Timothy C. Hain, MD Page last modified: June 12, 2016
Orientation of the otolithic organs Function Turnover of otoconia otoconia in disease
The utricle is one of two "otolithic organs" in the human ear, the utricle and saccule. On the diagram above, the utricle are located in the vestibule, between the semicircular canals (5), and the cochlea (9). There is an immense literature about the otoliths, including a huge literature concerning the otoliths of fish (which are quite large). Herein we will attempt to draw some general conclusions about otoliths and otoconia, relevant to human dizziness.
This figure shows a close up of the inner ear. The utricle is contained within a swelling adjacent to the semicircular canals, and the saccule is close to the cochlea. The black dots surrounding the utricle and saccule are the dark cells.
The otolith organs sense gravity and linear acceleration such as from due to initiation of movement in a straight line. Persons or animals without otolith organs or defective otoliths have poorer abilities to sense motion as well as orientation to gravity.
The schematic diagram above illustrates how they work. A set of hair cells are coupled to a mass of stones. When the stones accelerate, with respect to the hairs, they exert a shearing force on the hairs. This force is detected by the hair cells and sent to the brain via branches of the vestibular nerve. The utricle sends input to the brain via the superior division of the nerve, and the saccule, (mainly) via the inferior division. There is considerably more complexity to the organization of the utricle and saccule, including different types of hair cells and detail to the sensory macule (patch of sensory cells) that we have omitted.
The otolithic organs sense motion according to their orientation. The utricle is largely horizontal in the head, and largely registers accelerations acting in the horizontal plane of the head (called the axial plane by radiologists). The saccule is largely vertical, actually parasagittal, in the head, and registers accelerations in the vertical plane (called parasagittal or coronal plane).
The motion sensation from the otoliths is used for a large number of reflexes:
Damage to the otoliths or their central connections can impair ocular and body stabilization (Lempert et al, 1997).
The bilateral symmetry of the otolithic organs may provide a method for adaptation to loss of angular rate sensors (the canals), as centrifugal force on the otoconia provides a second method of signaling rotation. It also seems possible that intra-vestibular conflict -- otolithic sensors suggesting that the head is turning at a different rate than the canals, might be the reason for some types of motion intolerance.
|Otoconia are made of limestone mixed together with a protein matrix (40% by volume).||
Fish otoconia from Oxman et al, 2007. Argonite is on the left, vaterite on the right.
|Quail otoconia from Dickman et al (2004). On the left are the smaller striolar otoconia of the utricle. On the right are the larger otoconia from the base of the utricle.|
Turnover of otoconia:
At the present writing, it is seems likely that otoconia of humans turn over very slowly during life, and that there is a mixture of degeneration and turnover, with degeneration dominating. If the otoconia degenerate over ones lifetime, this might explain why balance inevitably worsens with time, and also explain why persons after head-injury never quite regain their former balance function. Think about professional hockey and football players ! On the other hand, it has been estimated that mice can withstand loss of about 80% of their otoconia before developing noticeable balance problems.
There is abundant evidence for a calcium secretory system (see below). Calcium labeling studies suggest that it takes months for turnover, but whether or not an entire otoconium can be replaced is presently unclear. Lets review some of the data.
The otoconia are made of calcium carbonate (CaCo3), combined with a protein matrix protein (about 40% of the volume). Calcium carbonate is also a constituent of "limestone", so otoconia are essentially a mixture of stone and a protein - -something like concrete with straw mixed in. However in otoconia, the protein is not only structural but also involved with calcium secretion.
In humans, otoconia have a hexagonal symmetry.
There are several crystalline forms of calcium carbonate, In birds and mammals, the "calcite" form of calcium carbonate is found. Aragonite is the name of the crystalline form of some fish, and vaterite -- a clear disk like form -- is used in other fish.
The matrix protein in birds and mammals is called otoconin-90. In fish, a different protein is found with a smaller molecular weight -- otoconin 22 and otoconin 55 The otoconins are closely related to a secretory protein, PLAS2, adapted in otoconia to form a calcium secretory system. (Thalmann et al, 2001).
Otoconia of humans are very small -- ranging in size from roughly 3 to 30 microns -- averaging about 10 microns. Without a high-resolution microscope, one would not be able to see the crystalline structure. Also, in humans, the stones are smallest towards the top of the utricle (the striola area). This is also where they are more thinly distributed. Some animals actually use granules of sand for otoliths. Otoconia of fish may be much larger than human.
Fish have three otolithic organs -- the saccule, lagena, and utricle. These contain, respectively, otoliths called the sagitta, asteriscus and lapillus. The saccule in fish is often the primary hearing organ, while the utricle is generally associated with vestibular function, although it may also have some auditory role. The function of the lagena is largely unknown, although it may also have an auditory role -- tentatively low frequency specific. Rather than having many crystals as is the case in humans, each "otolith" in fish is made of one large crystal. The density of the otoliths in fish is about 2.93 g/cm**3 (Oxman et al, 2007).
Otoconia are initially formed early in life during embryogenesis and their formation is completed in early postembryonic development. In mice, they are completely formed by post-natal day 7. After this initial burst of otoconia formation, subsequent turnover is probably very slow. Thalmann et al (2001) reviewed evidence for turnover. As of 2001, there was a "general consensus that, if turnover or incorporation of calcium does indeed occur, it proceeds at a far lower rate in mature otoconia than during development." Of course, this is not a very informative statement, as during development, formation of otoconia is lightning fast. What we really need to know is about ongoing turnover.
