s o l u t io n ,I n b o t h r a ts a n d m o n k e y s , t h e g la s s c o n e w a s i m m e d i -


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91t r a l m y e l i n a t e d a x o n s a n d g l i a l p r o c e s s e s p a c k e d w i t hf i l a m e n t s F i g . 4 B ) . T h e a d j a c e n t s u p e r f i c i a l c o r t e xs h o w e d d e n s e l y p a c k e d a s t r o c y t i c p r o c e s s e s f i l l e d w i t hf i l a m e n t s a n d a n o v e r l y i n g pi a l m e m b r a n e . T h e l e g a r e ao f r a t W I G - 4 w a s i m p l a n t e d w i t h t w o c o n es r e m o v e da f t e r o n e m o n t h . E x a m i n a t i o n o f t i ss u e f r o m t h e c o n e ss h o w n g r o s s l y i n F ig . 2 B ) r e v e a l e d s i m i l a r f in d i n g s i nb o t h s p e c i m e n s : s y n a p t i c p r o f il e s w e r e o b s e r v e d a l o n g

w i t h a fe w c e n t r a l m y e l i n a t e d a x o n s F i g . 4 C , D ) . I n a d -d i t i o n , r a r e n e u r o n a l c e l l b o d i e s , d e n d r i t e s , a n d c a p i l l a r -i e s w e r e p r e s e n t F i g . 4E ) .

T h e s e r e s u l t s i ll u s t ra t e a n u m b e r o f i m p o r t a n t p o i n t s .T h e p r e s e n c e o f c e n t r a l m y e l i n a t e d a x o n s , s y n a p t i c p r o -f il e s, d e n d r i t e s , b l o o d v e s s e l s a n d s u p p o r t i n g c e l l s s u c h a sg l i a s u g g e s t s t h a t n e u r a l t i s s u e g r e w i n t o t h e g l a s s c o n ea n d r e m a i n e d v i a b l e fo r m a n y m o n t h s . A l t e r n a t i v e l y ,s o m e o f t h e t is s u e m a y h a v e b e e n m e c h a n i c a l l y i n t r o -d u c e d i n t o th e c o n e d u r i n g i m p l a n t a t i o n o r w i th s u b s e -q u e n t m o v e m e n t s . H o w e v e r , t h e f i n d i n g i n p r e v i o u s e x -p e r i m e n t s t h a t n e i t h e r t i s s u e i n g r o w t h n o r e l e c t r o p h y s i -o l o g i c a l a c t i v i t y o c c u r s i n e m p t y c o n t r o l c o n e s , n = 5 [ 9]m i l i t a t e s a g a i n s t t h i s p o s s i b i l i t y .

T h e e l e c t r i c a l a c t i v i t y r e c o r d e d t h r o u g h t h e w i r e s i sl i k e l y d u e t o a c t i o n p o t e n t i a l s t r a v e l l i n g a l o n g t h e m y e l i -n a t e d a x o n s . S i n c e m u l t i p l e m y e l i n a t e d f i b e r s a r e f o u n di n s i d e t h e c o n e , i t c o m e s a s n o s u r p r i s e t h a t m u l t i p l e a c -t i o n p o t e n t i a l s a r e r e c o r d e d . T h e s e h a v e d i f f e re n t a m p l i -t u d e s , w i t h t h e l a r g e s t p r e s u m a b l y b e i n g c l o s e s t t o t h er e c o r d i n g w i r e , o r o p t i m a l l y j u x t a p o s e d b e t w e e n t w ow i r e s a s s h o w n i n F i g . 1. T h e s e d i f f e r e n t s i z e d p o t e n t i a l sa r e t h e n s e p a r a t e d u s i n g w a v e s h a p e a n a l y s i s t e c h n i q u e s .T h e t i m e r e q u i r e d f o r i n g r o w t h o f a x o n s w o u l d a l s o e x -p l a i n t h e d e l a y o f t h r e e w e e k s o r l o n g e r b e f o r e a c t i v i tyc a n b e r e c o r d e d [ 9 ] . D e n d r i t e s , t o o , w e r e o c c a s i o n a l l yf o u n d i n s i d e t h e c o n e t i s s u e , s u g g e s t i n g t h a t t h e y c a ng r o w i n a n d f o r m s y n a p t i c c o m p l e x e s s m a l l a r r o w s i nF ig . 4 C E ) .

