Long-term effect of prednisolone on functional blink recovery after transient peripheral facial motor paralysis.

OBJECTIVE: To determine the functional recovery in patients with severe transient peripheral facial motor paralysis (Bell palsy). STUDY DESIGN: Prospective controlled trial. SETTING: Academic medical center. SUBJECTS AND METHODS: Blink recovery was studied in 2 groups of severely affected Bell palsy patients during a follow-up period of 84 weeks. The patients in one group received prednisolone within the first week after the onset of symptoms. No medication was given to the other group. A control group of healthy subjects was also included. Simultaneous orbicularis oculi muscle activity and eyelid kinematics were recorded by surface electromyographic (EMG) recording and eyelid search coils, respectively. RESULTS: At the beginning of the paralysis, very little integrated orbicularis oculi muscle activity and eyelid movement was measured at the palsied side of the face. Thirteen weeks later, the integrated orbicularis oculi EMG and functional blink recovery gradually improved until 39 weeks. Beyond, only the integrated orbicularis oculi EMG slightly increased. At 84 weeks, the integrated orbicularis oculi EMG was significantly larger in the prednisolone group compared with the control group. The integrated EMG of the nonmedicated group recovered to normal values. Curiously enough, the functional blink recovery at the palsied side remained reduced to 64% compared with the healthy controls in the prednisolone-treated group and to 36% in the nonmedicated group. CONCLUSION: The authors demonstrate that prednisolone significantly increased the orbicularis oculi muscle activity and significantly improved functional blink recovery in severely affected Bell palsy patients. However, the increase of muscle activity was insufficient to restore functional blinking to normal values.

Anti-malaria drug mefloquine induces motor learning deficits in humans.

Mefloquine (a marketed anti-malaria drug) prophylaxis has a high risk of causing adverse events. Interestingly, animal studies have shown that mefloquine imposes a major deficit in motor learning skills by affecting the connexin 36 gap junctions of the inferior olive. We were therefore interested in assessing whether mefloquine might induce similar effects in humans. The main aim of this study was to investigate the effect of mefloquine on olivary-related motor performance and motor learning tasks in humans. We subjected nine participants to voluntary motor timing (dart throwing task), perceptual timing (rhythm perceptual task) and reflex timing tasks (eye-blink task) before and 24 h after the intake of mefloquine. The influence of mefloquine on motor learning was assessed by subjecting participants with and without mefloquine intake (controls: n = 11 vs mefloquine: n = 8) to an eye-blink conditioning task. Voluntary motor performance, perceptual timing, and reflex blinking were not affected by mefloquine use. However, the influence of mefloquine on motor learning was substantial; both learning speed as well as learning capacity was impaired by mefloquine use. Our data suggest that mefloquine disturbs motor learning skills. This adverse effect can have clinical as well as social clinical implications for mefloquine users. Therefore, this side-effect of mefloquine should be further investigated and recognized by clinicians.

Long-term changes in cerebellar activation during functional recovery from transient peripheral motor paralysis.

Localized altered cerebellar cortical activity can be associated with short-term changes in motor learning that take place in the course of hours, but it is unknown whether it can be correlated to long-term recovery from transient peripheral motor diseases, and if so, whether it occurs concomitantly in related brain regions. Here we show in a longitudinal fMRI study of patients with unilateral Bell's palsy that increases in ipsilateral cerebellar activity follow the recovery course of facial motor functions over at least one and a half years. These findings hold true for changes in brain activity related to both oral and peri-orbital activation, even though these processes are differentially mediated by unilateral and bilateral brain connectivities, respectively. Activation of non-facial musculature, which was studied for control, does not show any change in cerebellar activity over time. The localized changes in cerebellar activities following activation of facial functions occur concomitantly with increases in activity of the facial region in the contralateral primary motor cortex suggesting that the cerebellum acts together with the cerebral cortex in long-term adaptation to transient pathological sensorimotor processing.

Are locus coeruleus neurons involved in blinking?

To investigate the involvement of the noradrenergic locus coeruleus (LC) in the reflex blink circuit, c-Fos and neuronal tracer experiments were performed in the rat. LC neurons involved in reflex blink were localized by analyzing c-Fos protein expression after electrical stimulation of the supraorbital nerve. Subsequently, neuronal tracers were injected in two different nuclei which are part of the reflex blink circuit. Anterograde tracer experiments in the sensory trigeminal complex (STC) explored the trigemino-coerulear connection; retrograde tracer experiments in the latero-caudal portion of the superior colliculus (SC) established coerulear-collicular connections. The combination of retrograde tracer injections into the latero-caudal SC portion combined with electrical stimulation of the supraorbital nerve identified c-Fos positive LC neurons that project to the latero-caudal SC. Our results revealed the existence of a STC-LC-SC loop.

Blink recovery in patients with Bell's palsy: a neurophysiological and behavioral longitudinal study.

