1 Departments of Neurobiology and Behavior and Ophthalmology and 2 Department of Psychology, State University of New York at Stony Brook, Stony Brook, New York 11794-5230
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ABSTRACT |
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Schicatano, Edward J., Michele A. Basso, and Craig Evinger. Animal model explains the origins of the cranial dystonia benign essential blepharospasm. J. Neurophysiol. 77: 2842-2846, 1997. The current study demonstrates that combining two mild alterations to the rat trigeminal reflex blink system reproduces the symptoms of benign essential blepharospasm, a cranial dystonia characterized by uncontrollable spasms of blinking. The first modification, a small striatal dopamine depletion, reduces the tonic inhibition of trigeminal reflex blink circuits. The second alteration, a slight weakening of the lid-closing orbicularis oculi muscle, begins an adaptive increase in the drive on trigeminal sensory-motor blink circuits that initiates blepharospasm. By themselves, neither of these modifications causes spasms of lid closure, but combined, they induce bilateral forceful blinking and spasms of lid closure. A two-factor model based on these rodent experiments may explain the development of benign essential blepharospasm in humans. The first factor, a subclinical loss of striatal dopamine, creates a permissive environment within the trigeminal blink circuits. The second factor, an external ophthalmic insult, precipitates benign essential blepharospasm. This two-factor model may also be applicable to the genesis of other cranial dystonias.
Focal dystonias are involuntary muscle contractions of a single group of muscles that produce abnormal postures and movements. Although one of the more prevalent neurological disorders affecting people All experiments were performed with strict adherence to all Federal, State, and University regulations governing the use of animals. Male Sprague-Dawley rats underwent one of three procedures: 1) a complete (>90%) unilateral 6-hydroxydopamine (6-OHDA) lesion (n = 5); 2) a unilateral lesion of the zygomatic branch of the facial nerve (n = 4); and 3) a small (<30%) unilateral 6-OHDA lesion followed by a unilateral zygomatic branch lesion (n = 5).
As demonstrated previously (Basso et al. 1993
Both dopamine depletion and orbicularis oculi weakening increase the excitability of trigeminal reflex blinks by modifying trigeminal sensory-motor blink circuits. The basal ganglia modulates the excitability of trigeminal reflex blinks via the substantia nigra pars reticulata inhibition of the superior colliculus. The superior colliculus excites tonically active, serotonergic neurons in the nucleus raphe magnus, which in turn inhibit reflex blink circuits within the spinal trigeminal complex (Fig. 1A) (Basso and Evinger 1996
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
50 yr of age, the neurological basis for focal dystonias is poorly understood. Focal dystonias could be motor program disorders resulting from basal ganglia dysfunction, sensory impairment, or an inability to retrieve appropriate motor programs from a sensory input (e.g., Jankovic 1988
; Kaji et al. 1995a
,b
). In this latter interpretation, a focal dystonia develops from a disruption of the transformation of sensory magnitude to motor drive.
; Carella 1994; Elston et al. 1988
; Granadas et al. 1988
; Jankovic 1988
). In rats, we show that a disruption of the trigeminal sensory-motor transformation in blink circuits following a subclinical basal ganglia dysfunction produces blepharospasm that exhibits many of the characteristics of BEB.
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
for details). In the same surgery, rats in group 1 received a unilateral 6-OHDA injection to completely destroy the dopamine-containing cells in one substantia nigra pars compacta (see Basso et al. 1993
for details). Rats in group 3 were given a small, unilateral 6-OHDA injection to produce minimal destruction of compacta neurons. At least 20 days after the OOemg and SO electrodes were implanted, the rats in groups 2 and 3 were anesthetized and the zygomatic branch of the facial nerve contralateral to the 6-OHDA injection was sectioned to weaken the orbicularis oculi. After rats recovered from the surgery, the minimal trigeminal threshold stimulus for evoking SO reflex blinks was established and the excitability of trigeminal reflex blinks was measured with the use of the paired stimulus paradigm. SO stimulation evokes both a short-latency R1 and a longer-latency R2 component. Two identical SO stimuli at 2 times blink threshold were presented at interstimulus intervals of 50-300 ms and blink excitability was quantified by comparing the magnitude of the OOemg response to the second stimulus (test response) with the magnitude of the OOemg response evoked by the first stimulus (condition response). Thirty-five to 50 days after the facial nerve transection, animals were deeply anesthetized and transcardially perfused. Coronal sections of the brains were cut and reacted immunohistochemically with an antibody to tyrosine hydroxylase to identify dopamine-containing neurons in the substantia nigra pars compacta (see Basso et al. 1993
for details).
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
), 6-OHDA lesions that destroyed >90% of the dopamine-ontaining neurons in one substantia nigra pars compacta increased the R2 test/R2 condition ratio from normal values of <1 to values of 4-7.5, extreme trigeminal reflex blink hyperexcitability. The dopamine loss reduces tonic inhibition of the trigeminal blink circuits (Fig. 1A). Complete unilateral 6-OHDA lesions also produced reflex spasms of lid closure triggered by SO stimuli (Fig. 1B). Just as occurs in some humans with severe Parkinson's disease, spasms of lid closure occurred in response to trigeminal stimuli but did not occur spontaneously (e.g., Hotson and Bowman 1991). In contrast, 6-OHDA lesions that destroyed
30% of the nigral dopamine containing neurons in one substantia nigra slightly increased trigeminal reflex blink excitability to values of ~1 (Fig. 3D,
), but did not result in reflex-evoked or spontaneous spasms of lid closure.
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FIG. 1.
