Aging and the human vestibular nuclei: morphometric analysis

Mechanisms of Ageing and Development

114 (2000) 149–172

Aging and the human vestibular nuclei:morphometric analysis

J.C. Alvarez a, C. Dıaz a,b, C. Suarez c, J.A. Fernandez a,C. Gonzalez del Rey a, A. Navarro a, J. Tolivia a,*a Departamento de Morfologıa y Biologıa Celular, Facultad de Biologıa y Medicina,

Uni6ersidad de O6iedo, Julian Cla6erıa s/n, O6iedo 33006, Spainb Seccion de Otorrinolaringologıa, Hospital de San Agustın, A6iles, Spain

c Departamento de Otorrinolaringologıa, Hospital Central de Asturias, Asturias, Spain

Received 19 May 1999; received in revised form 6 February 2000; accepted 9 February 2000

Abstract

The data concerning the effects of age on the brainstem are scarce and few works aredevoted to the human vestibular nuclear complex. The study of the effects of aging in thevestibular nuclei could have clinical interest due to the high prevalence of balance controland gait problems in the elderly. We have used in this work eight human brainstems ofdifferent ages sectioned and stained by the formaldehyde-thionin technique. The neuron’sprofiles were drawn with a camera lucida and Abercrombie’s method was used to estimatethe total number of neurons. The test of Kolmogorov–Smirnov with the correction ofLilliefors was used to evaluate the fit of our data to a normal distribution and a regressionanalysis was done to determine if the variation of our data with age was statisticallysignificant. Aging does not affect the volume or length of the vestibular nuclear complex.Our results clearly show that neuronal loss occurs with aging in the descending (DVN),medial (MVN), and lateral (LVN) vestibular nuclei, but not in the superior (SVN). There arechanges in the proportions of neurons of different sizes but they are not statisticallysignificant. The neuronal loss could be related with the problems that elderly people have tocompensate unilateral vestibular lesions and the alterations of the vestibulospinal reflexes.The preservation of SVN neurons can explain why vestibulo-ocular reflexes are compensatedafter unilateral vestibular injuries. © 2000 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Structure; Vestibular nuclei; Morphometric; Cytoarchitectonic; Aging

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* Corresponding author. Tel.: +34-985-103061; fax: +34-985-103618.E-mail address: [email protected] (J. Tolivia)

0047-6374/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.

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J.C. Al6arez et al. / Mechanisms of Ageing and De6elopment 114 (2000) 149–172150

1. Introduction

Population in western world is aging and this trend will increase in the comingyears. The increased prevalence of dizziness with advancing age is the result ofspecific disease processes superimposed on normal aging physiology (Burke, 1995).Balance problems affect, according to some studies from one third to half thepersons more than 70-years-old and are more frequent in women (Sixt andLandahl, 1987; Grimby and Rosenhall, 1995). The balance problems are importantnot only due to the discomfort that they produce and its prevalence in thepopulation, but also because they can origin falls and potentially serious injuries(Tinnetti and Speechley, 1989). For these reasons the study of the effects of agingin the vestibular system is of clinical relevance.

Several works have been devoted to the effects of aging in the peripheralvestibular system (Bergstrom, 1973; Engstrom et al., 1977; Fuji et al., 1990). Theclinical consequences of the physiopathological changes found in aging animals andpersons in the peripheral vestibular system (loss of hair cells, ganglion cells andfibers of vestibular nerve), are not well known. The morphological effects of agingin the vestibular nuclear complex have been studied in different mammals (White-ford and Getty, 1966; Nanda and Getty, 1971, 1973; Johnson and Miquel, 1974;Sturrock 1989b) included the man (Blinkov and Ponomarev, 1965; Lopez et al.,1997; Alvarez et al., 1998) but its consequences are also uncertain.

The vestibular nuclear complex consists of four principal nuclei and other smallgroups of neurons (accessory nuclei). The main nuclei are classically nameddescending or inferior (DVN), medial (MVN), lateral (LVN) and superior (SVN)vestibular nucleus.

The DVN is characterized by the long descending fascicles that cephalocaudallytraverse the nucleus. These fibers originate from primary vestibular afferents orcome from the cerebellar vermis (Henkel and Martin, 1977b). Afferences from thevestibular peripheral organs distribute uniformly throughout the nucleus accordingto some authors (Siegborn and Grant, 1983) while others find them to be scarce(Kevetter and Perachio, 1986) or find a decreasing gradient from rostral to caudallevels (Suarez et al., 1989; Newman et al., 1992). The DVN receives a minimalamount of spinal afferents which reach the caudal part of the nucleus (Rubertoneand Haines, 1982; Baloh and Honrubia, 1990) and some afferents from cerebellarnuclei (Baloh and Honrubia, 1990). The DVN projects its efferent fibers to thecerebellum and reticular formation (Carleton and Carpenter, 1983) and to oculo-motor nuclei (Hoddevik et al., 1991; Labandeira-Garcıa et al., 1991). There are alsonumerous commissural efferents to the contralateral vestibular nuclei (Brodal,1972).

