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.

Blepharospasm in Japan: A Clinical Observational Study From a Large Referral Hospital in Tokyo

“…The most common symptoms reported by patients were difficulty opening the eyes due to persistent photophobia and/or ocular pain, suggesting that blepharospasm is associated with sensory-motor disintegration. [15][16][17] Although it is difficult to conclude whether the motor system or sensory system is primarily involved in the mechanism of blepharospasm, our other study 18 based on patients' statement indicates that a number of patients with drug-induced blepharospasm primarily or predominantly realise sensory disturbance such as photophobia and ocular or periocular pain/irritation. This results are compatible to the hypothesis in focal dystonia that abnormal processing of the somatosensory input in the central nervous system induces insufficient sensorimotor integration.…”

Reconfigurations within resonating communities of brain regions following TMS reveal different scales of processing

“…We use a phase-based undirected connectivity measurement and inspect graph metric changes at a single snapshot of the available parameters within the dynamic modularity framework we applied. This initial implementation of a graph theoretical approach on human neurostimulation effects may be expanded in the future to investigate the directed communication between these resonating communities (e.g., Reimann et al, 2017 ), cross-frequency communication (Canolty & Knight, 2010 ), and increased resolution across frequencies of the brain. The methodological choices within this work also focused on merely one spatiotemporal scale, which may not completely account for the spectral sensitivity across the regions of the brain, and the results target a wakeful resting state in individuals, and it may not extend to the active or sleeping brain (Hasson, Nusbaum, & Small, 2009 ; Massimini et al, 2005 ).…”

Viewpoints on the Clinical Heterogeneity of Blepharospasm

“…Other environmental factors, including dry eyes, greater exposure to sunlight and photophobia [41][42][43] may then trigger the clinical manifestations of BSP. In this regard, it has recently been suggested that greater exposure to sunlight may induce an increase in orbicularis oculi muscle drive, which is an adaptive process in healthy subjects but may turn into a maladaptive mechanism in subjects predisposed to BSP [44]. Other factors that affect blinking are the level of dopamine in the central nervous system and aging.…”