T h e o t h e r t i s s u e s f o u n d i n s i d e t h e c o n e c o n s i s t e d o fs u p p o r t i n g s t r o m a s u c h a s b l o o d v e s se l s a n d g l ia . T h i ss u g g e s t s t h a t n e a r - n o r m a l n e u r o p i l m a y t a k e u p r e s i -d e n c e i n s i de t h e c o n e e v e n a f t e r j u s t f o u r w e e k s { F i g.4 C E ) . R e a c t i v e g l i a l c h a n g e s , o f c o u r s e , m i g h t b e d e t r i -m e n t a l t o r e c o r d i n g e l e c t r i c a l e v e n t s , s i n c e g l i o s i s m i g h ti n c r e a s e t h e d i s t a n c e b e t w e e n t h e r e c o r d i n g w i r e t ip a n dt h e a x o n s . H o w e v e r , t h e r e c o r d i n g s d o n o t a p p e a r t o b ea f f e c t e d b y t h e s e f i b r i l l a r y g l i a l p r o c e s s e s s i n c e a c t i v i t yp e r s i s t e d t \~ r o v e r a y e a r in r a t s 1 G 2 1 , I G 3 2 ) a n d m o n -k e y C F 6 3 F i g . 3B ) o r h a l f a y e a r in n u m e r o u s r a t s a n di n m o n k e y C F 4 9 s c i a ti c n e r v e in s e r t p r i o r t o t h e M a -t r ig e l i m p l a n t ) , a n d m o n k e y R C Z I F i g . 3 C ) .

N o e v i d e n c e w a s f o u n d f o r r e m n a n t s o f th e o r i g i n a li n s e rt o f s c ia t ic n e r v e . I t w a s p r o b a b l y p h a g o c y t o s e d b ym a c r o p h a g e s o r m i c r o g l i a t h a t w e r e o b s e r v e d i n s o m e

A M o n k e y C F 6 3

B R a t W i g 4

Fig. 2. A: a glass cone and its tissue after rem oval from monkey CF 63 isshown lying on gridlines that are I mm apart. The sm ooth conicalshape of the center piece is due to the glass and is almost 2 mm inlength. Some small remnants of tissue extrude from th is end be[\)refolding backward. B: a close-up view of tissue extruding from the nar-row end o f another glass cone. Bubbles can be seen under the glass andon the tissue. The tissue narrows as it extends up the glass to the left),but in no case was it absent from inside the glass. It always extendedfrom one end to the o ther, Bar - 100 j4m.

s p e c i m e n s . P r e s u m a b l y , i t a c t e d a s a n a t t r a c t a n t f o r t hen e u r i te s . I t c o n t a i n s v a r i o u s f a c t o r s , s u c h a s n e r v eg r o w t h f a c t o r , f i b r o n e c t i n , l a m i n i n a n d o t h e r s t h a t m a yh a v e c o n t r i b u t e d t o t h e o b s e r v e d n e u r i te i n g r o w t h [ 5,l l ] .

T h e r e w a s e v i d e n c e o f J br e i gn b o d y r e a c t i o n o n l y inr a t I G 3 2 . W e h a d e x p e c t e d a p o s s i b l e r e a c t i o n t o t h ec y a n o a c r y l a t e g l u e h o l d i n g t h e w i r e s t o t h e g l a s s , a n d , t oa l e s s e r e x t e n t , t h e g o l d w i r e s , t h e i r T e f l o n i n s u l a t i o n ,a n d t h e g l as s . T h e r e f o r e , a n y p r o b l e m s e n c o u n t e r e d w i t hr e c o r d i n g n e u r a l a c t i v i t y a r e u n l i k e l y t o b e r e l a t e d t o f o r -e i g n b o d y r e a c t i o n . W h e n t h e r e c o r d i n g s c e a s e d , i t w a sa l w a y s b e c a u s e t h e c o n e w a s r e m o v e d f o r h i s t o l o g i c a le x a m i n a t i o n , o r b e c a u s e t h e su b j e c t d a m a g e d t h e im -p l a n t . E v e n w h e n t h i s o c c u r r e d a s i n s o m e o f t h e m o n -k e y s ), t h e c o n e s o m e t i m e s w a s r e t r ie v e d f o r t i s su e a n a l y -sis.


