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Summary. The somatosensory-evoked blink response (SBR) is a newly identified blink reflex elicited by electrical stimulation of peripheral nerves. The present ...
Brain (1998), 121, 281–291

Somatosensory-evoked blink response: investigation of the physiological mechanism Hideto Miwa, Chiyoko Nohara, Munehumi Hotta, Yasuji Shimo and Katuaki Amemiya Department of Neurology, Juntendo University School of Medicine, 2–1–1 Hongo, Bunkyo-ku, Tokyo 113, Japan

Correspondence to: Hideto Miwa, MD, Department of Neurology, Juntendo University School of Medicine 2–1–1 Hongo, Bunkyo-ku, Tokyo 113, Japan

Summary The somatosensory-evoked blink response (SBR) is a newly identified blink reflex elicited by electrical stimulation of peripheral nerves. The present study was performed to investigate the physiological mechanism underlying the SBR elicited by median nerve stimulation in normal subjects. The peripheral afferents responsible for the SBR included lowthreshold cutaneous fibres. In the SBR-positive subjects, the late (R2) component of the blink reflex elicited by supraorbital nerve stimulation and the SBR facilitated each other when both responses were induced at the same time, but they each caused long-lasting inhibition in the other when one stimulus was given as a conditioning stimulus. The extent of inhibition was correlated with the size of the preceding SBR. In the SBR-negative subjects, simultaneous inhibition of R2 was observed when median nerve stimulation was applied as a conditioning stimulus. Brainstem excitability, as evaluated

by blink-reflex recovery studies, did not differ between SBRpositive and SBR-negative subjects. Therefore, based on anatomical and physiological findings, it appears that the reflex pathways of the SBR and R2 converge within the brainstem and compete with each other, presumably by presynaptic inhibition at the premotor level, before entering the common blink-reflex pathway. The influence of median nerve stimulation upon tonic contraction of the orbicularis oculi muscle was studied to detect the latent SBR. There was not only a facilitatory period corresponding to the SBR but also an active inhibitory period (exteroceptive suppression), suggesting that the mechanism generating the SBR is not only influenced by blink-reflex volleys but also by active exteroceptive suppression. Thus, the SBR may appear as a result of integration of facilitatory and inhibitory mechanisms within the brainstem.

Keywords: somatosensory-evoked blink response; blink reflex; presynaptic inhibition; exteroceptive suppression; brainstem reticular formation Abbreviations: PT 5 perception threshold; R1/R2 5 early/late components of the blink response (trigeminofacial reflex); SBR 5 somatosensory-evoked blink response

Introduction The blink reflex has been investigated extensively in both basic and clinical studies (Kugelberg, 1952; Rushworth, 1962; Shahani and Young, 1972; Kimura, 1973; Holstege et al., 1995). However, the influence of peripheral nerve stimulation on the blink reflex is still under investigation (Rossi et al., 1992; Valls-Sole´ et al., 1994). It has been suggested that polysensory inputs enter the brainstem reticular formation and modulate the excitability of the facial nerve nucleus or adjacent structures (Rimpel et al., 1982; Holstege et al., 1995). Both electrical and hammer-tap stimulation applied to the extremities before elicitation of the blink reflex (the trigeminofacial reflex) are facilitatory for the early (R1) component but inhibitory for the late (R2) component (Rossi et al., 1992; Valls-Sole´ et al., 1994; Go´mez-Wong and Valls© Oxford University Press 1998

Sole´, 1996). On the other hand, auditory stimulation given as a conditioning stimulus can facilitate the R2 component of the trigeminofacial reflex, when given at the same time, or 50 ms prior to, trigeminal nerve stimulation (Nakashima et al., 1993). These findings suggest that blink-reflex activity is under both excitatory and inhibitory controls by the various sensory modalities. The somatosensory-evoked blink response (SBR) is a newly reported type of reflex: the blinking elicited by electrical stimulation of a peripheral nerve or the skin of the body or limbs. It was first reported in patients with Miller– Fisher syndrome, especially in the acute phase of this illness (Miwa et al., 1995). The SBR has also been detected in a few normal individuals and in patients with various neurological

