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Electrically and mechanically elicited blink reflexes in infants and children — maturation and recovery curves of blink reflex
Electroencephalography and clinical Neurophysiology, 1990, 76:39-46
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Elsevier Scientific Publishers Ireland, Ltd. EEG 89128
Electrically and mechanically elicited blink reflexes in infants and children - - maturation and recovery curves of blink reflex Takeshi Hatanaka, Aldhiro Yasuhara and Yohnosuke Kobayashi Department of Pediatrics, Kansai Medical University, Fumizonocho 1, Moriguchi, Osaka 570 (Japan)
(Accepted for publication: 9 October 1989)
Summary We studied the electrically and mechanically elicited blink reflexes in 2 groups of subjects, i.e., 237 newborn infants, 25-41 weeks of conceptional age, and 74 children, 1 month-12 years of age. In infants after 25 weeks of conceptional age we could usually induce the early response (R1) and ipsilateral late response (R2), while the contralateral late response (R2') of the electrical blink reflex became apparent after 33 weeks of conceptional age and the frequency of the appearance of R2' reached more than 60% after 38 weeks of conceptional age. After 7 months of age, R2' was usually observed. The R1 latency in full-term newborns was close to adult values, while the R2 and R2' latencies reached adult values at 7-12 years. After 1 year of age the latency of the R2 mechanical blink reflex had a tendency to be shorter than that of the electrical blink reflex. Under 35 weeks of conceptional age, the recovery curves of the blink reflex were considerably different from those of full-term infants, and premature infants showed little or no evidence of inhibition. These results indicate the absence of inhibitory interneurones in premature infants.
Key words: Blink reflex; Newborns; Children; Development; Recovery curves
T h e b l i n k reflex c a n b e i n d u c e d b y various k i n d s of stimulation, i.e., trigeminal, acoustic a n d visual. Since the first r e p o r t b y K u g e l b e r g (1952), the electrically a n d m e c h a n i c a l l y elicited b l i n k reflexes have b e e n studied, a n d t h e y c a n b e i n d u c e d even in n e w b o r n infants ( K i m u r a et al. 1977). I n recent years, m a t u r a t i o n a l changes in the electrical b l i n k reflex in n e w b o r n infants a n d c h i l d r e n have b e e n r e p o r t e d b y C l a y a n d R a m s e y e r (1976), B l a n k et al. (1983), Vecchierini-Blineau a n d G u i h e n e u c (1984) a n d K h a t e r - B o i d i n a n d D u r o n (1987). I n particular, o n l y K h a t e r - B o i d i n a n d D u r o n (1987) r e p o r t e d the d e v e l o p m e n t of the b l i n k reflex in p r e m a t u r e infants. W e also p u b l i s h e d a s u m m a r y c o n c e r n i n g the d e v e l o p m e n t of v a r i o u s k i n d s of b l i n k reflex in n e o n a t e s ( H a t a n a k a et al. 1988). K i m u r a a n d H a r a d a (1976) s t u d i e d the recovery
curves of the b l i n k reflex in a d u l t s using the p a i r e d shock technique. T h e recovery of the b l i n k reflex is r e p r e s e n t e d b y the interpulse interval at w h i c h the test r e s p o n s e r e t u r n s to the level of the c o n d i t i o n i n g response. T o o u r knowledge, a s t u d y on the electrically a n d m e c h a n i c a l l y elicited b l i n k reflexes t h r o u g h o u t c h i l d h o o d has n o t b e e n att e m p t e d a n d there h a s b e e n n o r e p o r t o n the d e v e l o p m e n t a l c h a n g e s in recovery curves in the newborn period. T h e p u r p o s e s of this s t u d y were to establish n o r m a l values a n d to a n a l y z e the d e v e l o p m e n t of the electrically a n d m e c h a n i c a l l y elicited b l i n k reflexes. I n a d d i t i o n , we wish to r e p o r t a s t u d y o n the recovery curves o f b l i n k reflexes in n e w b o r n s .
Subjects and methods Correspondence to: Takeshi Hatanaka, M.D., Department
of Pediatrics, Kansai Medical University, Fumizonoeho 1, Moriguchi, Osaka 570 (Japan).
Blink reflexes were i n d u c e d in 237 h e a l t h y newb o r n i n f a n t s a n d 74 h e a l t h y children. I n all cases, there was n o h i s t o r y of n e o n a t a l asphyxia, h y p e r -
0013-4649/90/$03.50 © 1990 Elsevier Scientific Publishers Ireland, Ltd.
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bilirubinemia or neurological abnormalities during the neonatal period. Newborn infants were divided into groups, i.e., 25 weeks of conceptional age (4 cases), 27 weeks (4), 28 weeks (7), 29 weeks (7), 30 weeks (10), 31 weeks (20), 32 weeks (20), 33 weeks (28), 34 weeks (25), 35 weeks (21), 36 weeks (19), 37 weeks (21), 38 weeks (14), 39 weeks (14), 40 weeks (13) and 41 weeks (10). Parental consent was obtained for all subjects. Each test was conducted after the third day after birth. The subjects lay supine in an incubator, or on a cot or bed in a warm room with the eyes open or gently closed. No sedation was used. The electrically elicited blink reflex (EBR) was obtained by stimulating the supraorbital nerve. Surface electrodes were used for stimulation of the nerve and for recording of the EBR. The recording electrode was 8 mm in diameter and the stimulating electrode 5 mm. The skin was cleaned with a regular skin preparation paste. The supraorbital nerve was stimulated with the cathode placed over the supraorbital foramen on one side. The active recording electrode was placed over the inferior portion of the orbicularis oculi muscle near the outer canthus and the reference electrode on the temple. A ground electrode was placed on the forehead. The stimulation was 0.2 msec in duration with a delay of at least 15 sec between stimuli. The stimulus intensity ranged from 40 to 200 V or 10-20 mA. It was progressively increased until stable responses were obtained and we used supramaximal intensity. Shock artifacts can be minimized when an optimal position of the stimulating electrode is selected by rotating the anode around the cathode. When the shock artifacts and R1 wave forms overlapped, we used the first standing point or notch for the measurement of the R1 latency. For each subject, at least 5 responses were recorded to assure the consistency and reproducibility of the action potential and we selected the response of the shortest latency. The responses were filtered with a bandpass of 100-1000 Hz. Simultaneous records were obtained from the bilateral orbicularis oculi muscles. The EBR consists of the early ipsilateral response (R1), late ipsilateral response (R2) and late contralateral response (R2'). The mechanically elicited blink reflex (glabella tap blink reflex, TBR) was obtained by tapping
