Neur05c1ence• 8106ehav10ra1Rev1ew5.V01. 15. pp. 159-164. Per9am0n Pre55p1c. 1991. Pr1nted1n the U.5.A.
0149-7634191 $3.00 + .00
7he C0mpara6111ty 0f Rat and Human V15ua1-Ev0ked P0tent1a15 H. K. H U D N E L L 2 A N D W . K. 8 0 Y E 5
NeUr0phy5101091ca1 70x1C0109Y 8ranch, NeUr0t0x1C0109Y D1v1510n Hea1th EffeCt5 Re5earCh La60rat0ry, U.5. Env1r0nmenta1 Pr0tect10n A9enCy Re5earch 7r1an91e Park, NC 27711
HUDNELL, H. K. AND W. K. 80YE5. 7he c0mpara6111ty0f rat and human v15ua1.ev0kedp0tent1a15. NEUR05C1 8108EHAV REV 15(1) 159-164, 1991.--A 5er1e5 0f exper1ment5 addre55ed the 155ue 0f c0mpara6111ty am0n9 neur01091ca1 pr0ce55e5 1n p19mented rat and human v15ua1 5y5tem5. 1n the f1r5t 5et 0f exper1ment5, tran51ent v15ua1-ev0ked p0tent1a15 (VEP5) were e11c1ted 6y the 0n5et 0f 51ne-wave 9rat1n95 0f var10u5 5pat1a1 fre4uenc1e5. 7he 5pat1a1 fre4uency-re5p0n5e pr0f11e5 0f the f1r5t p051t1ve and 1mmed1ate1y 5ucceed1n9 ne9at1ve c0mp0nent5 d1ffered fr0m 0ne an0ther, 6ut were 51m11ar1n the tw0 5pec1e5. 1n add1t10n, amp11tude 0f the ne9at1ve, 6ut n0t the p051t1ve, c0mp0nent wa5 5tr0n91y attenuated 1n 60th 5pec1e5 f0110w1n95tat10nary pattern adaptat10n. 1n the 5ec0nd 5et 0f exper1ment5, 5teady-5tate VEP5 were e11c1ted6y the 0n5et and 0ff5et 0f the 9rat1n95.7he 5pat1a1 fre4uency pr0f11e50f the 1F (re5p0n5e amp11tude at the fre4uency 0f 5t1mu1u5 0n5et-0ff5et) and 2F re5p0n5e c0mp0nent5 d1ffered fr0m 0ne an0ther, 6ut were 51m11ar 1n 60th 5pec1e5. 7he f1na1 5et 0f exper1ment5 1nd1cated that d1a2epam, a 6A8A a90n15t, reduced amp11tude 0f 2F, 6ut n0t 1F, 1n 60th 5pec1e5. 7he5e re5u1t5 5u99e5ted that at 1ea5t 50me funct10na1 5u65y5tem5 med1at1n9 5pat1a1 v1510n 1n human5 may have 4ua11tat1ve1y 51m11arc0unterpart5 1n rat5. Rat
Human
V1510n
Pat1em adaptat10n
Ev0ked p0tent1a15
V15ua1-ev0kedp0tent1a15
D1a2epam
ter5peC1e5 c0mpara6111ty 0f pattern and m0t10n v1510n, perceptua1 c0rre1ate5 0f the 0ther tw0 pr1mate pathway5, the parv0 + ma9n0 1nter6106 and ma9n0 pathway5, re5pect1ve1y. 7he 06ject1ve 0f the current 5tudy wa5 t0 Character12e 51m11ar1t1e5 and d1fference5 0f the rat and human v15ua1 5y5tem a5 ref1ected 6y neur0phy5101091ca1 mea5urement endp01nt5. 7h15 155ue wa5 addre55ed u51n9 a three-pr0n9ed appr0ach. 7he f1r5t wa5 t0 rec0rd VEP5 fr0m 60th 5pec1e5 a5 an 1ndex 0f v15ua1 funct10n. 7hat 15, the 5ame mea5urement endp01nt5 were c011ected fr0m human5 and rat5 under c0mpara61e exper1menta1 c0nd1t10n5. VEP5 were rec0rded fr0m human5 and rat5 wh0 were unane5thet12ed wh11e v1ew1n9 c0mpara61e v15ua1 5t1mu11.7he 5ec0nd pr0n9 wa5 t0 5y5temat1ca11y vary 5t1mu1u5 parameter5 wh11e rec0rd1n9 VEP5 fr0m 60th 5pec1e5. Parametr1c man1pu1at10n5 0f 5t1mu11 may 1nd1cate the extent t0 wh1ch VEP5 ref1ect 51m11ar under1y1n9 phy5101091ca1 pr0ce55e5. Effect5 0f 5pat1a1 fre4uency, 0r 6ar 512e 0f a 51ne-wave 9rat1n9, 0n 60th tran51ent and 5teady-5tate VEP5 were 1nve5t19ated. 1n add1t10n, effect5 0f 5tat10nary pattern adaptat10n 0n VEP5 e11c1ted fr0m 60th 5pec1e5 were 5tud1ed. 7he 5tat10nary pattern adaptat10n effect 15 kn0wn fr0m the human p5ych0phy51ca1 11terature. 1f human5 100k at a te5t 6ar pattern f0r 0ne m1nute 6ef0re mea5ur1n9 c0ntra5t thre5h01d f0r the 5ame pattern, thre5h01d 15 much h19her than 1f an 111um1nated 61ank f1e1d 15 v1ewed pr10r t0 te5t1n9 (2). 51m11ar1y, a h19h c0ntra5t tar9et appear5 faded