PURPOSE: To examine the recovery process of blinking in a longitudinal study of nine patients severely affected by Bell's palsy. METHODS: Kinematics of bilateral eyelid and eye movements and concomitant orbicularis oculi activity during voluntary blinking and air-puff- and acoustic-click-induced reflex blinking were determined by using the magnetic search coil technique and electromyographic recording of the orbicularis oculi muscle (OO-EMG). RESULTS: In the first 3 months of absence of OO-EMG activity, reduced eyelid and eye movement of the palsied eyelid were observed during all types of blinking. First OO-EMG activity was determined 3 months after onset of the affliction. After 1 year, OO-EMG activity was normalized and showed values similar to those on the nonpalsied side. Clinically, eyelid movements were normal after 1 year, although corresponding maximum amplitudes and corresponding velocities were two times smaller, expressed in reduced eyelid motility. Directions of eye movement during reflex blinking were normal after 1 year, although maximum amplitudes were smaller on the palsied side. Eye movements during voluntary blinking remained impaired. A simultaneous horizontal upward shift of both eyes in the same direction was recorded throughout the study. CONCLUSIONS: Although OO-EMG activity on the palsied side was normalized 1 year after onset of the affliction, the accompanying eyelid movements and their maximum amplitudes and velocities remained smaller throughout the study. The consistent impairment of eye movements in voluntary blinking during the study and reduced motility of eyelid movements indicates that higher brain structures, which modify eyelid and eye movement control during blinking, may be altered by the affliction.

Reticulo-collicular and spino-collicular projections involved in eye and eyelid movements during the blink reflex.

Reflex blinking provides a useful experimental tool for various functional studies on the peripheral and central nervous system, yet the neuronal circuitry underlying this reflex is not precisely known. In the present study, we investigated as to whether neurons in the reticular formation and rostral cervical spinal cord (C1) may be involved in the blink reflex in rats. To this end we investigated c-Fos expression in these areas following supraorbital nerve stimulation combined with retrograde tracing of gold conjugated horse radish peroxidase (Gold-HRP) from the superior colliculus. We observed many double labeled neurons in the parvocellular reticular nucleus, medullary reticular formation, and laminae IV and V of C1. Thus, these brain regions contain neurons that may be involved in blink reflexes as well as eye movements, because they both can be activated following peri-orbital stimulation and project to the superior colliculus. Consequently, we suggest that the medullary reticular formation and C1 region play a central role in the coordination of eye and eyelid movements during reflex blinking.

Eyelid movements during blinking in patients with Parkinson's disease.

We examined eyelid movements during spontaneous, voluntary, and trigeminal reflex blinks in 16 patients with mild to moderate Parkinson's disease (PD) off medication and 14 controls. Voluntary and reflex blink amplitudes tended to be smaller than normal for PD patients, whereas eyelid kinematics (amplitude-maximum velocity relationship) for all three blink types were normal. Spontaneous blink rate was less than normal for 10 patients and abnormally high for 6 patients. A significant positive correlation between spontaneous blink amplitude and blink rate was found. These observations suggest that PD modifies the gain of a premotor blink circuit shared by spontaneous, voluntary, and reflex blinks.

Reticulo-collicular projections: a neuronal tracing study in the rat.

Neuroanatomical tract-tracing methods were used to study the topography of the reticulocollicular projections. Injections of gold-HRP or BDA tracers into the medial and/or central portions of the superior colliculus resulted in labelled neurones mainly in the medial reticular formation, whereas injections into the lateral portion of the superior colliculus showed labelling in the medial and lateral reticular formation. When tracer was injected into the lateral portion of the caudal superior colliculus, extensive lateral labelling was observed in the contralateral parvocellular reticular nucleus and the contralateral dorsal medullary reticular nucleus, two areas involved in reflex blinking. The present study shows that these reticular areas project to the lateral superior colliculus, which is known to be involved in the coordination of eye and eyelid movements.

Connections between the lacrimal gland and sensory trigeminal neurons: a WGA/HRP study in the cynomolgous monkey.

The sensory innervation of the lacrimal gland (LG) in the cynomolgous monkey was studied using the retrograde wheat germ agglutinin/horsereadish peroxidase (WGA/HRP) tracer technique. A small solidified piece of WGA/HRP was implanted in the LG. Labelled sensory first-order neurons were found in the ipsilateral trigeminal ganglion (TG) and in the ipsilateral mesencephalic trigeminal nucleus (MTN). The distribution of labelled TG neurons was restricted to ophthalmic and maxillary ganglionic parts. Sensory innervation of LG by primary afferents is not only restricted to TG; an MTN involvement has also been found. This may imply that there is a central sensory role in the production and release of tears.

Projections from the superior colliculus to the trigeminal system and facial nucleus in the rat.