T. H A T A N A K A ET AL.
the glabella with a triggered plastic hammer (DISA). Recording was performed as in the case of EBR. The strength of the stimulus was not standardized but we applied a light tap at least 5 times on each subject without undue discomfort. TBR consists of the early component (R1) and late component (R2), bilaterally. The responses were filtered with a bandpass of 100-500 Hz. The paired shock technique was based on the method of Kimura and Harada (1976). We examined the recovery curves in 3 groups: 8 premature infants, 32-35 weeks; 6 newborns, 36-38 weeks; and 10 full-term babies, 40-43 weeks of conceptional age. To obtain the R1 and R2 recovery curves, the amplitude of the response obtained with a test stimulus was converted into a percentage of the amplitude in the case of a conditioning stimulus. In general, the integrated R2 amplitude provides a more accurate measure of the underlying neural activity than peak-to-peak amplitude, but in neonates R2 wave forms are immature and different from those of children and adults. It is therefore difficult to measure the exact duration of R2 response and the integrated amplitude. On the contrary, peak-to-peak measures were more practical and the reproducibility was good. We applied the conditioning and test stimuli from 2 to 5 times on all subjects. The strength of the stimuli was fixed during the test. When the subjects were crying and the test was disturbed, the test was temporarily halted. The results are expressed as the mean + S.D. and statistical analysis for paired groups was performed by Student's t test. The regression analysis of the latency in neonates was made.
Results Typical examples of the electrically (EBR) and mechanically elicited blink reflexes (TBR) in a normal infant are shown in Fig. 1. The latency was measured from the stimulating point to the first deflection of each component, and the amplitude was expressed as the peak-to-peak amplitude (Fig. 1). In neonates we could easily induce the blink reflexes and produce recovery curves without disturbance and undue discomfort, while in in-
ELECTRICALLY A N D MECHANICALLY ELICITED BLINK REFLEXES
R1 L
A. R i~ Z
f
20msec
atimulation
~t R1
R2
i
< Latency ;~
41
of R2' remained suppressed in the newborn period. In full-term newborns, the latency of R1 was 12.8 + 0.56 msec (n = 23). This value was greater than adult values ( P < 0.001), and the amplitude was smaller than that in adults ( P < 0.001). The R1 response was stable in latency, but the values of the latency of R2 were widely distributed when compared to that of R1. The R1 was often polyphasic or triphasic and prolonged in duration, while the R2 was usually polyphasic, occasionally separated by brief intervals. We examined the relationship between the latency and the conceptional age in the TBR in newborns (Fig. 4). After 25 weeks of conceptional age, we could usually induce R1 and R2 responses. The latency of R1 was almost equal to that of R1 in the EBR, but the latency of R2 was longer than that of R2 in the EBR after 30 weeks of conceptional age ( P < 0.01). The R1 was often polyphasic. The R2 was usually polyphasic, at times showing the separation by intervals. The age-related changes in EBR and TBR in children and adults are shown in Fig. 5. After 7
20msee
Fig. 1. Typical EBR (A) and TBR (B) in a 2-year-old child. EBR = electrically elicited blink reflex; TBR = glabella tap blink reflex mechanically elicited). L = left side; R = right side.
fants, especially in the first and second years of life, induction of the blink reflexes was often difficult. In these cases, milk feeding was often effective to pacify crying children. Fig. 2 shows the changes in the blink reflex pattern during growth in a premature baby who was born at 27 weeks of conceptional age. We examined the relationship between the latency and the conceptional age in the EBR in newborns (Fig. 3). After 25 weeks of conceptional age, we could usually induce R1 and 1{2 responses and observed that the latencies shortened with increasing age, although before 30 weeks of conceptional age, we observed significantly increased latency and reduced amplitude. After 33 weeks of conceptional age, the late contralateral response (R2') became apparent and the frequency of the appearance of R2' reached more than 60% after 38 weeks of conceptional age. But the amplitude
Electrically Elicited Blink Reflex
Glabella Tap Blink Reflex
C.A. L-
R- stimulation
32w R
35wRll:i!i!!: F
100msec
100rnsec
Fig. 2. Changes in EBR and TBR as functions of the conceptional age. This infant was born at 27 weeks gestation.
T. H A T A N A K A
42
LATENCY 80
ET AL.
LATENCY (msec
R2
[
8s
R~
80 R2
,° I
70
60
t ,I. I IIi
5O
6O
!
40 R1
40RI
30- ~ 2O
10 10
25
27
29
31
33
35
37
39
41
ADULT
CONCEPTIONAL AGE Fig. 3. Relationship
between the
25
latency
P < 0.001, n = 237. R 2 : Y = - 1 . 7 8 6 X + 109.638,
= 0.736, P < 0.001, n = 237. R 2 ' : Y =
29
of E B R and the
conceptional age in the newborn period. T h e y - a x i s indicates the latency, and ages are l i s t e d o n t h e x-axis. The extreme right l i n e shows the adult value (n = 6). R 1 : Y = - 0 . 6 9 1 X + 39.302, r = 0.841,
27
-2.151X+
r
130.127, r =
31
33
35
37
39
41 (we~.,a)
N:XJLT
CONCEPTIONAL AGE
Relationship between the latency of TBR and the conceptional age in the newborn period. Ages are l i s t e d o n the x - a x i s . T h e extreme right line shows the adult value ( n = 6). RI: Y = - 0 . 7 3 7 X + 4 0 . 7 0 7 , r = 0.834, P < 0.001, n = 205. R2: F i g . 4.