The MVN appears located beneath the floor of the fourth ventricle and it is thebiggest of all the vestibular nuclei and shows the higher neuronal density. Itsneurons vary in size (Suarez et al., 1997). The rostral part of the nucleus receivesafferents from the cristae ampulares while the intermediate part receives saccularand utricular afferents (Gacek, 1969). The cerebellum projects to the caudal regionof the MVN (Kotchabhakdi and Walberg, 1978). Efferents from the rostral part

J.C. Al6arez et al. / Mechanisms of Ageing and De6elopment 114 (2000) 149–172 151

supply the oculomotor nuclei and those from the caudal part go to the cervicalspinal cord (MacCrea et al., 1987; Shinoda et al., 1988). Other projections from theMVN reach the cerebellum, the reticular formation and the contralateral vestibularnuclei (Carleton and Carpenter, 1983). This nucleus seems important in compensa-tion processes after unilateral vestibular damage (Baloh and Honrubia, 1990).

The LVN or Deiter’s nucleus is characterized by the giant neurons or Deiter’sneurons. It has been divided in two parts in man: rostromedial and caudolateral(Sadjadpour and Brodal, 1968). Giant neurons are more abundant in the rostralpart (Suarez et al., 1997). The rostral part of the LVN receives its afferents from theutricle and the cristae ampulares (Gacek, 1969). The caudal region of the LVNreceives spinal afferents (Prihoda et al., 1991). The LVN receives also cerebellarafferents. Efferents from the rostral region of the LVN end in the oculomotornuclei (MacCrea et al., 1987). The LVN projects its axons somatotopically to theipsilateral spinal cord through the lateral vestibulospinal tract with some projec-tions that go in the medial vestibulospinal tract. This vestibular nucleus plays animportant role in the control of vestibulospinal reflexes specially those involving theforelimb (Brodal, 1984; Baloh and Honrubia, 1990).

The SVN is the smallest and more rostrally located of the principal nuclei. TheSVN has neurons of different sizes and large cells predominate in the central region(Gstoettner and Burian, 1987). The primary vestibular afferents from the cristaeampulares end mainly in the large cells of the central region (Gacek, 1969; Brodal,1974). This nucleus also receives input from the other vestibular nuclei and thecerebellum. The central region of the SVN projects to the nuclei of the extraocularmuscles the cerebellum and the dorsal pontine reticular formation (Mitsacos et al.,1983a,b). The SVN is the center for the vestibulo-ocular reflexes elicited by thesemicircular canals (Baloh and Honrubia, 1990).

In the present study we have made a morphometric study to detect the possiblestructural alterations that suffer the human vestibular nuclei with aging. We try toestablish a relationship between such modifications and the anomalies of balancecontrol and gait disorders of elderly people.

2. Materials and methods

In this study eight brainstems from men of ages 35, 46, 54, 62, 76, 77, 82 and89-years-old were used. None of the patients presented a previous inner ear orneurologic disease. The brainstems were obtained from necropsies within 6 h fromdeath and were fixed during 4 days in 4% paraformaldehyde and 5% acetic acid indistilled water. After fixation, the blocks were washed in distilled water, dehydratedthrough successive alcohols, cleared in butyl acetate, embedded in paraffin andblocked out in paraffin in a suitable mould.

Axial sections 20 mm in thickness were obtained and attached to gelatin-coveredslides, dried at 36°C, deparaffined, hydrated and stained with a modification offormaldehyde-thionin method (Tolivia et al., 1994), dehydrated, cleared in eucalyp-tol and mounted with Eukitt. The staining method was applied and commented in


previous papers (Navarro et al., 1994; Dıaz et al., 1996; Suarez et al., 1997; Alvarezet al., 1998).

