A Dynamic Circuit Hypothesis for the Pathogenesis of Blepharospasm

Abstract

Blepharospasm (sometimes called "benign essential blepharospasm," BEB) is one of the most common focal dystonias. It involves involuntary eyelid spasms, eye closure, and increased blinking. Despite the success of botulinum toxin injections and, in some cases, pharmacologic or surgical interventions, BEB treatments are not completely efficacious and only symptomatic. We could develop principled strategies for preventing and reversing the disease if we knew the pathogenesis of primary BEB. The objective of this study was to develop a conceptual framework and dynamic circuit hypothesis for the pathogenesis of BEB. The framework extends our overarching theory for the multifactorial pathogenesis of focal dystonias (Peterson et al., 2010) to incorporate a two-hit rodent model specifically of BEB (Schicatano et al., 1997). We incorporate in the framework three features critical to cranial motor control: (1) the joint influence of motor cortical regions and direct descending projections from one of the basal ganglia output nuclei, the substantia nigra pars reticulata, on brainstem motor nuclei, (2) nested loops composed of the trigeminal blink reflex arc and the long sensorimotor loop from trigeminal nucleus through thalamus to somatosensory cortex back through basal ganglia to the same brainstem nuclei modulating the reflex arc, and (3) abnormalities in the basal ganglia dopamine system that provide a sensorimotor learning substrate which, when combined with patterns of increased blinking, leads to abnormal sensorimotor mappings manifest as BEB. The framework explains experimental data on the trigeminal reflex blink excitability (TRBE) from Schicatano et al. and makes predictions that can be tested in new experimental animal models based on emerging genetics in dystonia, including the recently characterized striatal-specific D1R dopamine transduction alterations caused by the GNAL mutation. More broadly, the model will provide a guide for future efforts to mechanistically link multiple factors in the pathogenesis of BEB and facilitate simulations of how exogenous manipulations of the pathogenic factors could ultimately be used to prevent and reverse the disorder.

Keywords: blepharospasm; dopamine; dystonia; rodent models; striatum.

Figure 1

Orbicularis oculi EMG responses to paired pulse stimulations (“condition”, “test”) to the supraorbital branch (SO) of the trigeminal nerve. The R2 response component is labeled only for the test stimulus. (OO EMG is rectified, amplitude given in arbitrary units; all adapted from Schicatano et al., 1997). (A) Healthy animal, prior to OO and 6-OHDA lesions (from Schicatano Figure 2A top panel; solid and dotted responses are on separate, sequential days). (B) After OO weakening (from Schicatano Figure 2A bottom panel). (C) After minor 6-OHDA lesion (from Schicatano Figure 3A, temporally scaled to approximate stimulus timing in A,B). (D) After minor 6-OHDA lesion and approx. 20 days after OO weakening (from Schicatano Figure 3B, temporally scaled as in C). Note lid closure spasms (LCS) after test R2.

Figure 2

Basal ganglia to brainstem pathways influencing reflex blinks. Abbreviations: GPe, globus pallidus external segment; GPi, globus pallidus internal segment; NRM, nucleus raphe magnus; OO, orbicularis oculi; SC, superior colliculus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; SPN, spiny projection neurons; SpV, spinal trigeminal nucleus; STN, subthalamic nucleus; V, trigeminal ganglion, VII, facial motor nucleus.

Figure 3

Simplified schematic of the TRBE, overlaid with signaling cascades including not only short loops in brainstem but also long loops through suprasegmental structures. The conditioning stimulus evokes suprasegmental responses through thalamus, cortex, and basal ganglia output pathways back to trigeminal reflex circuits in brainstem [stimulus artifact omitted].