Y = - 2 . 0 4 9 X + 1 2 4 . 2 9 5 , r = 0.845, P < 0.001, n = 205.
0.654, P < 0.001, n = 47.
months of age, we usually observed the late contralateral response (R2') to electrical stimuli. R1 latencies in EBR and TBR were not significantly changed. Until 6 years, the R2 and R2' latencies in the EBR were not significantly changed but after 7 years each latency decreased with age ( 4 - 6 year group vs. 7 - 1 2 year group, P < 0.01), while after 1 year, the R2 latency in the TBR decreased with age ( 7 - 1 2 month group vs. 1 - 3 year group, P < 0.001; 4 - 6 year group vs. 7 - 1 2 year group, P < 0.05). In any case, the R2 (EBR and TBR) and R2' latencies (EBR) were longer than in adults ( P < 0.001). In particular, after 1 year of age, the R2 latencies of EBR and TBR had a tendency to be reversed, and after 4 years, the R2 latency of the TBR became shorter than that of the EBR. In addition, before 1 year, the amplitudes of R2 in TBR and that of R2' in EBR were significantly reduced. The significant differences between the R2 latency of EBR and that of TBR in each group are expressed in Fig. 5.
LATENCY H Electrically Elicited Blink Reflex O--O GlabelJa Tat) Blink Reflex
(msac) 50-
R2
40- R21~ i i
,
30 **
[~j NS
7y-'12y (16)
Adult (6)
28
18
lm'-6m (18)
7m-'12m (10)
ly~3y (161
4y-6y (10) AGE
Relationship between the latencies of EBR and age in children and adults. Ages are listed on with the number of subjects in each group given in ses. Levels of significance: * P < 0.05, * * P < 0.01, F i g . 5.
0.001, N S : n o t s i g n i f i c a n t .
and TBR the x - a x i s parenthe*** P <
ELECTRICALLYAND MECHANICALLY ELICITED BLINK REFLEXES Fig. 6 shows typical responses of R1 and R2 to paired stimuli in each case. The recovery curves for the 3 groups are shown in Fig. 7. Under 35 weeks of conceptional age, R1 of the test response was slightly potentiated or not changed, while R2 of the test response was slightly suppressed or not changed. After 36 weeks of conceptional age, R1 of the test response was potentiated at intervals of 20-80 msec, and at intervals of 60 msec maximal potentiation was obtained, while R2 of the test response had a tendency to be suppressed at intervals ranging from 20 to 4000 msec. In particular, after 40 weeks of conceptional age, conditioning stimuli suppressed R2 markedly at intervals of 120-250 msec. The test response returned to the level of the conditioning response at about 3000 msec.
case 1 (C.A. 35w)
Time Intervals c.s.T.S. ,k +
Discussion For the group of full-term newborns and children over the age of 1 month, our results for the EBR are almost in agreement with previous reports (Clay and Ramseyer 1976; Kimura et al. 1977; Vecchierini-Blineau and Guiheneuc 1984; Khater-Boidin and Duron 1987). The differences in the developmental changes in the R1 and R2 latencies are mainly caused by the different neuroanatomical reflex pathways. R1 responses are oligosynaptic, while R2 responses are polysynaptic (Hiraoka and Shimamura 1977; Ongerboer de Visser and Kuypers 1978; Kimura 1983). Wagner and Buchthal (1972) and Vecchierini-Blineau and Guiheneuc (1979) observed that the shortening of the R1 latency paralleled that of other peripheral
case 2 (C.A. 38w) C.S.T.S. ,1, ,/,
43
case 3 (C.A. 42w) C.S.T.S.
4om~
iiiiiii40msec __llOO~V ~ii..........~....... iiiiiiiiiiiiiiiiiiiilU/ill
120 ~'~I'Y"~ ~'~''', l I : iloo.v
J,
I
100msec
i~/ ~ i ~ i
iiiii/iii/iiiiiii//i 40msec Iloo~v
.1100~V
@ t ..
100msec
Iloow
1O0msec
Fig. 6. Typical responses of R1 and R2 to paired stimuli. C.A. = conceptional age; C.S. = conditioning stimuli; T.S. = test stimufi. The time intervals between conditioning and test stimuli are listed on the left.
T. HATANAKA ET AL.
44 C.A. 32 - 35w
%
n=8
180 160 140
T
120 100 80 R GO
20 40 60 80 100 120146 160 180 200
250
300
400
~
80Q 1000 1500 2OOG ~
250
30(] 400
500
800
25O
300
500
800 100~ 1500 2000 3OO0 400¢
C.A 36 - 38w n=6
180 160 140 120 100 80
l
60
40 R Z 20 0 20 40 60 80 100 120140 160 180 200
%
1000 1500 2000 3000 4000
C.A 40 43w n=10
I
PSO 160
I40
F~,
~20 I 100 ! gO
:1 20 4O OO 80 100 120 140 160 180 200
400
Interval between conditioning and test stimuli
(msec)
Fig. 7. The recovery curves f o r the R1 and R2 in the 3 groups.