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disorders such as Parkinson’s disease, hemifacial spasm (Miwa et al., 1996) and post-anoxic intention myoclonus (Lance–Adams syndrome) (Imamura et al., 1995). We have assumed that the SBR is not a variant of the startle blink reflex, but is one of the release phenomena of the basically programmed blink reflexes that protect the eyes from various invasive stimuli, and that it possibly appears due to increased excitability of the brainstem reticular formation (Imamura et al., 1995; Miwa et al., 1995, 1996). There are several pieces of evidence suggesting that the SBR is not a variant of the startle blink reflex, e.g. both the latency and duration of the SBR are shorter and the startle blink reflex usually occurs together with generalized startle jerks of the body and limbs (Miwa et al., 1995, 1996). On the other hand, whether the SBR is actually one of the blink reflexes has not been fully investigated. It is known that the shape and duration of the EMG responses responsible for the SBR resemble those of the R2 component of the blink reflex elicited by stimulation of the supraorbital nerve and that the SBR is confined to the orbicularis oculi muscles (Imamura et al., 1995; Miwa et al., 1995, 1996), but there has been little investigation of the physiological mechanisms that underlie the SBR. Accordingly, the present study was performed to investigate the physiological basis of the SBR.

Material and methods Subjects

The subjects were healthy volunteers (n 5 14) without any neurological abnormalities or medications (age range 24–37 years). Most of them were staff from our university hospital. Before starting electrophysiological experiments, a routine blink-reflex study was performed, and it was confirmed that the early and late components of the blink response (R1 and R2, respectively) were normal. Then the median nerve was supramaximally stimulated at the wrist to determine whether the SBR was present or absent. SBR positivity was defined largely according to our previously proposed criteria (Miwa et al., 1996), but only subjects who showed constant, stable EMG activity for the SBR were selected as positive subjects. As found in our previous study (Miwa et al., 1995), the SBR was not so common, and we could only detect a total of six SBR-positive subjects (three men and three women: mean age 28.5 years; range 24–37 years). The other eight subjects were SBR-negative (four male and four female: mean age 29.6 years; range 25–36 years). SBR-positive and SBRnegative subjects were analysed separately. Informed consent was obtained from all participants, and the study was approved by the ethics committee of the Juntendo University School of Medicine.

placed on the inferior part of the orbicularis oculi muscles to record EMG activity with a Neuropack 8 electromyograph (Nihon-Kohden, Japan). A 0.1-ms stimulus was given to the skin over the median nerve at the wrist, elbow or digit. The SBR is rapidly habituated, as previously reported (Miwa et al., 1995, 1996). To avoid the habituation in the present study electrical stimulation was given with an inter-stimulus interval of ù10–15 s. A session was performed once a day, and the maximum duration of each session was ,30 min. When two consecutive electrical stimuli failed to elicit any EMG discharges for the SBR, we considered that the SBR was habituated, and we then stopped the session. Stimulus intensity was set at supra-maximal or at various intensities which were multiples of the perception threshold (PT). The PT was defined as the minimum stimulus intensity at which that subject first noticed an electrical shock, when the stimulus intensity was increased in 0.2-mA increments with an interstimulus interval of several seconds. The EMG traces obtained were recorded on a hard disk or floppy disk for later analysis.

Experimental procedures Conditioning paradigm To study the effect of peripheral nerve stimulation on the trigeminofacial reflex, especially whether the peripheral input converged onto the blink-reflex pathways, an electric shock was given to the median nerve as a conditioning stimulus, and supraorbital stimulation was applied as the test stimulus. Test stimulation was repeated at intervals of ù15 s, and every second stimulus was combined with a conditioning stimulus. The percentage of the EMG area of R1, or R2, was calculated relative to that elicited by the preceding test stimulus alone. The effect of supraorbital nerve stimulation on appearance of the SBR was studied in the SBR-positive subjects. An electrical shock to the supraorbital nerve was given as the conditioning stimulus, and median nerve stimulation was used as the test stimulus. Test stimulation was repeatedly applied at intervals of ù10 s, and every second stimulus was combined with a conditioning stimulus. The percentage of the maximum EMG amplitude of the SBR was calculated relative to that elicited by the preceding test stimulus alone.

Blink-reflex recovery study To evaluate the excitability of the facial nucleus and the brainstem interneurons responsible for the trigeminofacial reflex volley, blink-reflex recovery was studied. Paired conditioning and test stimuli were applied to the supraorbital nerve at intervals of 40, 60, 80, 100, 200, 300 and 500 ms. The stimulus intensity was adjusted to that which was able to evoke a stable R2 response in each individual subject (5–8 times the PT). The interval between stimuli was ù10 s.