Two figures from Harada (1982) illustrating turnover of otoconia.
The outer, calcium containing part of the otoconia clearly turns over, perhaps rather slowly, but it is not clear if the inner part (the matrix) can be replaced in humans. This is important because the otoconia can fall off into the inner ear. When they do this, they are probably dissolved and reabsorbed by the "dark cells" of the labyrinth (Harada, 1982; Lim, 1973, 1984), which are found adjacent to the utricle and the crista. Although this idea is not accepted by all (see Zucca, 1998, and Buckingham, 1999), the evidence from pathology appears rather overwhelming.
The dark cells are melanocytes. They may recycle otoconia and produce calcium for generation of otoconia. One would think that individuals with no melanin (eg. albinos) might have more difficulty with their otoconia. As albinos commonly have other issues with their balance, perhaps this remains to be worked out. One would also think that one could develop a malignant melanoma of the dark cells. Presumably this would be very rare considering the small number of dark cells compaired to the usual complement in the skin.
So there is probably a mixture of otoconia degeneration and replacement, with degeneration eventually winning over time. Another bit of evidence suggesting that otoconia are not replaced is that VEMP's progressively worsen with age -- as VEMP's are mediated by the saccule, one way to explain this would be to postulate that otoconia are progressively lost over time. There are of course many other possible explanations including loss of vestibular neurons.
Loss of position reflex in guinea pig after centrifugation, from Parker et al, 1968.
Also supprting the that otoconia are never replaced is a NASA study by Parker et al, in which 12 Guinea pigs were centrifuged as high as 400g (to pull off their otoconia). Some of them were sacrificed acutely and others at 6 months. Exposure to this high acceleration for as little as 20 seconds at 100G was "sufficient to remove most of the otoconia from the maculae of the saccules and utricles". (Parker et al, 1968; Parker et al, 1965)
The figure above shows how the righting reflex is absent immediately after high accelleration. According to this study the righting reflexes sometimes improved at 6 months, although there was no replenishment of otoconia. They state that "There is no adequate evidence from this series of 12 animals that any particular reparative process occurs to explain the return of the rightin reflex after exposure". They were here commenting that the otoconia did NOT return. It would be interesting to see this study replicated. Recall also that guinea pigs and human beings differ very substantially.
In another study, when degeneration of otoconia are induced by streptomycin, they are apparently restored within 8-10 weeks (Thalmann et al, 2001).
In aging, the otoconia become roughened, fractured, and hollowed out (Campos et al, 1990). The main route of degeneration is demineralization. According to Walther and Westhoven (2007), the ratio of volume of utricular otoconia between young and elderly was 100:42, whereas it was 100:21 for the saccule. This is due to normal aging and may explain the progressive loss of VEMP amplitude (a measure of the otolith output) with age.
In Benign Paroxysmal Positional Vertigo (BPPV) , a common vertigo condition, dizziness is thought to be due to debris, probably otoconial, which has collected within a part of the inner ear. Testing of the utricle has been reported abnormal in BPPV (Hong et al, 2008). BPPV is much more common in the aged, perhaps due to the degeneration of the otoconia mentioned above.While otoconia are generally attributed in the literature as being the cause of BPPV, there is no particular reason why otoconial protein matrix, or fragments of other parts of the inner ear might not accumulate, but it would seem likely that such debris would be rapidly disposed, while small stones (otoconia), might persist. Some controversy exists about disposition of debris as some authors (e.g. Zucca et al), feel that stones might dissolve rapidly.
In Meniere's disease, it has been suggested by many authors that loose otoconia might block the utricular duct, ductus reuniens, or the endolymphatic duct. Of these three, the utricular duct is the most vulnerable, as it is only 1/20th of the size of the endolymphatic duct. Loose giant otoconia such as those that appear in aminoglycoside ototoxicity (see next) might be even more likely to block the duct.
In streptomycin ototoxicity (and presumably gentamicin ototoxicity), otoconia not only degenerate but may form giant otoliths. (Ross et al, 1976; Harada 1982). Degenerated otoconia in the aged appear hollowed out -- in ototoxicity they appear dysmorphic. One might then expect more BPPV in ototoxicity, perhaps accompanied by less nystagmus due to the damage to the inner ear. Giant otoliths might reasonably cause a more rapid and stronger nystagmus due to biomechanical considerations (Hain et al, 2005). They might also be more prone to cause hydrops (see above).
It seems likely that the same processes that damage the ear in general -- damage the otoliths. However, until recently, aside from autopsy, there was no method of measuring the damage. Some work is now being done using VEMP testing to quantify otolithic input (saccule). For example, Hsu et al (2008) reported that the saccule (VEMP) response exhibits a temporary threshold shift to noise, similar to cochlear hearing hair cells. It seems very likely to us that the saccule might be vulnerable to noise.
As there seems to be a large safety margin for otoliths, at least in mice, it may not matter that much if one loses, lets say, half of ones otoconia.
Processes that impair calcium metabolism -- i.e. that cause osteoporosis, probably also impair otoconia maintenance. As noted above, ear toxins such as aminoglycoside antibiotics clearly cause damage to otoconia as well as dysmorphic otoconia.
There are several methods available to estimate otolith function in humans. In general, the method is to stimulate the otoliths in some way, and then find a method of quantifying the response. Except for cervical VEMP's, and possibly ocular VEMP's, these methods are presently little used or investigational.
We are grateful for the help of Dr. Geoff McPherson, of James Cook University in Australia. Dr. McPherson has contributed some material mainly relevant to fish otoconia.