The x-axis indicates time intervals, and the y-axis indicates the percentage of the amplitude of the conditioning response.
motor nerve conduction velocities, which, during the first 6 months of life, increased significantly. Kimura et al. (1977) reported that the reflex pathways were considerably shorter in infants than in adults, but that the latency of R1 was substantially greater in infants. These findings show that for the R1 latency the conduction velocity is more important than the length of the reflex pathway. The nerve conduction velocity reflects the degree of myelination; therefore, the development of the R1 latency chiefly reflects the myelinization of the reflex pathway, and the same effects may also be present for the R2. Our results indicate that uncrossed interneurons are more or less mature after 25 weeks of conceptional age; the absence or
reduction of the contralateral R2 (R2') before 6 months and the low voltage of R2' before 1 year are considered to be due to the immaturity of crossed medullary interneurons. After 33 weeks, the R2' response became apparent, which indicates that crossed interneuronal connections are more or less activated by this time. In addition, inhibitory and facilitatory cortical control have been observed over the trigeminal system (Kuypers 1958; Wiesendanger and Felix 1969; Dubner and Sessle 1971; Berardelli et al. 1983; Ongerboer de Visser 1983; Vecchierini-Bhneau and Guiheneuc 1984; Kimura et al. 1985). Therefore, even if the pathway of the blink reflex is anatomically complete, it is possible that interneurons are not fully activated. The R2 component of both EBR and TBR is close to the adult pattern by about 7 years of age. This is consistent with the time of completion of development of the brain-stem reported by Dobbing and Sands (1973). Although the beginning of the first component in the TBR is not clear enough to evaluate the R1 latency exactly, the R1 latency of the TBR was almost equal to that of the EBR. Before 1 year of age, the R2 latency of TBR was longer than that of EBR, after which the R2 latency of TBR had a tendency to be shorter than that of EBR. KhaterBoidin and Duron (1987) found in newborns that the R1 latency of the mechanically evoked response was approximately 3 msec longer than that of the EBR and that R2 was 7 msec longer than that of the EBR. Compared with that of EBR, the R1 response of TBR was often polyphasic throughout life. This discrepancy is considered to be due to the different blink reflex methods used. As previously described, crossed medullary interneurons are immature before 1 year, so the shorter R2 latency of TBR observed after 1 year may be caused by an increase in excitability to the simultaneous stimulation of both sides. In TBR, the length of the afferent arc from the glabella to the supraorbital foramen is added to that of the pathway of the EBR. The delayed latency of TBR observed before 1 year may be due to the additional length of the pathway. The R1 and R2 recovery curves obtained for full-term newborns are similar to those for adults obtained by Kimura and Harada (1976). As in
ELECTRICALLY AND MECHANICALLY ELICITED BLINK REFLEXES adults, in full-term babies R1 showed increased a m p l i t u d e at intervals ranging f r o m 20 to 80 msec, while R2 r e m a i n e d p r o f o u n d l y suppressed up to 800 msec. O n the contrary, the recovery curves b e f o r e 35 weeks of c o n c e p t i o n a l age were considerably different f r o m those in full-term n e w b o r n s and adults and showed little or no evidence of inhibition. K i m u r a a n d H a r a d a (1976) r e p o r t e d that this dissociation of the recovery curves m a y be taken as a sign of r e d u c e d excitability at the i n t e r n e u r o n level after the passage of a p r e c e d i n g impuls e and that, as an e x p l a n a t i o n for the mechanism, there was possibly inhibitory feedback in the i n t e r n e u r o n a l network. In recent years it has been suggested that reflex i n h i b i t i o n is m e d i a t e d by the specific inhibitory neural system that involves the lateral t e g m e n t u m (Leiter et al. 1980, 1981; H o f f m a n et al. 1987). O u r results indicate that the m e c h a n i s m s of inhibition a n d excitation were not fully d e v e l o p e d in p r e m a t u r e babies, but an inhibitory system of i n t e r n e u r o n s was functionally c o m p l e t e d by 40 weeks of c o n c e p t i o n a l age. The se findings are also consistent with the results of studies on inhibition of the glabella tap blink reflex in the h u m a n infant ( H o f f m a n et al. 1987). H o w e v e r , it is possible that the m e c h a n i s m of inhibition f o u n d in n e w b o r n s differs physiologically from that in adults ( Z a m e t k i n et al. 1979). In conclusion, d e v e l o p m e n t o f the R1 c o m p o nent is c o n s i d e r a b l y different f r o m that of R2, and m a t u r a t i o n a l changes in R1 facilitation and R2 inhibition of the blink reflex o c c u r in the n e w b o r n period. This study was supported by Grants-in-Aid for the Encouragement of Young Scientists, Nos. 61770719 and 62770707, from the Ministry of Education, Japan, and the Mami Mizutani Foundation.
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Clay, S. and Ramseyer, J.C. The orbicularis oculi reflex in infancy and childhood. Neurology, 1976, 26: 521-524. Dobbing, J. and Sands, J. Quantitative growth and development of human brain. Arch. Dis. Child., 1973, 48: 757-767. Dubner, R. and Sessle, B.J. Presynaptic excitability changes of primary afferent and corticofugal fibers projecting to trigeminal brain stem nuclei. Exp. Neurol., 1971, 30: 223-238. Hatanaka, T., Yasuhara, A., Hori, A., Shuto, H., Iwase, S., Kobayashi, Y. and Yasuhara, M. Development of the blink reflex elicited by various kinds of stimuli in neonates. Electroenceph. clin. Neuropliysiol., 1988, 70: 118P. Hiraoka, M. and Shimamura, M. Neural mechanism of the corneal blinking response in cats. Brain Res., 1977, 125: 265-275. Hoffman, H.S., Cohen, M.E. and Andy, E.K. Inhibition of the eyeblink reflex in the human infant. Dev. Psychobiol., 1987, 20: 277-283. Khater-Boidin, J. and Duron, B. The orbicularis oculi reflexes in healthy premature and full-term newborns. Electroenceph. clin. Neurophysiol., 1987, 67: 479-484. Kimura, J. The blink reflex. In: J. Kimura (Ed.), Electrodiagnosis in Disease of Nerve and Muscle: Principles and Practice. Davis, Philadelphia, PA, 1983: 323-351. Kimura, J. and Harada, O. Recovery curves of the blink reflex during wakefulness and sleep. J. Neurol., 1976, 213: 189198. Kimura, J., Bodensteiner, J. and Yamada, T. Electrically elicited blink reflex in normal neonates. Arch. Neurol., 1977, 34: 246-249. Kimura, J., Wilkinson, J.T., Damasio, H., Adams, Jr., H.R., Shivapour, E. and Yamada, T. Blink reflex in patients with hemispheric cerebrovascular accident (CVA). Blink reflex in CVA. J. Neurol. Sci., 1985, 67: 15-28. Kugelberg, E. Facial reflexes. Brain, 1952, 75: 385-396. Kuypers, H.G.J.M. Corticobulbar connection to the pons and lower brainstem in man. An anatomical study. Brain, 1958, 81: 364-388. Leiter, D.S., Powers, A.S. and Hoffman, H.S. The neural substrate of the startle response. Physiol. Behav., 1980, 25: 291-294. Leiter, D.S., Powers, A.S., Stitt, C.L. and Hoffman, H.S. Midbrain reticular formation involvement in the inhibition of acoustic startle. Physiol. Behav., 1981, 26: 259-268. Ongerboer de Visser, B.W. Comparative study of corneal and blink reflex latencies in patients with segmental or with cerebral lesions. In: J.E. Desmedt (Ed.), Motor Control Mechanism in Health and Disease. Raven Press, New York, 1983: 757-772. Ongerboer de Visser, B.W. and Kuypers, H.G.J.M. Late blink reflex changes in lateral medullary lesions: an electrophysiological and neuroanatomical study of Wallenberg's syndrome. Brain, 1978, 101: 285-294. Vecchierini-Blineau, M.F. and Guiheneuc, P. Electrophysiological study of the peripheral nervous system in children. Changes in proximal and distal conduction velocities from birth to age 5 years. J. Neurol. Neurosurg. Psychiat., 1979, 42: 753-759.