Stimulation and recording

Averaging

The subjects were requested to sit in an armchair or lie on a bed comfortably in a quiet room. Surface electrodes were

The effect of peripheral nerve electrical stimulation on the EMG activity of orbicularis oculi was studied, to examine

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whether the SBR became stronger when the background activity of the orbicularis oculi muscle increased. The subjects were instructed to keep their eyes closed in order to obtain stable EMG activity while they listened to the EMG monitor. Then the median nerve was stimulated, and the data for the ipsilateral orbicularis oculi muscle were rectified and averaged. The stimulus intensity was usually 6–8 times the PT and 32–48 responses were averaged.

Statistics We measured the onset latency, peak amplitude and area (duration3amplitude) of EMG responses for R1, R2 and the SBR. For averaging, the latency of the onset and termination of identifiable facilitatory or inhibitory periods was determined by visual inspection. Results are represented as means 6 standard deviations. Statistical comparisons were done by using ANOVA followed by a post hoc t test; P , 0.05 was considered to indicate significance.

Results Appearance of the SBR The SBR was defined as phasic contraction confined to the orbicularis oculi muscles. As shown in Fig. 1A, the shape of the SBR varied to some extent, and thus there was inter-trial variability in both latency and duration. The onset latency of the EMG for the SBR elicited by median nerve stimulation in the six SBR-positive subjects was 42.9 6 4.1 ms (mean 6 SD) for the ipsilateral orbicular oculi muscle and 43.9 6 3.4 ms on the contralateral side. The duration of the SBR was 45.1 6 9.6 ms on the ipsilateral side and 43.1 6 7.3 ms on the contralateral side.

Afferent pathways for the SBR Electrical stimulation at intensities below the PT could not elicit any EMG for the SBR. Electrical stimulation applied upon the motor point of the median nerve at the wrist with an intensity just above the PT occasionally elicited the SBR, but the response was poorly reproducible. As the stimulus intensity was increased further, it became easier to obtain a stable SBR (Fig. 1B). The amplitude of the SBR was maximal at a stimulus intensity of 5 3 PT. The SBR could be elicited by stimulating not only the motor point of the peripheral nerves but also the skin 1 cm lateral to the nerve trunk and the skin at various sites on the body or limbs. In addition, the SBR could be elicited by electrical stimulation of the fingers using ring electrodes attached to the distal interphalangial and middle phalangial joints (Fig. 1B). However, the response was unstable, and it was necessary to increase the stimulus intensity to 8 3 PT before obtaining a reproducible response. In the following studies, a stimulus intensity of .5 3 PT was applied at the wrist to elicit the SBR.

Fig. 1 (A) Representative EMGs showing the SBR (somatosensory-evoked blink response). The EMGs were recorded from orbicularis oculi muscle unilaterally. The median nerve was stimulated at the wrist with an inter-stimulus interval of 15 s. Traces 1–5 were recorded successively. There was inter-trial variability in both latency and duration. (B) The median nerve was stimulated at the wrist at various stimulus intensities. The EMG activities in 10 trials were rectified and averaged. As the stimulus intensity increased, it became easier to elicit a stable SBR. The amplitude of the SBR was maximal at a stimulus intensity of five times the PT (perception threshold). The SBR could also be elicited by stimulation of the distal nerve of the second digit by use of ring electrodes (bottom trace).

In four SBR-positive subjects, we examined the conduction velocity of the afferent peripheral nerve. An electrical stimulus was applied to the motor point of the median nerve at a supramaximal intensity, either at the wrist or elbow, and the latency of the SBR was measured. The latency of the SBR varied between each response and it was difficult to determine the exact latency because of this marked variation. Therefore, the conduction velocity of the peripheral nerve responsible for the SBR was calculated using the mean latency from six successively

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Fig. 2 (A) Latencies of the SBRs elicited by electrical stimulation of the median nerve at either the wrist or the elbow in a SBR-positive subject. Each bar indicates the mean latency of the SBRs. (B) The corresponding rectified and averaged EMG responses (six trials each). Arrows indicate the onset of the EMG activity responsible for the SBR.

obtained responses (Fig. 2A). The conduction velocities calculated for each subject were 30.5, 24.5, 26.8 and 34.4 m/s. Next, the EMG responses elicited by median nerve stimulation were rectified and averaged. The peripheral conduction velocity for the SBR, calculated using the averaged onset latency, was 33.3, 35.3, 34.4 and 39.8 m/s, respectively (Fig. 2B).