Each one of the main vestibular nuclei was divided in three parts of the samelength. Equidistant sections of each part were studied (five sections in each part ofthe medial, four in the lateral and descending and three in the superior vestibularnucleus). The profiles of all neurons present in each section were drawn with the aidof a camera lucida under microscope magnification (×330). Only the neurons inwhich the nucleus was visible were considered, and special care was taken to discardglial cells. We also drew the profiles of the neurons’ nuclei at high magnification(×600) to calculate the equivalent diameter (the diameter of a circle of the samearea than the one we have drawn) in order to obtain the correction factor. Tocalculate the volume of the vestibular nuclei we drew the profile of each section ofevery nucleus and, according to Cavalieri principle, the volume is the sum ofproducts of the area of each section by the distance between two adjacent sections.

The total number of neurons was estimated by multiplying the mean number ofneurons counted in the sections by the number of sections that spanned the region.These data were corrected with a factor reported by Abercrombie (1946).

The neurons of the vestibular nuclei were separated according to their area infour arbitrary groups: small cells (B200 mm2), medium cells (200–500 mm2), largecells (500–1000 mm2) and giant cells (\1000 mm2), to establish the neuronaldistribution. These neuronal groups were the same established in previously relatedpapers (Dıaz et al., 1993, 1996; Suarez et al., 1993, 1997).

The study of morphometric parameters and the volume of the vestibular nuclearcomplex were accomplished with the microimage processing (MIP) program devel-oped by MICROM SPAIN for image analysis in an IMCO-10 KONTRON. Dataobtained from morphometric study were statistically tested to estimate the signifi-cance of the results. The test of Kolmogorov–Smirnov with the correction ofLilliefors was used to evaluate the fit of the data to a normal distribution. Aregression analysis was done to study the correlation between age and the variationof the number and size of the neurons. The significance level was established inPB0.05. Statistical study was accomplished with the program Systat 5.0 forMacintosh. Throughout this study, values are expressed as mean9S.E.M. Themethodology used in the present study was applied previously to study morphomet-ric characteristics of the nucleus supraopticus of the hamster (Navarro et al., 1994)and the human vestibular nuclei (Dıaz et al., 1993, 1996; Suarez et al., 1997;Alvarez et al., 1998).

3. Results

In the present study we describe first the general and qualitative alterations thatappear with aging in each vestibular nucleus, such as the neuronal deposits oflipofuscin, and then we show the quantitative variations of the nuclear size, thenumber and size of neurons.


3.1. Descending 6estibular nucleus (DVN)

It is located exclusively in the medulla oblongata, being its caudal pole at the levelof the rostral pole of the external cunneate nucleus and its rostral pole at the levelof the caudal pole of the motor nucleus of the facial nerve. Its caudal regionpresents an oval-shaped morphology in the transverse sections and is locatedventrolateral respect to the MVN. In the intermediate and rostral levels the DVNshows a triangular form, and lies lateral to the MVN. In the rostral pole the DVNis replaced progressively by the LVN. The DVN is crossed in all its length bynervous myelinated fibers in a rostrocaudal sense.

The neurons of the DVN are rounded, triangular or fusiform in morphology,with an arrangement relatively disperse due to the presence of nervous fascicles.The neuronal nucleus occupies a central position, with a single nucleolus (Fig. 1a).The average equivalent diameter of the neuronal nucleus is 9.9 mm, and thevariations with the age are scarce. Thus, the diameter ranges from 11 mm in the76-year-old individual to 9.3 mm in the 89-year-old individual (Table 1). Thedifferences observed in the different ages are not significant.

Fig. 1. Neurons of the vestibular nuclei. (a) Descending vestibular nucleus. (b) Medial vestibular nucleus.(c) Lateral vestibular nucleus. (d) Superior vestibular nucleus. (a) Bar=20 mm. (b–d) Bar=40 mm.


Table 1Diameter of neuronal nucleus (mm)

MVNDVN LVN SVNAge (years)

10.490.159.890.18 9.490.169.990.163546 1090.15 11.190.2 1090.149.990.19

10.390.18 9.890.169.690.219.990.175410.290.15 9.690.1662 10.190.14 10.190.1410.490.16 10.190.1510.390.1576 1190.15

9.790.149.990.17 10.690.2 9.790.17779.890.19 9.890.28.990.19.690.1782

89 9.490.189.390.22 9.390.158.390.17

Table 2Volume and length of the vestibular nuclei

LVNAge (years) SVNDVN MVN

Volume (mm3)28.76 12.3923.0214.453529.54 12.1346 15.64 24.0330.44 10.9516.3354 17.1

14.81 22.92 30.97 10.56238.36 11.0524.7776 18.13

20.3116.37 26.33 11.77720.6815.79 24.82 10.9582

27.35 10.1619.2889 14.87

Length (mm)9.135 46.8 6.69.646 4.87 5.49.9 4.75.6554 8.2

62 4.8 8.3 4.258.4 45.376 69.4 3.777 6.6 6.38.9 4.15.982 5.8

89 7.25.4 3.54.7

We could observe deposits of lipofuscin within the neurons that were greater andmore numerous with increasing age. The neurons that seem more affected are thoseof greater size (Fig. 2a,b).