46 Vecchierini-Blineau, M.F. and Guiheneuc, P. Maturation of the blink reflex in infants. Eur. Neurol., 1984, 23: 449-458. Wagner, A.L. and Buchthal, F. Motor and sensory conduction in infancy and childhood: reappraisal. Dev. Med. Child Neurol., 1972, 14: 189-216. Wiesendanger, M. and Felix, D. Pyramidal excitation of
T. HATANAKA El? AL. lemniscal neurons and facilitation of sensory transmission in the spinal trigeminal nucleus of the cat. Exp. Neurol., 1969, 25: 1-17. Zametkin, A.J., Stevens, J.R. and Pittman, R. Ontogeny of spontaneous blinking and of habituation of the blink reflex. Ann. Neurol., 1979, 5: 453-457.
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Elsevier Scientific Publishers Ireland, Ltd. EEG 89128
Electrically and mechanically elicited blink reflexes in infants and children - - maturation and recovery curves of blink reflex Takeshi Hatanaka, Aldhiro Yasuhara and Yohnosuke Kobayashi Department of Pediatrics, Kansai Medical University, Fumizonocho 1, Moriguchi, Osaka 570 (Japan)
(Accepted for publication: 9 October 1989)
Summary We studied the electrically and mechanically elicited blink reflexes in 2 groups of subjects, i.e., 237 newborn infants, 25-41 weeks of conceptional age, and 74 children, 1 month-12 years of age. In infants after 25 weeks of conceptional age we could usually induce the early response (R1) and ipsilateral late response (R2), while the contralateral late response (R2') of the electrical blink reflex became apparent after 33 weeks of conceptional age and the frequency of the appearance of R2' reached more than 60% after 38 weeks of conceptional age. After 7 months of age, R2' was usually observed. The R1 latency in full-term newborns was close to adult values, while the R2 and R2' latencies reached adult values at 7-12 years. After 1 year of age the latency of the R2 mechanical blink reflex had a tendency to be shorter than that of the electrical blink reflex. Under 35 weeks of conceptional age, the recovery curves of the blink reflex were considerably different from those of full-term infants, and premature infants showed little or no evidence of inhibition. These results indicate the absence of inhibitory interneurones in premature infants.
Key words: Blink reflex; Newborns; Children; Development; Recovery curves
T h e b l i n k reflex c a n b e i n d u c e d b y various k i n d s of stimulation, i.e., trigeminal, acoustic a n d visual. Since the first r e p o r t b y K u g e l b e r g (1952), the electrically a n d m e c h a n i c a l l y elicited b l i n k reflexes have b e e n studied, a n d t h e y c a n b e i n d u c e d even in n e w b o r n infants ( K i m u r a et al. 1977). I n recent years, m a t u r a t i o n a l changes in the electrical b l i n k reflex in n e w b o r n infants a n d c h i l d r e n have b e e n r e p o r t e d b y C l a y a n d R a m s e y e r (1976), B l a n k et al. (1983), Vecchierini-Blineau a n d G u i h e n e u c (1984) a n d K h a t e r - B o i d i n a n d D u r o n (1987). I n particular, o n l y K h a t e r - B o i d i n a n d D u r o n (1987) r e p o r t e d the d e v e l o p m e n t of the b l i n k reflex in p r e m a t u r e infants. W e also p u b l i s h e d a s u m m a r y c o n c e r n i n g the d e v e l o p m e n t of v a r i o u s k i n d s of b l i n k reflex in n e o n a t e s ( H a t a n a k a et al. 1988). K i m u r a a n d H a r a d a (1976) s t u d i e d the recovery
curves of the b l i n k reflex in a d u l t s using the p a i r e d shock technique. T h e recovery of the b l i n k reflex is r e p r e s e n t e d b y the interpulse interval at w h i c h the test r e s p o n s e r e t u r n s to the level of the c o n d i t i o n i n g response. T o o u r knowledge, a s t u d y on the electrically a n d m e c h a n i c a l l y elicited b l i n k reflexes t h r o u g h o u t c h i l d h o o d has n o t b e e n att e m p t e d a n d there h a s b e e n n o r e p o r t o n the d e v e l o p m e n t a l c h a n g e s in recovery curves in the newborn period. T h e p u r p o s e s of this s t u d y were to establish n o r m a l values a n d to a n a l y z e the d e v e l o p m e n t of the electrically a n d m e c h a n i c a l l y elicited b l i n k reflexes. I n a d d i t i o n , we wish to r e p o r t a s t u d y o n the recovery curves o f b l i n k reflexes in n e w b o r n s .