V15UAL-EV0KED p0tent1a15 (VEP5) are kn0wn t0 6e 5en51t1ve 1nd1cat0r5 0f neur0t0x1c effect5 1n the CN5. 0 u t 0f th1rty-5even c0mp0und5 te5ted u51n9 VEP techn14ue5 0n rat5, a11 c0mp0und5 1nd1cated t0 6e neur0t0x1c 6y 0ther meth0d01091e5 519n1f1cant1y affected VEP5 (6). D05a9e 1eve15 were 51m11ar t0 th05e c0mm0n1y u5ed 1n neur0t0x1c01091ca1 5tud1e5, and effect5 were 0ften 5een at re1at1ve1y 10w d05a9e5. C0mp0und5 n0t th0u9ht t0 6e neur0t0x1c 0r neur0act1ve d1d n0t a1ter VEP5 (6). 7heref0re, VEP data c011ected fr0m rat5, a 5tandard 5u6ject 1n neur0t0x1c01091ca1 5tud1e5, may p1ay an 1mp0rtant r01e 1n human hea1th r15k-a55e55ment ana1y5e5. H0wever, 11tt1e 15 kn0wn a60ut the c0mpara6111ty 0f rat and human v15ua1 5y5tem5. Few 5tud1e5 have c0mpared the phy5101091ca1 and pharmac01091ca1 pr0ce55e5 under1y1n9 v1510n 1n the tw0 5pec1e5 (15). 7heref0re, the accuracy w1th wh1ch human hea1th effect5 1n the v15ua1 5y5tem are pred1cted 6y rat data 15 unkn0wn. 7he uncerta1nty 1n extrap01at1n9 neur0t0x1c effect5 fr0m the rat t0 the human v15ua1 5y5tem can 6e reduced 6y 5tud1e5 wh1ch eva1uate the c0mpara6111ty 0f rat and human v15ua1 5y5tem5. 1t ha5 6een pr0p05ed that the pr1mate 9en1cu10c0rt1ca1 v15ua1 5y5tem c0n515t5 0f three para11e1 pathway5 (18,19). Rat v15ua1 neur0n5 1ack the de9ree 0f phy51ca1 5e9re9at10n 5een 1n the pr1mate 9en1cu10c0rt1ca1 5y5tem [d15cu55ed 1n (15)], wh1ch d1fferent1ate5 the three pathway5, and the perceptua1 c0rre1ate 0f 0ne 0f the pathway5, c010r v1510n. 7he current 5tudy f0cu5ed 0n the 1n-
~D15c1a1mer: 7h15 manu5cr1pt ha5 6een rev1ewed 1n acc0rdance w1th U.5. Env1r0nmenta1 Pr0tect10n A9ency p011cy and appr0ved f0r pu611cat10n. Ment10n 0f trade name5 0r c0mmerc1a1 pr0duct5 d0e5 n0t c0n5t1tute end0r5ement 0r rec0mmendat10n f0r u5e. 2Re4ue5t5 f0r repr1nt5 5h0u1d 6e addre55ed t0 Dr. H. K. Hudne11, U.5. Env1r0nmenta1 Pr0tect10n A9ency, Neur0t0x1c0109y D1v1510n, MD 748, Re5earch 7r1an91e Park, NC 27711. 159
160
HUDNELL AND 8 0 Y E 5
0r wa5hed 0ut f0110w1n9 pattern adaptat10n (3). A pattern adaptat10n parad19m wa5 u5ed 1n the current 5tudy t0 100k f0r a c0rre5p0nd1n9 phen0men0n 1n the VEP5 0f 60th 5pec1e5. 7he th1rd pr0n9 0f 0ur appr0ach wa5 t0 adm1n15ter the 5ame chem1ca1 c0mp0und5 t0 60th 5pec1e5. Dru9 man1pu1at10n5 may 1nd1cate the extent t0 wh1ch VEP5 ref1ect 51m11ar under1y1n9 pharmac01091ca1 5y5tem5 1n the tw0 5pec1e5. Effect5 0f d1a2epam, wh1ch p0tent1ate5 effect5 0f the 1nh161t0ry neur0tran5m1tter 6 A 8 A , 0n 5teady5tate VEP5 are rep0rted here. ME7H0D
5t1mu11 Pattem-0n5et VEP5 were e11c1ted 6y vert1ca1 51nu501da1 9rat1n95 0f 0.5, 1, 2, 4, 0r 8 cpd f0r human5 and 0f 0.04 0r 0.05, 0.1, 0.2, 0.4, 0r 0.8 cpd f0r rat5. 7he 6ar pattern appeared (a pre5et c0ntra5t va1ue, c0ntra5t = (Lmax - Lm1n)/(Lmax + Lm1n) × 100, L=1um1nance) and d15appeared (0% c0ntra5t) 1n temp0ra1 54uare-wave fa5h10n. 5pace-avera9ed 1um1nance wa5 he1d c0n5tant at 10 cd/m 2 f0r human5 and at 14.2 cd/m 2 f0r rat5. F1e1d 512e wa5 10 x 10 de9ree5 0f v15ua1 an91e f0r human5. F1e1d 512e f0r rat5 wa5 49 × 41 de9ree5 0f v15ua1 an91e 1n the tran51ent VEP exper1ment5 and 67 × 60 de9ree5 0f v15ua1 an91e 1n the 5teady5tate VEP exper1ment5.7he 1ar9er f1e1d 512e5 u5ed w1th rat5 he1ped t0 1n5ure that the 5t1mu11 were 1n v1ew dur1n9 te5t1n9. Pr0cedure5 f0r 9enerat1n9 and ca116rat1n9 the 5t1mu11 were pu6115hed prev10u51y (14,15).