Convergence of peripheral nerve activity onto the blink-reflex pathway To examine whether the sensory signals produced by peripheral nerve stimulation converge into trigeminofacial reflex volleys, median nerve stimulation and supraorbital nerve stimulation were performed with appropriate timing. It might be considered necessary to adjust the stimulation time to make the SBR and R2 appear simultaneously. However, since the onset latency and the duration of both SBR were not so different from those of R2, the two nerves were stimulated together in the present study. When supraorbital and median nerve stimulation were given at an appropriate intensity, a facilitatory effect was observed (Fig. 3A and B). Supraorbital nerve stimulation at an intensity producing the maximal response did not have any facilitatory effect on median nerve stimulation, so it was necessary to use a stimulus intensity inducing a stable R2 with an appropriate amplitude. When supraorbital nerve stimulation was given at an intensity yielding R2 at ~50% of the maximum amplitude, significant facilitation was observed (Student’s t, P , 0.03).

SBR conditioning by elicitation of the trigeminal blink reflex The influence of prior stimulation of the supraorbital nerve (also evoking a blink reflex) upon the subsequently elicited SBR was studied in the SBR-positive subjects. The EMG for the SBR elicited by median nerve stimulation was markedly suppressed by a preceding stimulus to the supraorbital nerve (Fig. 4A). The reduction of the EMG activity was most marked when the supraorbital nerve stimulus was given 100–200 ms prior to median nerve stimulation, and it gradually recovered when the interstimulus interval was increased from 500 to 1000 ms (Fig. 4B). The influence of median nerve stimulation on the subsequently elicited trigeminofacial reflex (R1 and R2 components) was also studied, in both SBR-positive and SBR-negative subjects. By definition, only the SBR-positive subjects showed preceding elicitation of the SBR. In both groups, however, median nerve stimulation caused shortlasting facilitation of the subsequent R1 component and longlasting inhibition of the subsequent R2 component, and no significant difference was observed between the SBR-positive and SBR-negative subjects (Fig. 5A). Additionally, the timecourse of inhibition of both components (R1 and R2) was not so different from that of the SBR induced by preceding elicitation of the blink reflex. The EMG activity related to the SBR varied considerably between trials. Thus, in the SBR-positive subjects, the relationship between the initial SBR EMG and the subsequent R2 EMG activity was evaluated; data obtained with inter-stimulus intervals of 100–200 ms were compared, since a definite inhibitory influence on R2 was observed

Somatosensory-evoked blink response

Fig. 3 (A) Rectified and averaged EMG responses: (a) the EMG activity responsible for the SBR elicited by median nerve stimulation at the wrist; (b) the R2 component of the blink reflex elicited by supraorbital nerve stimulation; and (c) the median nerve and the supraorbital nerve were stimulated simultaneously. (B) The areas of the EMG responses of (a) and (c) are shown as means and SDs. The data are presented as percentages of the mean value of the area of the EMG activity responsible for the R2 component of the blink reflex in (b). *P , 0.03

with such intervals. There was a significant negative correlation (P 5 0.038, r 5 –0.29), indicating that inhibition of R2 was dependant on the size of the preceding SBR.

Blink-reflex recovery There were no qualitative or quantitative differences of blink-reflex recovery between the SBR-positive and SBRnegative subjects. The R1 component was markedly facilitated at inter-stimulus intervals of ,100 ms and it returned to near-baseline levels at inter-stimulus intervals of .100 ms. On the other hand, the R2 response was generally inhibited and was most reduced at inter-stimulus intervals of 100–200 ms (Fig. 6).

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Fig. 4 (A) The EMG activity of the orbicularis oculi muscle responsible for the SBR elicited by median nerve stimulation (upper trace) and that elicited by the supraorbital nerve stimulation prior to a median nerve stimulus (lower trace). Arrows indicate the time points at which the electrical stimuli were applied to the nerves. The bars (a and b) indicate the EMG activity responsible for the SBR (following stimulation of the median nerve). Note that the SBR was reduced by prior stimulation of the supraorbital nerve. (B) The SBRs conditioned by a prior blink reflex (supraorbital nerve stimulation) are shown. Data represent means and SDs. Data were obtained by pooling the results for the SBR-positive subjects (n 5 5). Note that the reductions in the SBR are marked for inter-stimulus intervals of 100–200 ms.