Basal ganglia regulation of trigeminal reflex blink excitability. A: schematic circuit linking a basal ganglia output nucleus, the substantia nigra pars reticulata (SNr), to the superior colliculus (SC), the nucleus raphe magnus (NRM), and the reflex blink circuits within the spinal trigeminal complex (V-RB). B: spasm of lid closure in a rat with complete (>90%) destruction of dopamine containing neurons in the right substantia nigra pars compacta. Stimulation of the left supraorbital branch of the trigeminal nerve (LSO Stim) initiated the spasm. The 2 records show the rectified orbicularis oculi electromyographic (OOemg) activity on the left (L OOemg) and right (R OOemg) during the spasm (top traces) and the reflex response at the onset of the spasm (inset).
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FIG. 3.
Effect of combining a small 6-hydroxydopamine (6-OHDA) lesion with weakening of the orbicularis oculi on trigeminal reflex blink excitability. A: after a small (<35%) unilateral 6-OHDA lesion, the response to the 2nd stimulus to the SO (arrowhead) was unaffected by the occurrence of the 1st stimulus and reflex blink evoked 100 ms earlier. B: 20 days after weakening of the orbicularis oculi muscle of the rat shown in A, the trigeminal reflex blink was extremely hyperexcitable. Records in A and B are averages of 5 rectified OOemg responses. C: 21 days after orbicularis oculi weakening, an SO stimulus produced prolonged spasms of lid closure. Single rectified record. D: R2 test response magnitude/R2 condition response magnitude as a function of interstimulus interval before lesioning ( , Pre), after a small 6-OHDA lesion (
, 6-OHDA), and 20 days after orbicularis oculi weakening in addition to the 6-OHDA lesion (
, BLEPH). Each point is the mean of
10 responses from each of 5 rats. E: change in the slope of the line relating OOemg activity with stimulus intensity. Slope was established by calculating the change in A/D units of OOemg activity (ADU) as a function of SO stimulus current (µA). Slope increased for all 5 rats from the small 6-OHDA lesion condition (6-OHDA) to the small 6-OHDA lesion combined with orbicularis oculi weakening (BLEPH).
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FIG. 2.
Effect of weakening the orbicularis oculi on excitability of trigeminal reflex blinks. A: 2nd (Test) of a pair of identical stimuli delivered to the supraorbital branch of the trigeminal nerve (SO, arrowhead) with a 50-ms interstimulus interval evoked a smaller R2 response than the 1st (Condition) stimulus. Top traces: data collected on 2 separate days to illustrate the reliability of the suppression. Bottom trace: increase in the magnitude of the R2 response evoked by the 2nd stimulus relative to the 1st 32 days after the orbicularis oculi muscle was weakened. Each trace is the average of 10 rectified OOemg responses. B: R2 test response magnitude/R2 condition response magnitude as a function of interstimulus interval before ( ) and 3 (
), 10 (
), and 32 (
) days after orbicularis oculi weakening. Each point is the mean of
10 responses.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
; Basso et al. 1996
). Dopamine depletion increases nigral inhibition of the superior colliculus, which reduces the nucleus raphe magnus inhibition of trigeminal reflex blink circuits.
). These changes have the effect of elevating the slope of the relationship between stimulus magnitude and evoked blink size to SO stimuli ipsilateral to the weakened orbicularis oculi. If orbicularis oculi weakening produced a general increase in blink excitability or an increase in the axotomized facial nucleus, then the threshold for eliciting a trigeminal blink should have decreased for the OOemg response ipsilateral to the nerve cut regardless of which SO nerve was stimulated. Thus these data argue that orbicularis oculi weakening primarily modified trigeminal sensory-motor circuits ipsilateral to the facial nerve transection.
; Kimura 1973
). Because there is progressive dopamine cell loss in the substantia nigra pars compacta with aging (e.g., Fearnley and Lees 1991
), it is not surprising that trigeminal reflex blink excitability increases with age. Trigeminal reflex blink excitability escalates during normal aging, and starting in the fifth decade of life these increases become most pronounced (Evinger et al. 1995
). Our model predicts that when a subclinical increase in basal ganglia output significantly reduces nucleus raphe magnus inhibition of the trigeminal complex, an individual will become susceptible to blepharospasm that can be initiated by to an external ophthalmic insult.
). In otherwise normal individuals, treatment of the dry eye eliminates the excessive blinking associated with dry eye. However, when basal ganglia dysfunction creates a permissive trigeminal sensory-motor blink environment, the adaptive process initiated by the dry eye appears to lose its set point or the set point continually increases, which results in blepharospasm.
) as well as blink reflexes, any progressive basal ganglia dysfunction will eventually create the permissive environment for a normally adaptive change in oral sensory-motor circuits to develop into an orofacial dystonia. The idea that inappropriate motor learning produces cranial dystonia may also be applicable to focal limb dystonias. Byl et al. (1996)
report that repetition of stereotyped hand movements in a motor learning paradigm can produce a dedifferentiation of hand representation in cortex and dystonic hand movements in monkeys.
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ACKNOWLEDGEMENTS |
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We thank D. M. Schmidt for expert technical assistance. We also acknowledge the crucial insights gathered at symposia organized by the Benign Essential Blepharospasm Research Foundation.
This work was supported by National Eye Institute Grant EY-07391 to C. Evinger and Parkinson's Disease Summer Fellowships to M. A. Basso.
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FOOTNOTES |
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Present address of M. A. Basso: Laboratory of Sensorimotor Research, National Eye Institute, Bethesda, MD 20892-4435.
Address reprint requests to C. Evinger.
Received 9 October 1996; accepted in final form 22 January 1997.
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