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A Mo nkey CF6 C Monkey RCZ2 3

3 B R a t R 3 4

3

F i g . 3. A : e x a m p l e s o f r e c o r d i n g s f r o m m o n k e y C F 6 3 1 5 m o n t h s a f t e r i m p l a n t a t i o n . T h e s p i k e s a r e t r a n s ie n t c h a n g e s i n a m p l i t u d e r e f l e c ti n g t h ee l e c tr i c a l e v e n t s a d j a c e n t t o t h e r e c o r d i n g w i r e s. T h e s e t r a n s i e n t s o r i g i n a t e m o s t l i k e ly f r o m t h e m y e l i n a t e d a x o n s , a n d o n t h a t b a s i s a r e c l a s si f ie d a sa c t i o n p o t e n t i a l s . M o r e d e t a i ls o f r e c o r d i n g m e t h o d s a n d r e s u l t s a r e d e s c r i b e d e l s e w h e r e [9 ] . B : a s i m i la r e x a m p l e f r o m r a t R 3 4 3 m o n t h s a f t e ri m p l a n t a t i o n . C a l i b r a t i o n b a r s = 2 0 m V a n d 1 0 m s f o r b o t h A a n d B . C : a f u r t h e r e x a m p l e f r o m m o n k e y R C Z s h o w i n g 1 2 5 m s o f r e c o r d i n g s t o p t r a ce ) ,w i t h i n d i v id u a l s p i k e s 1 , 2 , a n d 3 d i s p l a y e d o n a s h o r t e r t i m e b a s e o f 2 0 m s . H o r i z o n t a l c a l i b r a t i o n b a r = 2 0 m s f o r t h e u p p e r t r a c e , 3 .3 m s f o r t h e l o w e r

t h r ee t r ace s . V e r t i ca l c a l i b r a t i o n b a r = 2 0 m V fo r a l l t r a ce s .

T h i s s t u d y d o e s n o t d e m o n s t r a t e a n y o b v i o u s h i s t ol o g -i c a l a d v a n t a g e t o u s i n g s c i a t i c n e r v e o r a s u b s t r a t e s u c ha s M a t r i g e l . H o w e v e r t h e ea s e w i t h w h i c h M a t r i g e l c a nb e d r a w n i n t o t h e g l a s s c o n e c o m p a r e d t o t h e h o u r sn e e d e d t o o b t a i n a f r e s h n e rv e s p e c i m e n a n d i n s e r t it i n t ot h e c o n e [ 9 ] w o u l d s t r o n g l y f a v o r u s i n g M a t r i g e l w h e n -e v e r p o s s i b le . T h u s w e r e c o m m e n d u s i n g M a t r i g e l inrats .

T h e g r o w t h o f n e u r i t e s i n t o t h e s c i a t i c n e r v e i s n o ts u r p r i si n g . T h e r e i s p re c e d e n c e f o r t h i s o b s e r v a t i o n i n t h ew o r k o f A g u a y o a n d c o l le a g u e s w h o i m p l a n t e d a u t o l o -g o u s s c i a t i c n e r v e i n t h e c e n t r a l n e r v o u s s y s t e m o f r a t sa n d s h o w e d t h a t n e u r i t e s g ro w i n t o t h e l e n g th o f n e r v ef or a f ew cen t im e te r s [2 3 7 8 12 15] . I n these s tud iesh o w e v e r n o f u n c t i o n a l l y u s e f u l t i ss u e b ri d g e f o r m e d d u et o t h e o v e r a b u n d a n c e o f c o n n e ct i o n s .