Exteroceptive suppression and facilitation To detect a latent SBR in the SBR-negative subjects, the effect of median nerve stimulation on the ongoing EMG activity of orbicularis oculi was first assessed by averaging in the SBR-positive subjects. In all SBR-positive subjects (n 5 6), median nerve stimulation showed monophasic facilitation of the ongoing, weak and tonic voluntary contraction of orbicularis oculi when stimulation was repeated at an interval of 10 s, i.e. a frequency of 0.1 Hz. The appearance of the facilitatory EMG response was in a good agreement to that of the SBR (Fig. 7A). The onset latency of the EMG activity related to facilitation in the SBR-positive subjects was 42.2 6 4.3 ms (mean 6 SD) and the duration was 56.8 6 16.8 ms. Just like the SBR, the SBR-like facilitatory period showed habituation readily. When the stimulus frequency was .0.2 Hz, the facilitatory effect became less evident. Reproducibility of the waveforms was lost when the stimulus frequency was .0.5 Hz.

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Fig. 5 Influences of prior stimulation of the median nerve on the R1 (A) and R2 (B) components of the blink reflex evoked by supraorbital nerve stimulation. Data were obtained by pooling results for the SBR-positive subjects (open circles) and SBRnegative subjects (filled circles).

Fig. 6 Recovery curve of the R1 (A) and R2 (B) components of the trigeminofacial reflex. Data represent means and SDs. Data were obtained by pooling results for the SBR-positive subjects (open circles) and SBR-negative subjects (filled circles), respectively.

Next, the relationship between the EMG pattern and the background level of muscle contraction was studied to determine the baseline level most effectively inducing a latent SBR. Trials with various levels of background EMG activity were averaged. As background activity increased, SBR-like facilitation first increased and was then lost, and the inhibitory phase became clearer (Fig. 7B). Therefore, for identification of SBR-like facilitation, a background of relatively weak muscle contraction was considered to be more appropriate, and trials to detect a latent SBR were performed in the SBR-negative subjects using weak background contraction (~10–20% of maximum) and median nerve stimulation. The results obtained in the SBR-negative subjects (n 5 8) were not constant. In two subjects, there was no reproducible effect, either facilitatory or inhibitory, on the averaged EMG activity. However, in the other six SBRnegative subjects, a facilitatory period of EMG activity, possibly corresponding to the SBR, was observable. The latency and the duration of the facilitatory period were 48.3 6 5.9 ms and 24.1 6 9.9 ms (mean 6 SD), respectively. The onset latency of the facilitatory period

was significantly longer in the SBR-negative subjects than in the SBR-positive subjects (P , 0.01, by Student’s t test). Similarly, the duration of the facilitatory period was significantly shorter in the SBR-negative subjects than in the SBR-positive subjects (P , 0.0001, by Student’s t test). There was also an inhibitory phase appearing prior to, or after, the SBR-like facilitation in the SBR-negative subjects. The onset latency and the duration of the inhibitory period prior to SBR-like facilitation were 42.5 6 9.2 ms and 11.9 6 4.8 ms, respectively, and those of the inhibitory period following SBR-like facilitation were 69.5 6 5.8 ms and 11.8 6 5.7 ms, respectively. As described above, the inhibitory phase emerged when the background activity increased, but there was no significant difference in mean baseline level activity between the SBR-negative and SBR-positive subjects (13.0 6 7.6 µV and 11.7 6 5.3 µV, respectively). As with the SBRpositive subjects, the reproducibility of either facilitatory or inhibitory effecs was lost when the stimulus frequency was .0.2 Hz in the SBR-negative subjects (e.g. see Fig. 8A). Finally, it was noted that voluntary limb movements clearly suppressed the SBR-like facilitation in both SBR-

Somatosensory-evoked blink response

Fig. 7 The effect of background activity on the rectified and averaged EMG responses of the orbicularis oculi muscle elicited by median nerve stimulation in a SBR-positive subject. The arrow indicates the time point at which the peripheral nerve was stimulated. The horizontal line beneath the sweep indicates the zero level of the EMG activity. (A) When the background contraction of the orbicularis oculi muscle is low, a monophasic facilitation identical to the SBR is seen. (B) When the background contraction is mild, two phasic inhibitory phases are identifiable, before and after the SBR-like facilitation. As the background activity increases, the facilitatory phase disappears and, instead, broad inhibition occurs (C and D).

positive and -negative subjects. When the subjects depressed a pedal to trigger electrical stimulation to the median nerve at self-paced intervals of ~10 s, SBR-like facilitation was lost (Fig. 8B).

