Eyelid Opening with Trigeminal Proprioceptive Activation Regulates a Brainstem Arousal Mechanism

Published: August 5, 2015DOI: 10.1371/journal.pone.0134659

Introduction

We previously reported temporary or permanent blepharoptosis and brow ptosis after Müller muscle resection, lacrimal gland tumor resection with the lacrimal nerve, anesthesia of the Müller muscle or branches of the lacrimal nerve, and blowout fracture due to external force to the eyelid and globe [1–4]. We also previously reported that intraoperative stretching of the Müller muscle electromyographically induces an involuntary reflex contraction of the ipsilateral levator palpebrae superioris muscle (LPSM) [5]. This contraction appeared to correspond with the periodontal jaw muscle reflex as a model of reflex contractions of the LPSM slow-twitch fibers based on extrinsic mechanoreceptor stretching. Voluntary contractions of the jaw-closing fast-twitch muscle fibers stretch the extrinsic periodontal mechanoreceptor to evoke trigeminal proprioception, which in turn continuously induces reflex contractions of the jaw-closing slow-twitch muscle fibers via the mesencephalic trigeminal nucleus [6–9]. Thus, we have been exploring the extrinsic mechanoreceptors in the Müller muscle that induce reflex contractions of slow-twitch fibers in the LPSM and frontalis muscle to tonically sustain eyelid and eyebrow positions against gravity as well as elastic resistance [10] and its related mesencephalic trigeminal proprioceptive nucleus. The supratarsal Müller muscle, which is located between the LPSM and tarsus under the levator aponeurosis (Fig 1), is innervated not only by sparse, unmyelinated sympathetic efferent fibers but also by abundant, myelinated trigeminal proprioceptive afferent fibers [1, 2, 11]. The trigeminal proprioceptive fibers innervate the intramuscular connective tissues, including the interstitial cells of Cajal [11], which are like a palisade among the smooth muscle fibers and converge as a transverse nerve that runs on the proximal Müller muscle to join the lacrimal branch of the ophthalmic trigeminal nerve in humans [1]. Because the trigeminal proprioceptive neurons are connected to each other with gap junctions [12], Fluorogold, which passes through gap junctions, was applied as a tracer to the proximal stump of the trigeminal proprioceptive nerve in rats [3]. Fluorogold densely labeled the cell bodies of the trigeminal proprioceptive neurons in the ipsilateral mesencephalic trigeminal nucleus and a part of the locus coeruleus but not in any other rat brain region, including the trigeminal ganglion.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image (706KB)
• TIFF
  original image (1.19MB)

Fig 1. Neuroanatomy of upgaze with trigeminal proprioceptive activation to regulate a brainstem arousal mechanism.

We have confirmed the presence of a Hoffmann reflex in the LPSM and frontalis slow-twitch muscle fibers [6]. In humans, unilateral electrical stimulation to the trigeminal proprioceptive fibers innervating the mechanoreceptors in the supratarsal Müller muscle induces the following: a phasic short-latency response in the ipsilateral LPSM via the mesencephalic trigeminal nucleus and oculomotor neurons (Fig 1) [13, 14], a phasic short-latency response in the ipsilateral frontalis muscle via the mesencephalic trigeminal nucleus and facial motor neurons, and tonic long-latency bilateral responses in frontalis muscles with ipsilateral dominance via the mesencephalic trigeminal nucleus, an unknown nucleus at the reticular formation, and facial motor neurons [15]. Regarding the clinical significance of this finding, we previously proposed [5, 16–21] that during primary gaze, weak proprioceptive evocation via mild stretching of the mechanoreceptors in Müller's muscle invoked by voluntary contractions of the LPSM and superior rectus fast-twitch fibers induced reflex contractions of the LPSM slow-twitch fibers to sustain eyelid position against gravity and elastic resistance [10, 22, 23] (Fig 1). We further proposed that during upgaze (Fig 1), increased proprioceptive evocation by increased stretching of these mechanoreceptors would enhance reflex contractions of the LPSM slow-twitch fibers and evoke reflex contractions of the frontalis slow-twitch fibers to sustain eyelid and eyebrow positions against gravity and elastic resistance [10].

The cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway in the mesencephalic trigeminal neurons ensures long-term excitability [24]. Continuous evocation of trigeminal proprioception may involuntarily maintain continuous reflex contractions of the LPSM and frontalis slow-twitch fibers to sustain eyelid and eyebrow positions against gravity and elastic resistance, depending on the degree of mechanoreceptor stretching in the supratarsal Müller muscle. In humans, the mesencephalic trigeminal neurons comingle with cells in the locus coeruleus on both sides of the mesencephalic tract [25]. According to our anterograde tracing study in rats [3], the cell bodies of trigeminal proprioceptive neurons potentially make gap-junctional connections with cells of the locus coeruleus, which is implicated in arousal and autonomic function [26]. Thus, we hypothesized that eyelid opening with trigeminal proprioceptive activation by stretching mechanoreceptors in the supratarsal Müller muscle could stimulate the locus coeruleus and is an arousal reaction, as suggested by its use to diagnose coma or impaired consciousness [27].

A direct regulatory relationship between the ventromedial prefrontal cortex activity and skin conductance measurements has been reported as a useful physiological index of arousal [28, 29]. To clarify functional connectivity among the mesencephalic trigeminal nucleus, locus coeruleus, and ventromedial prefrontal cortex in arousal and autonomic function, we assessed whether upgaze with enhanced evocation of the trigeminal proprioception via mechanoreceptor stretching activates sympathetically innervated sweat glands and the ventromedial prefrontal cortex (Fig 1).