Subjects and methods Correspondence to: Takeshi Hatanaka, M.D., Department
of Pediatrics, Kansai Medical University, Fumizonoeho 1, Moriguchi, Osaka 570 (Japan).
Blink reflexes were i n d u c e d in 237 h e a l t h y newb o r n i n f a n t s a n d 74 h e a l t h y children. I n all cases, there was n o h i s t o r y of n e o n a t a l asphyxia, h y p e r -
0013-4649/90/$03.50 © 1990 Elsevier Scientific Publishers Ireland, Ltd.
40
bilirubinemia or neurological abnormalities during the neonatal period. Newborn infants were divided into groups, i.e., 25 weeks of conceptional age (4 cases), 27 weeks (4), 28 weeks (7), 29 weeks (7), 30 weeks (10), 31 weeks (20), 32 weeks (20), 33 weeks (28), 34 weeks (25), 35 weeks (21), 36 weeks (19), 37 weeks (21), 38 weeks (14), 39 weeks (14), 40 weeks (13) and 41 weeks (10). Parental consent was obtained for all subjects. Each test was conducted after the third day after birth. The subjects lay supine in an incubator, or on a cot or bed in a warm room with the eyes open or gently closed. No sedation was used. The electrically elicited blink reflex (EBR) was obtained by stimulating the supraorbital nerve. Surface electrodes were used for stimulation of the nerve and for recording of the EBR. The recording electrode was 8 mm in diameter and the stimulating electrode 5 mm. The skin was cleaned with a regular skin preparation paste. The supraorbital nerve was stimulated with the cathode placed over the supraorbital foramen on one side. The active recording electrode was placed over the inferior portion of the orbicularis oculi muscle near the outer canthus and the reference electrode on the temple. A ground electrode was placed on the forehead. The stimulation was 0.2 msec in duration with a delay of at least 15 sec between stimuli. The stimulus intensity ranged from 40 to 200 V or 10-20 mA. It was progressively increased until stable responses were obtained and we used supramaximal intensity. Shock artifacts can be minimized when an optimal position of the stimulating electrode is selected by rotating the anode around the cathode. When the shock artifacts and R1 wave forms overlapped, we used the first standing point or notch for the measurement of the R1 latency. For each subject, at least 5 responses were recorded to assure the consistency and reproducibility of the action potential and we selected the response of the shortest latency. The responses were filtered with a bandpass of 100-1000 Hz. Simultaneous records were obtained from the bilateral orbicularis oculi muscles. The EBR consists of the early ipsilateral response (R1), late ipsilateral response (R2) and late contralateral response (R2'). The mechanically elicited blink reflex (glabella tap blink reflex, TBR) was obtained by tapping
T. H A T A N A K A ET AL.
the glabella with a triggered plastic hammer (DISA). Recording was performed as in the case of EBR. The strength of the stimulus was not standardized but we applied a light tap at least 5 times on each subject without undue discomfort. TBR consists of the early component (R1) and late component (R2), bilaterally. The responses were filtered with a bandpass of 100-500 Hz. The paired shock technique was based on the method of Kimura and Harada (1976). We examined the recovery curves in 3 groups: 8 premature infants, 32-35 weeks; 6 newborns, 36-38 weeks; and 10 full-term babies, 40-43 weeks of conceptional age. To obtain the R1 and R2 recovery curves, the amplitude of the response obtained with a test stimulus was converted into a percentage of the amplitude in the case of a conditioning stimulus. In general, the integrated R2 amplitude provides a more accurate measure of the underlying neural activity than peak-to-peak amplitude, but in neonates R2 wave forms are immature and different from those of children and adults. It is therefore difficult to measure the exact duration of R2 response and the integrated amplitude. On the contrary, peak-to-peak measures were more practical and the reproducibility was good. We applied the conditioning and test stimuli from 2 to 5 times on all subjects. The strength of the stimuli was fixed during the test. When the subjects were crying and the test was disturbed, the test was temporarily halted. The results are expressed as the mean + S.D. and statistical analysis for paired groups was performed by Student's t test. The regression analysis of the latency in neonates was made.
Results Typical examples of the electrically (EBR) and mechanically elicited blink reflexes (TBR) in a normal infant are shown in Fig. 1. The latency was measured from the stimulating point to the first deflection of each component, and the amplitude was expressed as the peak-to-peak amplitude (Fig. 1). In neonates we could easily induce the blink reflexes and produce recovery curves without disturbance and undue discomfort, while in in-
ELECTRICALLY A N D MECHANICALLY ELICITED BLINK REFLEXES
R1 L
A. R i~ Z
f
20msec
atimulation
~t R1
R2
i
< Latency ;~
41
of R2' remained suppressed in the newborn period. In full-term newborns, the latency of R1 was 12.8 + 0.56 msec (n = 23). This value was greater than adult values ( P < 0.001), and the amplitude was smaller than that in adults ( P < 0.001). The R1 response was stable in latency, but the values of the latency of R2 were widely distributed when compared to that of R1. The R1 was often polyphasic or triphasic and prolonged in duration, while the R2 was usually polyphasic, occasionally separated by brief intervals. We examined the relationship between the latency and the conceptional age in the TBR in newborns (Fig. 4). After 25 weeks of conceptional age, we could usually induce R1 and R2 responses. The latency of R1 was almost equal to that of R1 in the EBR, but the latency of R2 was longer than that of R2 in the EBR after 30 weeks of conceptional age ( P < 0.01). The R1 was often polyphasic. The R2 was usually polyphasic, at times showing the separation by intervals. The age-related changes in EBR and TBR in children and adults are shown in Fig. 5. After 7
20msee
Fig. 1. Typical EBR (A) and TBR (B) in a 2-year-old child. EBR = electrically elicited blink reflex; TBR = glabella tap blink reflex mechanically elicited). L = left side; R = right side.
fants, especially in the first and second years of life, induction of the blink reflexes was often difficult. In these cases, milk feeding was often effective to pacify crying children. Fig. 2 shows the changes in the blink reflex pattern during growth in a premature baby who was born at 27 weeks of conceptional age. We examined the relationship between the latency and the conceptional age in the EBR in newborns (Fig. 3). After 25 weeks of conceptional age, we could usually induce R1 and 1{2 responses and observed that the latencies shortened with increasing age, although before 30 weeks of conceptional age, we observed significantly increased latency and reduced amplitude. After 33 weeks of conceptional age, the late contralateral response (R2') became apparent and the frequency of the appearance of R2' reached more than 60% after 38 weeks of conceptional age. But the amplitude
Electrically Elicited Blink Reflex
Glabella Tap Blink Reflex
C.A. L-
R- stimulation
32w R
35wRll:i!i!!: F
100msec
100rnsec
Fig. 2. Changes in EBR and TBR as functions of the conceptional age. This infant was born at 27 weeks gestation.