Discussion Afferent pathway of the SBR The SBR is possibly of cutaneous origin, because it can be elicited by electrical stimulation of not only the motor point of a peripheral nerve trunk but also the skin at various sites on the upper or lower limbs and body (Imamura et al., 1995; Miwa et al., 1995). Since the present study showed that the minimum stimulus intensity for inducing the SBR was just above the PT, the afferent fibres involved may include lowthreshold cutaneous fibres. The large variation of SBR latency made it difficult to determine the conduction velocity in the ascending limb of the reflex, but the present study suggested a velocity of ~30 m/s, which is slower than that of Ia or Ib afferents. This finding also supports the concept that the SBR is a cutaneous reflex.

The blink reflex and SBR The blink reflex elicited by supraorbital nerve stimulation (the trigeminofacial reflex) consists of two components: R1

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Fig. 8 The effect of stimulus frequency on the rectified and averaged EMG responses of the orbicularis oculi muscle elicited by median nerve stimulation in a SBR-positive subject. The arrow indicates the time point at which electrical stimulation was applied to the the median nerve stimulation. Thirty-two responses were averaged. (A) When stimulation was applied at a rate of 0.1 Hz, facilitation identical to the SBR was observed. (B) When the stimulation was applied at a rate of 0.5 Hz, the facilitation was less evident but still clearly occurred. (C) When the subject controlled the stimulation using a trigger pedal, the SBR-like facilitation was suppressed.

and R2 (Kugelberg, 1952; Shahani and Young, 1972). R1 appears ipsilaterally and R2 appears bilaterally in humans (Holstege et al., 1995). Both reflexes are transmitted via the brainstem reticular formation. Our previous studies suggesed that the SBR may be an analogue of the R2 elicited by stimulation of the extra-trigeminal region on the basis of the similarity of their EMG waveforms (Imamura et al., 1995; Miwa et al., 1995). It has previously been reported that the extra-trigeminal electrical stimulation can sometimes produce reflex contraction of the orbicularis oculi, and this response may be identical to the SBR (Gandiglio and Fra, 1967). However, there have been no detailed studies of the SBR. Therefore, it is relevant to consider the pathophysiological relationship between the SBR and the blink reflex induced by supraorbital nerve stimulation, especially the R2 component. It is clear that the final common output of both R2 and the SBR are the orbicularis oculi motor neurons. The first problem is whether or not both responses have a common premotor mechanism before entering the motor neuron pool of orbicularis oculi, as has been suggested physiologically (Rimpel et al., 1982) or anatomically (Holstege et al., 1995). The present finding that the SBR and R2 exerted a facilitatory influence on each other when both responses were induced at the same time indicates that these responses have an excitatory convergence at some point, but it remains uncertain whether convergence occurs at the premotor level or the motor neuron level. Another interesting finding of the present study was that the SBR and R2 had a long-lasting inhibitory

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Fig. 9 (A) A schematic diagram illustrating reflex pathways subserving the SBR and other blink reflexes. Blink reflexes, by nature, have reflex pathways able to respond to multiple modalities of sensory stimulation, such as trigeminal, somatic, photic and auditory stimulation. Sensory impulses, particularly those originating from peripheral nerves and the trigeminal nerve inhibit each other, possibly at the presynaptic level (gating by presynaptic inhibition). Impulses are in turn transmitted to the common blink premotor interneurons in the brainstem reticular formation. A gating mechanism might also be present within polysynaptic interneurons (gating by polysynaptic interneuron). Finally, sensory signals reach the orbicularis oculi motor neurons (motor output). In this schema, presynaptic mutual inhibitions of the SBR and R2 are transmitted via an inhibitory interneuron simultaneously, according to a hypothesis proposed by Rossi and Scarpini (1992). (B) A schematic diagram of the proposed mechanisms underlying the generation of the SBR. The peripheral somatic inputs influence the orbicularis oculi motor neuron activities by at least two different reflex mechanisms. One is facilitation (the SBR), and the other is inhibition (exteroceptive suppression). The brainstem reticular formation might be an integrator of both excitation and inhibition in the presence of various supranuclear influences.