E1ectr0phy5101091ca1 7echn14ue5 511ver-ch10r1de cup e1ectr0de5 were p051t10ned 0n human 5ca1p at 02 (act1ve), 0n 60th ma5t01d5 (reference 11nked thr~u9h 6ra55 amp11f1er), 0n the f0rehead (9r0und) and a60ve and 6e10w the r19ht eye (f0r 0n-11ne reject10n 0f tr1a15 c0ntam1nated 6y eye 611nk5 0r 1ar9e eye m0vement5). Pr0cedure5 f0r rec0rd1n9 and ca116rat1n9 the VEP5 were pu6115hed prev10u51y (14,15). 5ta1n1e55 5tee1 5crew-rec0rd1n9 e1ectr0de5 were 5ur91ca11y 1mp1anted 1nt0 adu1t ma1e L0n9-Evan5 rat 5ku115 u51n9 pr0cedure5 pu6115hed e15ewhere (7). V01ta9e5 rec0rded fr0m rat5 were 9enera11y 1ar9er than th05e rec0rded fr0m human5, 51nce the 1mp1antat10n meth0d e11m1nated e1ectr1ca1 1mpedance 0f the 5ku11. Rat5 were re5tra1ned 1n c10th harne55e5 f0r te5t1n9 (15) 1n 11eu 0f u51n9 ane5thet1c5. Rat5 were m0n1t0red 0n c105e-c1rcu1t te1ev1510n and te5t1n9 wa5 5u5pended when rat5 were n0t attend1n9 t0 the te5t 5creen. E1ectr0phy5101091ca1 pr0cedure5 u5ed t0 rec0rd VEP5 fr0m rat5 have 6een de5cr16ed 1n 9reater deta11 prev10u51y (7).
7ran51ent VEP5 VEP5 were rec0rded fr0m three tra1ned human 065erver5, w1th n0rma1 0r c0rrected t0 n0rma1 v15ua1 acu1ty, u51n9 a repeatedmea5ure5 de519n and pr0cedure5 pu6115hed prev10u51y (14,15). Each c0nd1t10n wa5 pre5ented 1n rand0m 0rder 0nce per 5e5510n f0r three 5e5510n5 w1th each 5u6ject. Ju5t pr10r t0 each te5t, 5u6ject5 v1ewed a 119ht adaptat10n 5creen (60 x 80 de9ree5 0f v15ua1 an91e 5et t0 60 cd/m 2) f0r 0ne m1nute. 5u6ject5 then v1ewed a 61ank f1e1d 0r a 5tat10nary 9rat1n9 0f the 5ame 5pat1a1 fre4uency and 0r1entat10n a5 the te5t 9rat1n9 5et t0 60% c0ntra5t f0r 0ne m1nute. F1fty tr1a15 0f VEP5 e11c1ted 6y te5t 9rat1n95 5et t0 20% c0ntra5t were rec0rded dur1n9 each te5t per10d, and 1nd1v1dua1 tr1a15 were 5eparated 6y rand0m 1en9th per10d5 (0.5-1.5 5) 0f adaptat10n tar9et and/0r 61ank f1e1d v1ew1n9. VEP5 were rec0rded fr0m rat5 u51n9 pr0cedure5 pu6115hed prev10u51y (14). N1neteen rat5 were te5ted 0nce w1th each c0nd1t10n
0f 61ank f1e1d v1ew1n9 f0110wed 6y the c011ect10n 0f VEP5 e11c1ted 6y 9rat1n95 0f 30% 0r 50% c0ntra5t. 7he5e data were p001ed 51nce 5tat15t1ca1 ana1y515 revea1ed n0 519n1f1cant effect 0f c0ntra5t 1eve1. H19her 5t1mu1u5 c0ntra5t5 were re4u1red f0r rat5 than human5 1n 0rder t0 rec0rd re11a61e wavef0rm5. 5eventeen d1fferent rat5 were te5ted 1n c0nd1t10n5 0f 61ank f1e1d 0r 5tat10nary te5t-pattern adaptat10n f0r 0ne m1nute f0110wed 6y the c011ect10n 0f VEP5. C0ntra5t 0f 60th the adaptat10n and te5t 9rat1n95 wa5 50%. A11 c0nd1t10n5 were pre5ented 1n rand0m 0rder. Data f0r 60th 5pec1e5 were ana1y2ed 6y p1ck1n9 peak5 1n each 1nd1v1dua1 wavef0rm 6y eye and then mea5ur1n9 the peak amp11tude and 1atency. Re5u1t5 were te5ted f0r 519n1f1cance w1th repeated mea5ure5 A N 0 V A ana1y5e5. Effect5 519n1f1cant acr055 5pat1a1 fre4uency were f0110wed 6y t-te5t5 at 1nd1v1dua1 5pat1a1 fre4uenc1e5.