To determine the influence of the superior colliculus (SC) in orienting behaviors, we examined SC projections to the sensory trigeminal complex, the juxtatrigeminal region, and the facial motor nucleus in rats. Anterograde tracer experiments in the SC demonstrated predominantly contralateral colliculotrigeminal projections. Microinjections in the deep layers of the lateral portion showed labeled nerve fibers and terminals in the ventromedial parts of the caudal principal nucleus and of the rostral oral subnucleus and in the medial part of the interpolar subnucleus. Some terminals were also observed in the juxtatrigeminal region and in the dorsolateral part of the facial motor nucleus contralaterally, overlying the orbicularis oculi motoneuronal region. Verification by retrograde tracer injections into the trigeminal target regions showed labeled SC neurons mostly in lateral portions of layers 4-7. When the juxtatrigeminal region was involved, a remarkable increase of labeled neurons was observed, having a patch-like arrangement with a decreasing gradient from lateral to medial SC portions. Retrograde tracer injections in the dorsolateral VII nucleus showed bilateral labeled neurons mainly in the deep lateral SC portion. Retrograde BDA microinjections into the same trigeminal or juxtatrigeminal regions, followed by gold-HRP into the dorsolateral VII nucleus, demonstrated a significant number of SC neurons in deep layers 6-7 projecting to both structures by axon collaterals. These neurons are mediolaterally grouped in patches along the rostrocaudal SC extent; a subset of them are immunoreactive for glutamic acid decarboxylase (GAD). They could be involved in the coordination of facial movements. Simultaneous anterograde and retrograde tracer injections into the lateral SC portion and the VII nucleus respectively localized trigeminofacial neurons receiving collicular input in the trigeminal principal nucleus and pars oralis. Therefore the SC should play a crucial role in regulating motor programs of both eye and eyelid movements.

Eyelid movements: behavioral studies of blinking in humans under different stimulus conditions.

The kinematics and neurophysiological aspects of eyelid movements were examined during spontaneous, voluntary, air puff, and electrically induced blinking in healthy human subjects, using the direct magnetic search coil technique simultaneously with electromyographic recording of the orbicularis oculi muscles (OO-EMG). For OO-EMG recordings, surface electrodes were attached to the lower eyelids. To measure the vertical lid displacement, a search coil with a diameter of 3 mm was placed 1 mm from the rim on the upper eyelid on a marked position. Blink registrations were performed from the zero position and from 28 randomly chosen positions. Blinks elicited by electrical stimulation of the supraorbital nerve had shortest duration and were least variable. In contrast, spontaneous blinks had longer duration and greater variability. Blinks induced by air puff had a slightly longer duration and similar variability as electrically induced blinks. There was a correlation between the maximal down phase amplitude and the integrated OO-EMG. Blink duration and maximal down phase amplitude were affected by eye position. Eyes positioned 30 degrees above horizontal displayed the shortest down phase duration and the largest maximal down phase amplitude and velocity. At 30 degrees below horizontal, blinks had the longest total duration, the longest down phase duration, and the lowest maximal down phase amplitude and velocity. The simultaneously recorded integrated OO-EMG was largest in the 30 degrees downward position. In four subjects, the average blinking data showed a linear relation between eye position and OO-EMG, maximal down phase amplitude, and maximal downward velocity.

Organization of trigeminocollicular connections and their relations to the sensory innervation of the eyelids in the rat.

Relationships between the trigeminal component of blinking and the superior colliculus (SC) were studied in rats. To localize primary afferent eyelid projections in the sensory trigeminal complex, neuronal tracing experiments were performed as well as analysis of c-Fos protein expression after supraorbital (SO) nerve stimulation. Labelled nerve fibers were found to enter ventrally within the ipsilateral sensory trigeminal complex. Labelled boutons were observed at the junction of the principal nucleus (5P) and the pars oralis (5o) and in the pars caudalis (5c). The c-Fos immunoreactivity was observed in neurons located in the ipsilateral ventral parts of 5P, 5o, and the pars interpolaris (5i) and bilaterally in 5c. Injections in 5P, 5o, 5i, and 5c resulted in anterogradely labelled fibers, with a contralateral preponderance, within the intermediate and deeper SC layers. Injections in 5P or 5o showed anterogradely labelled nerve fibers, profusely terminating in small patches in the medial and central portions of SC layer 4. Subsequently, dense labelling was found in the lateral portion of SC layers 4-7, without patch-like organization. Injections in SC showed retrogradely labelled neurons predominantly within the contralateral part of the sensory trigeminal complex (28% in 5P, 20% in 5o, 50% in 5i, and 2% in 5c). Colocalization of the retrograde tracer after SC injections and c-Fos immunoreactivity in neurons demonstrated that some 5P, 5o, and 5i neurons receive SO nerve inputs and project to SC. This implies that intermediate and deeper SC layers receive sensory information from the eyelids and may be directly involved in the regulation of eye-eyelid coordination.