influence on each other when applied as conditioning stimuli. However, as shown in the present study and as reported previously by others (Rossi et al., 1992), median nerve conditioning stimulation causes short-lasting facilitation of R1 when the inter-stimulus interval is ,100 ms, raising the possibility that excitability of the orbicularis oculi motor neurons is up-regulated rather than inhibited by peripheral nerve stimulation. This odd response, in which R1 is facilitated but R2 is inhibited, suggests that inhibition between SBR and R2 possibly occurs at the premotor level. It has been suggested that multiple sensory modalities, such as tactile, auditory and visual sensation, may have a common premotor mechanism for the blink reflex (Rimpel et al., 1982; Holstege et al., 1986b). Therefore, it is likely that reflex volleys subserving both the SBR and R2 may have at least a partial common premotor mechanism, leading to tonic and long-lasting inhibition of each other. The next problem is to consider the mechanism of such inhibition. Two mechanisms may be suggested, as follows. The first is that the common blink interneuron pathway itself may have such an inhibitory effect. Habituation is a common response of polysynaptic pathways. However, the recovery curve of the SBR conditioned by R2 was not so different from the recovery curve of R2 itself and was faster than expected, because the SBR is rapidly habituated and it is usually not easy to obtain a stable response with stimulation at intervals of ,10 s (Miwa et al., 1996). Therefore, it appears

likely that the process concerned with rapid habituation of SBR is not associated solely with a gating mechanism produced within common blink relay neurons. Another possible mechanism of inhibition is presynaptic inhibition. Animal studies have revealed that trigeminal or peripheral nerve afferent volleys modulate trigeminofacial reflex activity, especially at the second order neuron level (Darian-Smith, 1965; Stewart and King, 1966; Baldissera et al., 1967). This inhibitory influence of peripheral afferents on the trigeminal nucleus has been chiefly attributed to presynaptic depolarization of the trigeminal primary afferents (Baldissera et al., 1967). Also in humans, Rossi et al. (1992) speculated that the primary mechanism of inhibitory control of the trigeminofacial reflex by extra-trigeminal afferents is presynaptic inhibition. Presynaptic inhibition is one of the principal mechanisms that underlies reflex physiology in both humans and animals (Hultborn et al., 1987; Rudomin, 1990), and the time course of presynaptic inhibition reported in animal experiments does not differ markedly from our results for R2 and the SBR (Darian-Smith, 1965; Stewart and King, 1966). Therefore, trigeminal and extra-trigeminal sensory inputs may simultaneously exert presynaptic inhibition on different modalities before entering a common, non (modality) specific, blink-reflex pathway. The present finding of a negative correlation between the size of the SBR induced as a conditioning response and that of the subsequent elicited R2, may also be interpreted similary, i.e. as the inflow of extra-

Somatosensory-evoked blink response trigeminal sensory impulses increases, there is increasing inhibition of the inflow of trigeminal inputs responsible for induction of R2 into the common blink pathway. The next important problem is to consider which mechanism is responsible for generating or releasing the SBR. In other words, why is the SBR present in some normal subjects and absent in others? We have previously suggested that increased excitability of interneurons of the brainstem reticular formation contributes to generating the SBR (Imamura et al., 1995; Miwa et al., 1995, 1996), but the present results did not support this idea. Since recovery of the blink reflex is widely known as a useful marker for evaluating the excitability of neurons responsible for the trigeminofacial reflex (Kimura, 1973), it is relevant to study blink-reflex recovery and to compare it between SBR-negative and SBR-positive subjects. R2 is transmitted via polysynaptic pathways widely distributed within the brainstem or high cervical reticular formation, and it is considered that reduction of R2 induced by a conditioning stimulus is the result of changes in the excitation of interneurons in the brainstem reticular formation. The present finding, that there was no significant difference of blink-reflex recovery between the R1 and R2 components in the SBR-positive and SBRnegative subjects, suggests that increased excitability of brainstem interneurons is not essential for generation of the SBR. This may be compatible with our previously reported finding that the SBR is often elicitable in patients with Parkinson’s disease and hemifacial spasm but less often elicitable in patients with dystonia (Miwa et al., 1996), unless increased excitability has been reported in these disorders (Kimura, 1973; Berardelli et al., 1985; Tolosa et al., 1988; Valls-Sole´ and Tolosa, 1989; Carella et al., 1994; Katayama et al., 1996). Therefore, the key mechanism generating the SBR may exist before somatosensory signals enter the common blink interneuronal networks. A mechanism that modulates the functionally organized linkage between a sensory input and the corresponding motor output is generally known as a ‘sensory-motor gating mechanism’. However, the sensory gating mechanism is only hypothetical, and the actual anatomical/physiological features responsible for such a mechanism still remain unclear. Several structures have been suggested, such as the parabrachial nucleus, superior colliculus, or raphe nucleus (Lidsky et al., 1985; Schneider, 1987; Basso and Evinger, 1996; Basso et al., 1996). One possibility is that the appearance of the SBR may depend on the level of activity in such a gating mechanism which exerts inhibition on the inflow of the somatic input. As discussed above, it may be possible that that a mechanism such as presynaptic inhibition contributes to gating at the level before sensory impulses enter the common blink-reflex pathway. Individuals with less habituation of the gating mechanism, either normally or abnormally, would be SBR-positive.