T. H A T A N A K A
42
LATENCY 80
ET AL.
LATENCY (msec
R2
[
8s
R~
80 R2
,° I
70
60
t ,I. I IIi
5O
6O
!
40 R1
40RI
30- ~ 2O
10 10
25
27
29
31
33
35
37
39
41
ADULT
CONCEPTIONAL AGE Fig. 3. Relationship
between the
25
latency
P < 0.001, n = 237. R 2 : Y = - 1 . 7 8 6 X + 109.638,
= 0.736, P < 0.001, n = 237. R 2 ' : Y =
29
of E B R and the
conceptional age in the newborn period. T h e y - a x i s indicates the latency, and ages are l i s t e d o n t h e x-axis. The extreme right l i n e shows the adult value (n = 6). R 1 : Y = - 0 . 6 9 1 X + 39.302, r = 0.841,
27
-2.151X+
r
130.127, r =
31
33
35
37
39
41 (we~.,a)
N:XJLT
CONCEPTIONAL AGE
Relationship between the latency of TBR and the conceptional age in the newborn period. Ages are l i s t e d o n the x - a x i s . T h e extreme right line shows the adult value ( n = 6). RI: Y = - 0 . 7 3 7 X + 4 0 . 7 0 7 , r = 0.834, P < 0.001, n = 205. R2: F i g . 4.
Y = - 2 . 0 4 9 X + 1 2 4 . 2 9 5 , r = 0.845, P < 0.001, n = 205.
0.654, P < 0.001, n = 47.
months of age, we usually observed the late contralateral response (R2') to electrical stimuli. R1 latencies in EBR and TBR were not significantly changed. Until 6 years, the R2 and R2' latencies in the EBR were not significantly changed but after 7 years each latency decreased with age ( 4 - 6 year group vs. 7 - 1 2 year group, P < 0.01), while after 1 year, the R2 latency in the TBR decreased with age ( 7 - 1 2 month group vs. 1 - 3 year group, P < 0.001; 4 - 6 year group vs. 7 - 1 2 year group, P < 0.05). In any case, the R2 (EBR and TBR) and R2' latencies (EBR) were longer than in adults ( P < 0.001). In particular, after 1 year of age, the R2 latencies of EBR and TBR had a tendency to be reversed, and after 4 years, the R2 latency of the TBR became shorter than that of the EBR. In addition, before 1 year, the amplitudes of R2 in TBR and that of R2' in EBR were significantly reduced. The significant differences between the R2 latency of EBR and that of TBR in each group are expressed in Fig. 5.
LATENCY H Electrically Elicited Blink Reflex O--O GlabelJa Tat) Blink Reflex
(msac) 50-
R2
40- R21~ i i
,
30 **
[~j NS
7y-'12y (16)
Adult (6)
28
18
lm'-6m (18)
7m-'12m (10)
ly~3y (161
4y-6y (10) AGE
Relationship between the latencies of EBR and age in children and adults. Ages are listed on with the number of subjects in each group given in ses. Levels of significance: * P < 0.05, * * P < 0.01, F i g . 5.
0.001, N S : n o t s i g n i f i c a n t .
and TBR the x - a x i s parenthe*** P <
ELECTRICALLYAND MECHANICALLY ELICITED BLINK REFLEXES Fig. 6 shows typical responses of R1 and R2 to paired stimuli in each case. The recovery curves for the 3 groups are shown in Fig. 7. Under 35 weeks of conceptional age, R1 of the test response was slightly potentiated or not changed, while R2 of the test response was slightly suppressed or not changed. After 36 weeks of conceptional age, R1 of the test response was potentiated at intervals of 20-80 msec, and at intervals of 60 msec maximal potentiation was obtained, while R2 of the test response had a tendency to be suppressed at intervals ranging from 20 to 4000 msec. In particular, after 40 weeks of conceptional age, conditioning stimuli suppressed R2 markedly at intervals of 120-250 msec. The test response returned to the level of the conditioning response at about 3000 msec.
case 1 (C.A. 35w)
Time Intervals c.s.T.S. ,k +
Discussion For the group of full-term newborns and children over the age of 1 month, our results for the EBR are almost in agreement with previous reports (Clay and Ramseyer 1976; Kimura et al. 1977; Vecchierini-Blineau and Guiheneuc 1984; Khater-Boidin and Duron 1987). The differences in the developmental changes in the R1 and R2 latencies are mainly caused by the different neuroanatomical reflex pathways. R1 responses are oligosynaptic, while R2 responses are polysynaptic (Hiraoka and Shimamura 1977; Ongerboer de Visser and Kuypers 1978; Kimura 1983). Wagner and Buchthal (1972) and Vecchierini-Blineau and Guiheneuc (1979) observed that the shortening of the R1 latency paralleled that of other peripheral
case 2 (C.A. 38w) C.S.T.S. ,1, ,/,
43
case 3 (C.A. 42w) C.S.T.S.
4om~
iiiiiii40msec __llOO~V ~ii..........~....... iiiiiiiiiiiiiiiiiiiilU/ill
120 ~'~I'Y"~ ~'~''', l I : iloo.v
J,
I
100msec
i~/ ~ i ~ i
iiiii/iii/iiiiiii//i 40msec Iloo~v
.1100~V
@ t ..