5teady-5tate VEP5 7hree tra1ned human 065erver5 w1th n0rma1 v15ua1 acu1ty were te5ted 0ver f0ur 5e5510n5. E1even rat5 were te5ted 1n 0ne 5e5510n. 80th the human and rat exper1ment5 c0n515ted 0f twenty-f1ve c0nd1t10n5 pre5ented 1n rand0m 0rder. F1ve 9rat1n95 0f d1fferent 5pat1a1 fre4uency were m0du1ated at 3, 5, 7, 10, and 20 H2. 7he 9rat1n95 were 5et t0 20% c0ntra5t f0r 60th 5pec1e5. Human 5u6ject5 v1ewed the 1ar9e 119ht adaptat10n 5creen f0r 0ne m1nute and then v1ewed a 61ank f1e1d 0n the te5t 5creen f0r 0ne m1nute pr10r t0 data c011ect10n. 7he te5t 5t1mu1u5 wa5 pre5ented f0r 2048 m5 dur1n9 each tr1a1 and data wa5 c011ected dur1n9 the 1a5t 1024 m5. 5ucce551ve tr1a15 were 5eparated 6y rand0m 1en9th per10d5 0f 61ank f1e1d v1ew1n9 ran91n9 1n durat10n fr0m 650-750 m5. F1fty tr1a15 were rec0rded dur1n9 each te5t per10d f0r 60th 5pec1e5. Rat5 v1ewed a 61ank f1e1d 0f 119ht 0n the te5t 5creen f0r tw0 m1nute5 pr10r t0 each te5t. 7he te5t 5t1mu1u5 wa5 pre5ented c0nt1nu0u51y 1n 0rder t0 5h0rten the te5t per10d durat10n, and data wa5 c011ected 1n 5ucce551ve 1024 m5 ep0ch5. Each 5u6ject•5 data f11e5 were ana1y2ed u51n9 a 5pectra1 ana1y515 techn14ue 1n wh1ch a fa5t F0ur1er tran5f0rm c0nverted the data fr0m the t1me d0ma1n t0 the fre4uency d0ma1n. Data p01nt5 were expre55ed a5 amp11tude (p,V, 6a5ed 0n a ca116rat10n fact0r) at each 1nte9er 5pat1a1 fre4uency up t0 100 H2. M05t 0f the p0wer 1n the wavef0rm5 wa5 c0ncentrated at the 0n5et-0ff5et fre4uency (the 1F c0mp0nent), and tw1ce the 0n5et-0ff5et fre4uency (2F), w1th 50me p0wer at h19her harm0n1c5 0f the fundamenta1.6r0upavera9e amp11tude5 0f the 1F and 2F c0mp0nent5 are rep0rted here. 7he pha5e 0f each c0mp0nent wa5 ca1cu1ated a150, and the5e data were u5ed a5 1nd1cat0r5 0f re11a6111ty (1.e., t0 determ1ne when 519na15 exceeded the n015e 1eve1).
D1a2epam 7he 5teady-5tate VEP pr0cedure5 u5ed 1n the d1a2epam exper1ment5 were 51m11ar t0 th05e de5cr16ed f0r 5teady-5tate VEP5, except that the 5t1mu11 were m0du1ated at 0n1y 0ne temp0ra1 fre4uency, 5 H2, and c0ntra5t wa5 30%. F0rty-f0ur rat5 and th1rty na1ve human5 (w1th n0rma1 0r c0rrected t0 n0rma1 v15ua1 acu1ty) 5erved a5 5u6ject5. Ha1f 0f the 5u6ject5 1n each 9r0up rece1ved a p1ace60 and ha1f rece1ved d1a2epam. Exp05ure c0nd1t10n wa5 a5519ned at rand0m 1n d0u61e-611nd exper1ment5. 5u6ject5 were te5ted 6ef0re and after treatment. 7he d05a9e f0r rat5 wa5 e1ther 0, 0.067, 0.125, 0.25 0r 0.5 m9/k9, wherea5 a11 human5 rece1ved 10 m9 (appr0x1mate1y 0.14 m9/k9 0n avera9e). Re5u1t5 were te5ted f0r 0vera11 exp05ure effect5 w1th AN0VA5 and 519n1f1cant effect5 were further ana1y2ed w1th t-te5t5. RE5UL75
7ran51ent VEP5 Pattern-0n5et VEP5 were e11c1ted fr0m human5 and rat5 6y
RA7 AND HUMAN V15UAL-EV0KED P07EN71AL5
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R A 7 P1
161
RA7
HUMAN P0
8LANK F1ELD pA77ERN
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0.04 0R)
e~ 1
0
--
311 0
-51-
50
100 150 200 250 300 350
7 ~ (nme)
-41
-31 -21 -1 0.04
0.1
0.2 0.4 5PA71AL
0.5
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FRE~Y (cpd)
2
4
F16. 1. 6r0up-avera9e amp11tude5 fr0m 1nd1v1dua15u6ject•5 va1ue5 f0r the f1r5t p051t1veand 1mmed1ate1y5ucceed1n9ne9at1vec0mp0nent5 acr055 5pat1a1 fre4uency. 7he p051t1vec0mp0nent f0r 60th 5pec1e5 wa5 character12ed 6y a 10w-pa555pat1a1fre4uency pr0f11e. 7he rat N2 c0mp0nent had a 6and-pa55 5pat1a1 fre4uency pr0f11e, wherea5 the human N1 c0mp0nent wa5 1ar9e5t at the h19he5t 5pat1a1 fre4uency te5ted.