Active suppression by peripheral nerve stimulation The present study revealed another notable finding on the relationship between the peripheral somatosensory input and

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orbicularis oculi muscle activity. Sustained contraction of the muscle being examined is widely used for detection of a latent or subtle response (Matthews, 1986). In the present study, we investigated whether peripheral nerve stimulation can induce a EMG response identical to the SBR using an averaging technique and found monophasic facilitation very similar to the SBR. However, in some SBR-negative subjects, this SBR-related facilitation was not always detectable. Instead, phasic suppression was present before and after the onset of SBR-like facilitation. Even in the SBR-positive subjects, the SBR-like facilitation disappeared when the subjects performed self-stimulation. Therefore, orbicularis oculi muscle activity is not only under facilitatory but also inhibitory control. This type of active suppression of sustained muscle contraction in the head and neck region has already been reported. Trigeminal nerve simulation exerts exteroceptive suppression on the muscles of mastication (Meier-Evert et al., 1974; Ongeboer de Visser and Goor, 1976; Cruccu et al., 1986) and the sternocleidomastoid muscle (Nakashima et al., 1989). It is thus possible to speculate that the neuronal mechanisms underlying the SBR and exteroceptive suppression may coexist in the brainstem and that the SBR may occur as a result of integration of the facilitatory and inhibitory mechanisms. If this is the case, SBR-positive subjects would show a facilitatory shift of the balance between facilitation and inhibition. However, further studies are required to determine the exact mechanism underlying exteroceptive suppression.

General conclusions The blink reflex is a primitive response protecting the eyes and consists of two identifiable components in humans (R1 and R2). The R2 component contributes to actual closure of the eyelids (Shahani and Young, 1972). For the eye closure to occur, the blink motor neurons must receive strong projections from somewhere in the CNS (Holstege et al., 1995). Based on anatomical studies, there are two sites having such connections in the brainstem reticular formation of the cat: the pontine and medullary blink premotor areas (Holstege et al., 1986a, b). Anatomical findings have suggested that multiple modalities of sensory stimulation, such as tactile, auditory and visual stimuli, have a common blink premotor mechanism (Rimpel et al., 1982; Holstege et al., 1986b). Therefore, the SBR may be one of the blink reflexes sharing common neural substrates to a certain extent. However, in certain individuals the SBR may not normally be present because it has been habituated or inhibited. A possible reflex pathway responsible for the SBR is illustrated in Fig. 9A. Generation of the SBR may be related to the sensory gating mechanism responsible for interruption of the excessive inflow of somatosensory stimuli. The SBR may be chronically habituated or inhibited at the level of such a gating mechanism which, presumably, may be at least partly under the control of a presysynaptic mechanism. It may appear either in some normal individuals with a relatively less

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habituated gating mechanism or in patients with symptomatic malfunction of the gating mechanism. Another finding possibly related to the pathophysiological mechanism of the SBR is that oribicularis oculi contraction shows simultaneous exteroceptive suppression. Therefore, the mechanism generating the SBR is influenced not only by blink-reflex volleys but also by active exteroceptive suppression, possibly to avoid tonic eye closure. This exteroceptive suppression mechanism seems reasonable, since the eye is an organ for seeing. The SBR may appear as a result of the integration of facilitatory and inhibitory mechanisms within the brainstem (Fig. 9B). Further studies are required to understand influences exerted by higher centres, such as the basal ganglia, cerebellum or cortex, all of which may be possibly related to the generation of the SBR.

Acknowledgement We wish to thank Professor Yoshikuni Mizuno for his helpful comments on the present study.

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Received May 22, 1997. Revised August 28, 1997. Accepted September 8, 1997