T h e c o n e e l e c t r o d e is c o n c e p t u a l l y b a s e d u p o n t h e s e

f i n d i n g s o f A g u a y o a n d c o l le a g u e s . It w a s d e s i g n e d s p e -c i fi c a ll y f o r l o n g - t e r m r e c o r d i n g s a s a p r o s t h e t i c n e u r a lc o n t r o l l e r r e q u i r i n g a s m a l l n u m b e r o f s i g na l s n o t n e c e s -s a r i ly t h e s a m e a l l t h e t i m e t h a t t h e p a t i e n t c a n v o l u n t a r -i ly con t r o l f o r yea r s . W i th these s igna ls i t i s pos s ib le tha tp a r a l y z e d p a t i e n t s w i l l c o n t r o l m u s c l e s t i m u l a t o r s f o rr e s to r a t ion of m ovem ent . The cone e lec t r ode i s l e s s we l ls u i t e d f o r e x p e r i m e n t a l p a r a d i g m s i f v e r y p r ec i s e h i s t o -l o g i c al l o c a l i z a t i o n o f t h e r e c o r d e d n e u r o n s i s a r e q u is i te .I n t h e s e i n s ta n c e s i t w o u l d b e d i f f ic u l t t o d e t e r m i n e t h ec e ll s o f o r i g i n o f t h e m y e l i n a t e d a x o n s . O t h e r e l e c t r o d e sdes ign ed spec i f i ca lly f o r th i s pur pos e [ 1 13] a r e bu i l t a sa r r a y s o f e t c h e d s i li c o n s h a f ts b e a r i n g m u l t i p l e r e c o r d i n gs i te s p u s h e d i n t o t h e c o r t e x . S o f a r r e c o r d e d a c t i v i t y h a sn o t p e r s i s te d b e y o n d a f e w w e e k s b u t t h e e x p e c t a t i o n i st h a t t h e s e a r r a y s w i l l re c o r d o v e r y e a rs . I n h e r e n t m o v e -m e n t p r o b l e m s t h a t l e a d t o g l io s is a r o u n d t h e t i p o f th e


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Fig . 4 . Tissue wi th in cone. Al l bars - 1 /am. A: monkey CF 63 15 mon ths a l ter im plan ta t ion o f sc ia tic nerve-fil led cone. Despi te poor p reservat ion o ft issue, cen t ra l myel inated axons (arrows) an d a cap i l la ry (*) are no ted , x3920. B: ra t WI G 2 fo l lowing 4 month s im plan ta t ion oJ Matrigel-f il led cone.A g l ia l p rocess (G) f i lled wi th in term edia te f i laments is seen a long w i th cen t ra l myel inated axons, x3640. ( ' , l ) : ra t W IG 4 fo l lowing I m onthimp lantatio n of Matrigcl-f i l led cone. Ne urop il is notcd with synapses {small arrm~s), ce mr al my elinated axon> (large arro\~s), neurites, and a fewdi la ted processes. (7. 6720; D, 8580. E: ra t W IG 4 . In an other reg ion , a cap i l la r 5 (*) is no ted wi th in neuropi l con ta in ing rg t rc neuronal perikarya

(N), dendrites (large arrow), and synapses (small arrows). 5880.

s h a f t s m a y s e p a r a t e t h e r e c o r d i n g s u r f a c e f r o m t h e r e -c o r d e d n e u r o n s a n d r e d u c e t h e s i g n a l - t o - n o i s e l e x el .S u c h p r o b l e m s w e r e p r e v io u s l y e n c o u n t e r e d w i t h a h a tp i n e l e c t r o d e ; w a x i n g a n d w a n i n g o f s i g n a ls o c c u r r e d a st h e e l e c t r o d e m o v e d [ 14 ]. N e v e r t h e l e s s , o n e h a t p i n e l e c-t r o d e d i d r e c o r d f o r th r e e y e a r s. T h e c o n e e l e c t r o d e , o nt h e o t h e r h a n d , c o n t a i n s t h e t i ss u e b e i n g r e c o r d e d , s o

t h a t a s t h e b r a in m o v e s d u r i n g a c t iv i t y , t h e r e c o r d e d t is -s u e m o v e s w i t h th e e l e c t r o d e . T h i s m a y e x p l a i n t h e p e r -s i s t c n c e a n d s t a b i l i t y o f t h e r e c o r d e d a c t i v i t y in t h e c o n ee l e c t r o d e .