f0ur 9rat1n95 5pann1n9 a 5pat1a1 fre4uency ran9e 0f appr0x1mate1y 1 109 un1t. 7he 5pat1a1 fre4uenc1e5 u5ed w1th rat5 were a60ut 1 109 un1t 10wer than th05e u5ed w1th human5, 51nce rat5 are una61e t0 detect 6ar5 a5 5ma11 a5 th05e detected 6y human5 (7). 7he 5tudy f0cu5ed 0n the 5pat1a1 fre4uency-amp11tude funct10n5 0f the ftr5t p051t1ve and 1mmed1ate1y 5ucceed1n9 ne9at1ve c0mp0nent5 1n the wavef0rm5 0f 60th 5pec1e5.7he f1r5t p051t1ve c0mp0nent f0r rat5, P1, and f0r human5, P0, a5 we11 a5 the f0110w1n9 ne9at1ve c0mp0nent5, N2 f0r rat5 and N1 f0r human5, were 1a6e1ed acc0rd1n9 t0 pr10r c0nvent10n (7, 16, 21). Avera9e 1atenc1e5 0f the human c0mp0nent5 were 84 and 112 m5, wherea5, th05e f0r rat5 were 92 and 1 13 m5. A5 5h0wn 1n F19. 1, amp11tude 0f the p051t1ve c0mp0nent 1ncrea5ed a5 5pat1a1 fre4uency decrea5ed f0r 60th 5pec1e5. 7hat 15, the 5pat1a1 fre4uency pr0f11e5 0f the p051t1ve c0mp0nent5 had 10wpa55 5hape5. 7he 0vera11 effect 0f 5pat1a1 fre4uency 1n rat5 wa5 5tat15t1ca11y 519n1f1cant, F(3,144) = 22.02, p
0149-7634191 $3.00 + .00
7he C0mpara6111ty 0f Rat and Human V15ua1-Ev0ked P0tent1a15 H. K. H U D N E L L 2 A N D W . K. 8 0 Y E 5
NeUr0phy5101091ca1 70x1C0109Y 8ranch, NeUr0t0x1C0109Y D1v1510n Hea1th EffeCt5 Re5earCh La60rat0ry, U.5. Env1r0nmenta1 Pr0tect10n A9enCy Re5earch 7r1an91e Park, NC 27711
HUDNELL, H. K. AND W. K. 80YE5. 7he c0mpara6111ty0f rat and human v15ua1.ev0kedp0tent1a15. NEUR05C1 8108EHAV REV 15(1) 159-164, 1991.--A 5er1e5 0f exper1ment5 addre55ed the 155ue 0f c0mpara6111ty am0n9 neur01091ca1 pr0ce55e5 1n p19mented rat and human v15ua1 5y5tem5. 1n the f1r5t 5et 0f exper1ment5, tran51ent v15ua1-ev0ked p0tent1a15 (VEP5) were e11c1ted 6y the 0n5et 0f 51ne-wave 9rat1n95 0f var10u5 5pat1a1 fre4uenc1e5. 7he 5pat1a1 fre4uency-re5p0n5e pr0f11e5 0f the f1r5t p051t1ve and 1mmed1ate1y 5ucceed1n9 ne9at1ve c0mp0nent5 d1ffered fr0m 0ne an0ther, 6ut were 51m11ar1n the tw0 5pec1e5. 1n add1t10n, amp11tude 0f the ne9at1ve, 6ut n0t the p051t1ve, c0mp0nent wa5 5tr0n91y attenuated 1n 60th 5pec1e5 f0110w1n95tat10nary pattern adaptat10n. 1n the 5ec0nd 5et 0f exper1ment5, 5teady-5tate VEP5 were e11c1ted6y the 0n5et and 0ff5et 0f the 9rat1n95.7he 5pat1a1 fre4uency pr0f11e50f the 1F (re5p0n5e amp11tude at the fre4uency 0f 5t1mu1u5 0n5et-0ff5et) and 2F re5p0n5e c0mp0nent5 d1ffered fr0m 0ne an0ther, 6ut were 51m11ar 1n 60th 5pec1e5. 7he f1na1 5et 0f exper1ment5 1nd1cated that d1a2epam, a 6A8A a90n15t, reduced amp11tude 0f 2F, 6ut n0t 1F, 1n 60th 5pec1e5. 7he5e re5u1t5 5u99e5ted that at 1ea5t 50me funct10na1 5u65y5tem5 med1at1n9 5pat1a1 v1510n 1n human5 may have 4ua11tat1ve1y 51m11arc0unterpart5 1n rat5. Rat
Human
V1510n
Pat1em adaptat10n
Ev0ked p0tent1a15
V15ua1-ev0kedp0tent1a15
D1a2epam
ter5peC1e5 c0mpara6111ty 0f pattern and m0t10n v1510n, perceptua1 c0rre1ate5 0f the 0ther tw0 pr1mate pathway5, the parv0 + ma9n0 1nter6106 and ma9n0 pathway5, re5pect1ve1y. 7he 06ject1ve 0f the current 5tudy wa5 t0 Character12e 51m11ar1t1e5 and d1fference5 0f the rat and human v15ua1 5y5tem a5 ref1ected 6y neur0phy5101091ca1 mea5urement endp01nt5. 7h15 155ue wa5 addre55ed u51n9 a three-pr0n9ed appr0ach. 7he f1r5t wa5 t0 rec0rd VEP5 fr0m 60th 5pec1e5 a5 an 1ndex 0f v15ua1 funct10n. 7hat 15, the 5ame mea5urement endp01nt5 were c011ected fr0m human5 and rat5 under c0mpara61e exper1menta1 c0nd1t10n5. VEP5 were rec0rded fr0m human5 and rat5 wh0 were unane5thet12ed wh11e v1ew1n9 c0mpara61e v15ua1 5t1mu11.7he 5ec0nd pr0n9 wa5 t0 5y5temat1ca11y vary 5t1mu1u5 parameter5 wh11e rec0rd1n9 VEP5 fr0m 60th 5pec1e5. Parametr1c man1pu1at10n5 0f 5t1mu11 may 1nd1cate the extent t0 wh1ch VEP5 ref1ect 51m11ar under1y1n9 phy5101091ca1 pr0ce55e5. Effect5 0f 5pat1a1 fre4uency, 0r 6ar 512e 0f a 51ne-wave 9rat1n9, 0n 60th tran51ent and 5teady-5tate VEP5 were 1nve5t19ated. 1n add1t10n, effect5 0f 5tat10nary pattern adaptat10n 0n VEP5 e11c1ted fr0m 60th 5pec1e5 were 5tud1ed. 7he 5tat10nary pattern adaptat10n effect 15 kn0wn fr0m the human p5ych0phy51ca1 11terature. 1f human5 100k at a te5t 6ar pattern f0r 0ne m1nute 6ef0re mea5ur1n9 c0ntra5t thre5h01d f0r the 5ame pattern, thre5h01d 15 much h19her than 1f an 111um1nated 61ank f1e1d 15 v1ewed pr10r t0 te5t1n9 (2). 51m11ar1y, a h19h c0ntra5t tar9et appear5 faded