100msec
Iloow
1O0msec
Fig. 6. Typical responses of R1 and R2 to paired stimuli. C.A. = conceptional age; C.S. = conditioning stimuli; T.S. = test stimufi. The time intervals between conditioning and test stimuli are listed on the left.
T. HATANAKA ET AL.
44 C.A. 32 - 35w
%
n=8
180 160 140
T
120 100 80 R GO
20 40 60 80 100 120146 160 180 200
250
300
400
~
80Q 1000 1500 2OOG ~
250
30(] 400
500
800
25O
300
500
800 100~ 1500 2000 3OO0 400¢
C.A 36 - 38w n=6
180 160 140 120 100 80
l
60
40 R Z 20 0 20 40 60 80 100 120140 160 180 200
%
1000 1500 2000 3000 4000
C.A 40 43w n=10
I
PSO 160
I40
F~,
~20 I 100 ! gO
:1 20 4O OO 80 100 120 140 160 180 200
400
Interval between conditioning and test stimuli
(msec)
Fig. 7. The recovery curves f o r the R1 and R2 in the 3 groups.
The x-axis indicates time intervals, and the y-axis indicates the percentage of the amplitude of the conditioning response.
motor nerve conduction velocities, which, during the first 6 months of life, increased significantly. Kimura et al. (1977) reported that the reflex pathways were considerably shorter in infants than in adults, but that the latency of R1 was substantially greater in infants. These findings show that for the R1 latency the conduction velocity is more important than the length of the reflex pathway. The nerve conduction velocity reflects the degree of myelination; therefore, the development of the R1 latency chiefly reflects the myelinization of the reflex pathway, and the same effects may also be present for the R2. Our results indicate that uncrossed interneurons are more or less mature after 25 weeks of conceptional age; the absence or
reduction of the contralateral R2 (R2') before 6 months and the low voltage of R2' before 1 year are considered to be due to the immaturity of crossed medullary interneurons. After 33 weeks, the R2' response became apparent, which indicates that crossed interneuronal connections are more or less activated by this time. In addition, inhibitory and facilitatory cortical control have been observed over the trigeminal system (Kuypers 1958; Wiesendanger and Felix 1969; Dubner and Sessle 1971; Berardelli et al. 1983; Ongerboer de Visser 1983; Vecchierini-Bhneau and Guiheneuc 1984; Kimura et al. 1985). Therefore, even if the pathway of the blink reflex is anatomically complete, it is possible that interneurons are not fully activated. The R2 component of both EBR and TBR is close to the adult pattern by about 7 years of age. This is consistent with the time of completion of development of the brain-stem reported by Dobbing and Sands (1973). Although the beginning of the first component in the TBR is not clear enough to evaluate the R1 latency exactly, the R1 latency of the TBR was almost equal to that of the EBR. Before 1 year of age, the R2 latency of TBR was longer than that of EBR, after which the R2 latency of TBR had a tendency to be shorter than that of EBR. KhaterBoidin and Duron (1987) found in newborns that the R1 latency of the mechanically evoked response was approximately 3 msec longer than that of the EBR and that R2 was 7 msec longer than that of the EBR. Compared with that of EBR, the R1 response of TBR was often polyphasic throughout life. This discrepancy is considered to be due to the different blink reflex methods used. As previously described, crossed medullary interneurons are immature before 1 year, so the shorter R2 latency of TBR observed after 1 year may be caused by an increase in excitability to the simultaneous stimulation of both sides. In TBR, the length of the afferent arc from the glabella to the supraorbital foramen is added to that of the pathway of the EBR. The delayed latency of TBR observed before 1 year may be due to the additional length of the pathway. The R1 and R2 recovery curves obtained for full-term newborns are similar to those for adults obtained by Kimura and Harada (1976). As in
ELECTRICALLY AND MECHANICALLY ELICITED BLINK REFLEXES adults, in full-term babies R1 showed increased a m p l i t u d e at intervals ranging f r o m 20 to 80 msec, while R2 r e m a i n e d p r o f o u n d l y suppressed up to 800 msec. O n the contrary, the recovery curves b e f o r e 35 weeks of c o n c e p t i o n a l age were considerably different f r o m those in full-term n e w b o r n s and adults and showed little or no evidence of inhibition. K i m u r a a n d H a r a d a (1976) r e p o r t e d that this dissociation of the recovery curves m a y be taken as a sign of r e d u c e d excitability at the i n t e r n e u r o n level after the passage of a p r e c e d i n g impuls e and that, as an e x p l a n a t i o n for the mechanism, there was possibly inhibitory feedback in the i n t e r n e u r o n a l network. In recent years it has been suggested that reflex i n h i b i t i o n is m e d i a t e d by the specific inhibitory neural system that involves the lateral t e g m e n t u m (Leiter et al. 1980, 1981; H o f f m a n et al. 1987). O u r results indicate that the m e c h a n i s m s of inhibition a n d excitation were not fully d e v e l o p e d in p r e m a t u r e babies, but an inhibitory system of i n t e r n e u r o n s was functionally c o m p l e t e d by 40 weeks of c o n c e p t i o n a l age. The se findings are also consistent with the results of studies on inhibition of the glabella tap blink reflex in the h u m a n infant ( H o f f m a n et al. 1987). H o w e v e r , it is possible that the m e c h a n i s m of inhibition f o u n d in n e w b o r n s differs physiologically from that in adults ( Z a m e t k i n et al. 1979). In conclusion, d e v e l o p m e n t o f the R1 c o m p o nent is c o n s i d e r a b l y different f r o m that of R2, and m a t u r a t i o n a l changes in R1 facilitation and R2 inhibition of the blink reflex o c c u r in the n e w b o r n period. This study was supported by Grants-in-Aid for the Encouragement of Young Scientists, Nos. 61770719 and 62770707, from the Ministry of Education, Japan, and the Mami Mizutani Foundation.
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45
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