T h e s e e x p e r i m e n t s w e r e c a r r i c d o u t w i t h t h e p e r m i s -s io n o f t h e In s t i tu t i o n a l A n i m a l C a r e a n d U s e C o m m i t -


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~4tee of both Yerkes Research Cente r of Emory Universi tyand the Georgia Inst i tute of Technology. Margaret L.Miles provided excellent technical assistance with theelectron microscopic s tudies . Donn Johnson providedthe illustr ations in Fig. 1. This inves tigati on was sup-ported in part by NIH Grant RR-00165 from the Na-t ional Center for Research Resources to the Yerkes Re-gional Primate Research Center. The Yerkes Center isful ly accredi ted by the Americ an Associat io n of Labora-tory Anima l Care. The invest igat ion was also supportedin part by a grant from the Americ an Paralysis Associa-t ion to Dr. Kennedy.

1 BeMent , S.L., Wise, K.D., Anderson, D.J., Najafi, K. and Drake,K.L., Solid-state electrodes for multichannel multiplexed intracorti-cal neuronal recording, IEEE Trans. Biomed. Eng., 33 (1986) 230-241.

2 Benfey, M, and Aguayo, A.-J., Extensive elongation of axons fromrat brain into peripheral nerve grafts, Nature, 296 (1982) 150-152.

3 David, S. and Aguayo, A.-J., Axonal elongation into peripheralnerve system bridges after central nervous system injury in adultrats, Science, 214 (1981) 931 033.

4 David, S. and Aguayo, A.-J., Axonal regeneration after crush injuryof rat central nervous system fibers innervating peripheral nervegrafts, J. Neurocytol., 14 (1985) l- 12.

5 DiStefano, ES. and Johnson, E.M., Induction of nerve growth fac-tor (NGF) receptors on cultured rat Schwann cells, Soc. Neurosci.Abstr., 12 (1986) 392.

6 Gasser, U.E. and Hatten, M.E., Neuron-gila interactions of rat hip-pocampal cells In vitro: glial-guided neuronal migration and neu-

ronal regulation of glial differentiation, J. Neurosci., 4 (1984) 12761285.

7 Gauthier, E and Rasminsky, M., Activity of medullary respiratoryneurons regenerating axons into peripheral nerve grafts in adult rat.Brain Res., 438 (t988) 225 236.

8 Keirstead, S .A. , Rasminsky, M., Fukuda, Y., C arter, D.A.,Aguayo, A.-J. and Vidal-Sanz, M., Electrophysiological responsesin hamster superior colliculus evoked by regenerating retinal axons.Science, 246 (1989) 255- 257.

9 Kennedy, ER., The cone electrode: a long-term electrode that ~e-cords from neurites grown onto its recording surface. J. Neurosci.Methods, 29 (1989) 181 193.

I0 Kennedy, ER., Bakay, R.A.E., Oyesiku, N. and Banks, D.M.,Long-term recording of cortical units using the Cone Electrode inmonkeys, Soc. Neurosci. Abstr., 16 (1990) 1134.

11 Letourneau, E, Pech, I., McCarthy, J., Palm, S., Skubitz, A.,Charonis, A. and Furcht, L.T., Interactions of nerve fibers withfibronectin and laminin, Int. Symp. Neural Regen. Abstr., Asilo-mar, 1987, 16.

12 Munz, M., Rasminsky, M., Aguayo, A.-J., Vidal-Sanz, M. andDevor, M.G.~ Functional activity of rat brainstem neurons regener-ating axons along peripheral nerve grafts, Brain Res., 340 (1985)115 125.

13 Najafi, K. and Wise, K.D., An implantable multielectrode arraywith on-chip signal processing, IEEE J. Solid-State Circuits, SC-21(1986) 1035-1044.

t4 Schmidt, E.M., McIntosh, J.S. and Bak, M.J. , Long-term implantsof Parylene-C coated microelectrodes, Med, Biol. Eng. Comp., 26(1988) 96 101.15 So, K.-F. and Aguayo, A.-J ., Lengthy regrowth of cut axons fromganglion cells after peripheral nerve transplantation into the retinaeof adult rats, Brain Res.. 238 (1985) 349-354.

(1992) Chronic Electrode Implantation [Kennedy]

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