V15UAL-EV0KED p0tent1a15 (VEP5) are kn0wn t0 6e 5en51t1ve 1nd1cat0r5 0f neur0t0x1c effect5 1n the CN5. 0 u t 0f th1rty-5even c0mp0und5 te5ted u51n9 VEP techn14ue5 0n rat5, a11 c0mp0und5 1nd1cated t0 6e neur0t0x1c 6y 0ther meth0d01091e5 519n1f1cant1y affected VEP5 (6). D05a9e 1eve15 were 51m11ar t0 th05e c0mm0n1y u5ed 1n neur0t0x1c01091ca1 5tud1e5, and effect5 were 0ften 5een at re1at1ve1y 10w d05a9e5. C0mp0und5 n0t th0u9ht t0 6e neur0t0x1c 0r neur0act1ve d1d n0t a1ter VEP5 (6). 7heref0re, VEP data c011ected fr0m rat5, a 5tandard 5u6ject 1n neur0t0x1c01091ca1 5tud1e5, may p1ay an 1mp0rtant r01e 1n human hea1th r15k-a55e55ment ana1y5e5. H0wever, 11tt1e 15 kn0wn a60ut the c0mpara6111ty 0f rat and human v15ua1 5y5tem5. Few 5tud1e5 have c0mpared the phy5101091ca1 and pharmac01091ca1 pr0ce55e5 under1y1n9 v1510n 1n the tw0 5pec1e5 (15). 7heref0re, the accuracy w1th wh1ch human hea1th effect5 1n the v15ua1 5y5tem are pred1cted 6y rat data 15 unkn0wn. 7he uncerta1nty 1n extrap01at1n9 neur0t0x1c effect5 fr0m the rat t0 the human v15ua1 5y5tem can 6e reduced 6y 5tud1e5 wh1ch eva1uate the c0mpara6111ty 0f rat and human v15ua1 5y5tem5. 1t ha5 6een pr0p05ed that the pr1mate 9en1cu10c0rt1ca1 v15ua1 5y5tem c0n515t5 0f three para11e1 pathway5 (18,19). Rat v15ua1 neur0n5 1ack the de9ree 0f phy51ca1 5e9re9at10n 5een 1n the pr1mate 9en1cu10c0rt1ca1 5y5tem [d15cu55ed 1n (15)], wh1ch d1fferent1ate5 the three pathway5, and the perceptua1 c0rre1ate 0f 0ne 0f the pathway5, c010r v1510n. 7he current 5tudy f0cu5ed 0n the 1n-
~D15c1a1mer: 7h15 manu5cr1pt ha5 6een rev1ewed 1n acc0rdance w1th U.5. Env1r0nmenta1 Pr0tect10n A9ency p011cy and appr0ved f0r pu611cat10n. Ment10n 0f trade name5 0r c0mmerc1a1 pr0duct5 d0e5 n0t c0n5t1tute end0r5ement 0r rec0mmendat10n f0r u5e. 2Re4ue5t5 f0r repr1nt5 5h0u1d 6e addre55ed t0 Dr. H. K. Hudne11, U.5. Env1r0nmenta1 Pr0tect10n A9ency, Neur0t0x1c0109y D1v1510n, MD 748, Re5earch 7r1an91e Park, NC 27711. 159
160
HUDNELL AND 8 0 Y E 5
0r wa5hed 0ut f0110w1n9 pattern adaptat10n (3). A pattern adaptat10n parad19m wa5 u5ed 1n the current 5tudy t0 100k f0r a c0rre5p0nd1n9 phen0men0n 1n the VEP5 0f 60th 5pec1e5. 7he th1rd pr0n9 0f 0ur appr0ach wa5 t0 adm1n15ter the 5ame chem1ca1 c0mp0und5 t0 60th 5pec1e5. Dru9 man1pu1at10n5 may 1nd1cate the extent t0 wh1ch VEP5 ref1ect 51m11ar under1y1n9 pharmac01091ca1 5y5tem5 1n the tw0 5pec1e5. Effect5 0f d1a2epam, wh1ch p0tent1ate5 effect5 0f the 1nh161t0ry neur0tran5m1tter 6 A 8 A , 0n 5teady5tate VEP5 are rep0rted here. ME7H0D
5t1mu11 Pattem-0n5et VEP5 were e11c1ted 6y vert1ca1 51nu501da1 9rat1n95 0f 0.5, 1, 2, 4, 0r 8 cpd f0r human5 and 0f 0.04 0r 0.05, 0.1, 0.2, 0.4, 0r 0.8 cpd f0r rat5. 7he 6ar pattern appeared (a pre5et c0ntra5t va1ue, c0ntra5t = (Lmax - Lm1n)/(Lmax + Lm1n) × 100, L=1um1nance) and d15appeared (0% c0ntra5t) 1n temp0ra1 54uare-wave fa5h10n. 5pace-avera9ed 1um1nance wa5 he1d c0n5tant at 10 cd/m 2 f0r human5 and at 14.2 cd/m 2 f0r rat5. F1e1d 512e wa5 10 x 10 de9ree5 0f v15ua1 an91e f0r human5. F1e1d 512e f0r rat5 wa5 49 × 41 de9ree5 0f v15ua1 an91e 1n the tran51ent VEP exper1ment5 and 67 × 60 de9ree5 0f v15ua1 an91e 1n the 5teady5tate VEP exper1ment5.7he 1ar9er f1e1d 512e5 u5ed w1th rat5 he1ped t0 1n5ure that the 5t1mu11 were 1n v1ew dur1n9 te5t1n9. Pr0cedure5 f0r 9enerat1n9 and ca116rat1n9 the 5t1mu11 were pu6115hed prev10u51y (14,15).
