Animal Model Explains the Origins of the Cranial Dystonia Benign Essential Blepharospasm

Abstract

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.

Animal Models for Investigating Benign Essential Blepharospasm

“…The eye irritation environmental trigger, however, is consistent with the human data [36-39] and the evidence that changes in the basal ganglia plays a role in the predisposing condition is compelling [40, 97-99]. Thus, the Schicatano et al (1997) model [100] suggests an outline for abnormal neural circuit interactions that support BEB.…”

“…If the cerebellum receives abnormal trigeminal inputs from maladaptive learning processes, then the cerebellum will support and maintain this abnormal motor learning that originated in trigeminal blink circuits. Like previous studies indicating that the cerebellum is essential for the expression of dystonic movements, [118-120] the Schicatano et al (1997) rat model [100] predicts that the cerebellum is essential for maintaining spasms of eyelid closure created by abnormal trigeminal blink circuit motor learning enabled by a dysfunctional basal ganglia input This focus on abnormal motor learning as the proximate cause of BEB points to novel approaches to alleviate spasms of eyelid closure in BEB through modifying trigeminal motor learning.…”

“…One rodent model of BEB mimicked the dystonia by creating a predisposing condition using minimal dopamine depletion and initiating an environmental trigger by creating a transient dry eye condition [100]. Rats received a unilateral, 6-OHDA lesion that caused a small loss of dopaminergic cells in the substantia nigra pars compacta.…”

“…This animal model [100] based on the two-hit hypothesis of focal dystonia is unlikely to have identified the ‘predisposing condition’ that allows BEB in humans. If dopamine loss was the predisposing condition in human BEB, a reasonable prediction is that BEB patients would be more likely to develop Parkinson’s disease than individuals without BEB.…”

“…In pathological conditions, such as Parkinson’s disease, abnormal basal ganglia activity disrupts trigeminal blink circuits. [22-24] In the Schicatano et al (1997) animal model, [100] the predisposing condition distorts trigeminal blink circuit activity patterns so that maladaptive modifications occur in response to eye irritation [35]. The cerebellum is also critical in blink adaptation processes [101, 108, 109].…”