E1ectr0phy5101091ca1 7echn14ue5 511ver-ch10r1de cup e1ectr0de5 were p051t10ned 0n human 5ca1p at 02 (act1ve), 0n 60th ma5t01d5 (reference 11nked thr~u9h 6ra55 amp11f1er), 0n the f0rehead (9r0und) and a60ve and 6e10w the r19ht eye (f0r 0n-11ne reject10n 0f tr1a15 c0ntam1nated 6y eye 611nk5 0r 1ar9e eye m0vement5). Pr0cedure5 f0r rec0rd1n9 and ca116rat1n9 the VEP5 were pu6115hed prev10u51y (14,15). 5ta1n1e55 5tee1 5crew-rec0rd1n9 e1ectr0de5 were 5ur91ca11y 1mp1anted 1nt0 adu1t ma1e L0n9-Evan5 rat 5ku115 u51n9 pr0cedure5 pu6115hed e15ewhere (7). V01ta9e5 rec0rded fr0m rat5 were 9enera11y 1ar9er than th05e rec0rded fr0m human5, 51nce the 1mp1antat10n meth0d e11m1nated e1ectr1ca1 1mpedance 0f the 5ku11. Rat5 were re5tra1ned 1n c10th harne55e5 f0r te5t1n9 (15) 1n 11eu 0f u51n9 ane5thet1c5. Rat5 were m0n1t0red 0n c105e-c1rcu1t te1ev1510n and te5t1n9 wa5 5u5pended when rat5 were n0t attend1n9 t0 the te5t 5creen. E1ectr0phy5101091ca1 pr0cedure5 u5ed t0 rec0rd VEP5 fr0m rat5 have 6een de5cr16ed 1n 9reater deta11 prev10u51y (7).
7ran51ent VEP5 VEP5 were rec0rded fr0m three tra1ned human 065erver5, w1th n0rma1 0r c0rrected t0 n0rma1 v15ua1 acu1ty, u51n9 a repeatedmea5ure5 de519n and pr0cedure5 pu6115hed prev10u51y (14,15). Each c0nd1t10n wa5 pre5ented 1n rand0m 0rder 0nce per 5e5510n f0r three 5e5510n5 w1th each 5u6ject. Ju5t pr10r t0 each te5t, 5u6ject5 v1ewed a 119ht adaptat10n 5creen (60 x 80 de9ree5 0f v15ua1 an91e 5et t0 60 cd/m 2) f0r 0ne m1nute. 5u6ject5 then v1ewed a 61ank f1e1d 0r a 5tat10nary 9rat1n9 0f the 5ame 5pat1a1 fre4uency and 0r1entat10n a5 the te5t 9rat1n9 5et t0 60% c0ntra5t f0r 0ne m1nute. F1fty tr1a15 0f VEP5 e11c1ted 6y te5t 9rat1n95 5et t0 20% c0ntra5t were rec0rded dur1n9 each te5t per10d, and 1nd1v1dua1 tr1a15 were 5eparated 6y rand0m 1en9th per10d5 (0.5-1.5 5) 0f adaptat10n tar9et and/0r 61ank f1e1d v1ew1n9. VEP5 were rec0rded fr0m rat5 u51n9 pr0cedure5 pu6115hed prev10u51y (14). N1neteen rat5 were te5ted 0nce w1th each c0nd1t10n
0f 61ank f1e1d v1ew1n9 f0110wed 6y the c011ect10n 0f VEP5 e11c1ted 6y 9rat1n95 0f 30% 0r 50% c0ntra5t. 7he5e data were p001ed 51nce 5tat15t1ca1 ana1y515 revea1ed n0 519n1f1cant effect 0f c0ntra5t 1eve1. H19her 5t1mu1u5 c0ntra5t5 were re4u1red f0r rat5 than human5 1n 0rder t0 rec0rd re11a61e wavef0rm5. 5eventeen d1fferent rat5 were te5ted 1n c0nd1t10n5 0f 61ank f1e1d 0r 5tat10nary te5t-pattern adaptat10n f0r 0ne m1nute f0110wed 6y the c011ect10n 0f VEP5. C0ntra5t 0f 60th the adaptat10n and te5t 9rat1n95 wa5 50%. A11 c0nd1t10n5 were pre5ented 1n rand0m 0rder. Data f0r 60th 5pec1e5 were ana1y2ed 6y p1ck1n9 peak5 1n each 1nd1v1dua1 wavef0rm 6y eye and then mea5ur1n9 the peak amp11tude and 1atency. Re5u1t5 were te5ted f0r 519n1f1cance w1th repeated mea5ure5 A N 0 V A ana1y5e5. Effect5 519n1f1cant acr055 5pat1a1 fre4uency were f0110wed 6y t-te5t5 at 1nd1v1dua1 5pat1a1 fre4uenc1e5.
5teady-5tate VEP5 7hree tra1ned human 065erver5 w1th n0rma1 v15ua1 acu1ty were te5ted 0ver f0ur 5e5510n5. E1even rat5 were te5ted 1n 0ne 5e5510n. 80th the human and rat exper1ment5 c0n515ted 0f twenty-f1ve c0nd1t10n5 pre5ented 1n rand0m 0rder. F1ve 9rat1n95 0f d1fferent 5pat1a1 fre4uency were m0du1ated at 3, 5, 7, 10, and 20 H2. 7he 9rat1n95 were 5et t0 20% c0ntra5t f0r 60th 5pec1e5. Human 5u6ject5 v1ewed the 1ar9e 119ht adaptat10n 5creen f0r 0ne m1nute and then v1ewed a 61ank f1e1d 0n the te5t 5creen f0r 0ne m1nute pr10r t0 data c011ect10n. 7he te5t 5t1mu1u5 wa5 pre5ented f0r 2048 m5 dur1n9 each tr1a1 and data wa5 c011ected dur1n9 the 1a5t 1024 m5. 5ucce551ve tr1a15 were 5eparated 6y rand0m 1en9th per10d5 0f 61ank f1e1d v1ew1n9 ran91n9 1n durat10n fr0m 650-750 m5. F1fty tr1a15 were rec0rded dur1n9 each te5t per10d f0r 60th 5pec1e5. Rat5 v1ewed a 61ank f1e1d 0f 119ht 0n the te5t 5creen f0r tw0 m1nute5 pr10r t0 each te5t. 7he te5t 5t1mu1u5 wa5 pre5ented c0nt1nu0u51y 1n 0rder t0 5h0rten the te5t per10d durat10n, and data wa5 c011ected 1n 5ucce551ve 1024 m5 ep0ch5. Each 5u6ject•5 data f11e5 were ana1y2ed u51n9 a 5pectra1 ana1y515 techn14ue 1n wh1ch a fa5t F0ur1er tran5f0rm c0nverted the data fr0m the t1me d0ma1n t0 the fre4uency d0ma1n. Data p01nt5 were expre55ed a5 amp11tude (p,V, 6a5ed 0n a ca116rat10n fact0r) at each 1nte9er 5pat1a1 fre4uency up t0 100 H2. M05t 0f the p0wer 1n the wavef0rm5 wa5 c0ncentrated at the 0n5et-0ff5et fre4uency (the 1F c0mp0nent), and tw1ce the 0n5et-0ff5et fre4uency (2F), w1th 50me p0wer at h19her harm0n1c5 0f the fundamenta1.6r0upavera9e amp11tude5 0f the 1F and 2F c0mp0nent5 are rep0rted here. 7he pha5e 0f each c0mp0nent wa5 ca1cu1ated a150, and the5e data were u5ed a5 1nd1cat0r5 0f re11a6111ty (1.e., t0 determ1ne when 519na15 exceeded the n015e 1eve1).
D1a2epam 7he 5teady-5tate VEP pr0cedure5 u5ed 1n the d1a2epam exper1ment5 were 51m11ar t0 th05e de5cr16ed f0r 5teady-5tate VEP5, except that the 5t1mu11 were m0du1ated at 0n1y 0ne temp0ra1 fre4uency, 5 H2, and c0ntra5t wa5 30%. F0rty-f0ur rat5 and th1rty na1ve human5 (w1th n0rma1 0r c0rrected t0 n0rma1 v15ua1 acu1ty) 5erved a5 5u6ject5. Ha1f 0f the 5u6ject5 1n each 9r0up rece1ved a p1ace60 and ha1f rece1ved d1a2epam. Exp05ure c0nd1t10n wa5 a5519ned at rand0m 1n d0u61e-611nd exper1ment5. 5u6ject5 were te5ted 6ef0re and after treatment. 7he d05a9e f0r rat5 wa5 e1ther 0, 0.067, 0.125, 0.25 0r 0.5 m9/k9, wherea5 a11 human5 rece1ved 10 m9 (appr0x1mate1y 0.14 m9/k9 0n avera9e). Re5u1t5 were te5ted f0r 0vera11 exp05ure effect5 w1th AN0VA5 and 519n1f1cant effect5 were further ana1y2ed w1th t-te5t5. RE5UL75
7ran51ent VEP5 Pattern-0n5et VEP5 were e11c1ted fr0m human5 and rat5 6y
RA7 AND HUMAN V15UAL-EV0KED P07EN71AL5
1t121
R A 7 P1
161
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HUMAN P0
8LANK F1ELD pA77ERN
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311 0
-51-
50
100 150 200 250 300 350
7 ~ (nme)
-41
-31 -21 -1 0.04
0.1
0.2 0.4 5PA71AL
0.5
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FRE~Y (cpd)
2
4
F16. 1. 6r0up-avera9e amp11tude5 fr0m 1nd1v1dua15u6ject•5 va1ue5 f0r the f1r5t p051t1veand 1mmed1ate1y5ucceed1n9ne9at1vec0mp0nent5 acr055 5pat1a1 fre4uency. 7he p051t1vec0mp0nent f0r 60th 5pec1e5 wa5 character12ed 6y a 10w-pa555pat1a1fre4uency pr0f11e. 7he rat N2 c0mp0nent had a 6and-pa55 5pat1a1 fre4uency pr0f11e, wherea5 the human N1 c0mp0nent wa5 1ar9e5t at the h19he5t 5pat1a1 fre4uency te5ted.
f0ur 9rat1n95 5pann1n9 a 5pat1a1 fre4uency ran9e 0f appr0x1mate1y 1 109 un1t. 7he 5pat1a1 fre4uenc1e5 u5ed w1th rat5 were a60ut 1 109 un1t 10wer than th05e u5ed w1th human5, 51nce rat5 are una61e t0 detect 6ar5 a5 5ma11 a5 th05e detected 6y human5 (7). 7he 5tudy f0cu5ed 0n the 5pat1a1 fre4uency-amp11tude funct10n5 0f the ftr5t p051t1ve and 1mmed1ate1y 5ucceed1n9 ne9at1ve c0mp0nent5 1n the wavef0rm5 0f 60th 5pec1e5.7he f1r5t p051t1ve c0mp0nent f0r rat5, P1, and f0r human5, P0, a5 we11 a5 the f0110w1n9 ne9at1ve c0mp0nent5, N2 f0r rat5 and N1 f0r human5, were 1a6e1ed acc0rd1n9 t0 pr10r c0nvent10n (7, 16, 21). Avera9e 1atenc1e5 0f the human c0mp0nent5 were 84 and 112 m5, wherea5, th05e f0r rat5 were 92 and 1 13 m5. A5 5h0wn 1n F19. 1, amp11tude 0f the p051t1ve c0mp0nent 1ncrea5ed a5 5pat1a1 fre4uency decrea5ed f0r 60th 5pec1e5. 7hat 15, the 5pat1a1 fre4uency pr0f11e5 0f the p051t1ve c0mp0nent5 had 10wpa55 5hape5. 7he 0vera11 effect 0f 5pat1a1 fre4uency 1n rat5 wa5 5tat15t1ca11y 519n1f1cant, F(3,144) = 22.02, p