The average volume of the DVN in all the ages studied was 15.9 mm3. The valueranges from 18.13 mm3 in the 76-year-old individual to 14.81 mm3 in the 62-year-old individual (Table 2). The average length estimated was 6.35 mm, with amaximum of 8.2 mm in the 54-year-old individual and a minimum of 5 mm in the62-year-old individual (Table 2). The variations found in volume and length fits toa normal distribution and we did not find them to be significant.


Fig. 2. Lipofuscin differential coloration (Fuchsin–Ziehl–Neelsen) of the vestibular nuclei in normal andaging subjects. (a) DVN 35 years. (b) DVN 89 years. (c) MVN 35 years. (d) MVN 89 years. (e) LVN35 years. (f) LVN 89 years. (g) SVN 35 years. (h) SVN 89 years. Bar=44 mm.


The number of neurons in DVN ranges from 41 3729351 in the 35-year-oldindividual to 38 4819287 in the 89-year-old individual (Table 3, Fig. 5). Theneurons decrease correlates negatively with the age (r= −0.633; P=0.046), whatis statistically significant (Fig. 3a).

Table 3Number of neurons in the vestibular nuclei (number9S.E.M.)

Age (years) MVNDVN LVN SVN

122 241965 53 42192635 24 55891141 37293546 22 37391032 910921112 26395548 341930

27 518914 20 456910103 60897346 8709265477 505935 40 215919 24 57591062 34 625916

76 32 039915 62 017930 21 398911 23 63691237 212924 23 60991180 75193721 60291277

82 299928 31 81592182 22 72491031 81491875 915945 25 677915 17 32391389 38 481928

Fig. 3. Comparison of neuronal population in normal and aging subjects. (a) DVN 35 years. (b) DVN89 years. (c) MVN 35 years. (d) MVN 89 years. Bar=90 mm.


Table 4Percentage of the different types of neurons in the vestibular nuclei

Age (years) 500–1000 mm2B200 mm2 \1000 mm2200–500 mm2

DVN35 7.6534.36 0.3657.6346 6.3335.55 0.2857.84

10.95 0.2072.3154 16.5470.3210.68 18.59 0.416270.8813.39 15.07 0.6676

17.83 0.6267.4377 14.1282 68.81 8.76 0.4222.01

12.55 0.8562.1189 24.49

MVN33.38 57.85 8.51 0.263536.50 53.57 9.72 0.2146

6.02 0.6765.8154 17.541.13 49.50 9.18 0.3462

18.41 0.7967.1913.617615.83 0.4477 16.05 67.68

5.48 0.1568.7982 25.5810.3989 0.2525.05 64.31

LVN35 11.2127.89 2.0858.82

17.45 58.53 19.55 4.47466.67 54.69 27.50 11.1454

23.47 3.9164.6062 8.0261.227.25 25.97 5.5676

25.78 3.4759.8977 10.8664.4822.69 11.06 1.7782

24.36 64.30 9.86 1.4889

SVN19.2235 2.0515.95 62.7816.28 0.3058.5524.8746

48.1922.27 25.40 4.335461.7319.34 18.06 0.8762

17.99 0.9357.6676 23.4213.7277 1.2625.56 59.4616.9 0.4560.4882 22.17

59.7227.71 12.23 3489

The neurons of medium size are the most abundant, followed by the small ones.In the 35-year-old individual, the small represent 34.36%, the medium 57.63%, thelarge 7.65% and the giant 0.36% of the neuronal population. There is a slightdecrease with aging in the group of small neurons, which constitute 20–25% in theoctogenarian subjects, and an increase in the other groups (Table 4). These changesare seen mainly in the caudal and intermediate thirds.


3.2. Medial 6estibular nucleus (MVN)

The MVN is located in the inferior third of the pons and the two rostral thirdsof the medulla oblongata, caudal to the SVN, and medial to the LVN and DVN.This nucleus is always beneath the floor of the fourth ventricle. In its intermediatethird appears separated from the fourth ventricle by the stria acustica. In thetransverse sections its shape is triangular, with the longest side parallel to the floorof the fourth ventricle. In the rostral region, the MVN is reduced to a group ofneurons interposed among the LVN, the SVN and the floor of the IV ventricle. Itsrostral pole is found at the level of the nucleus abducens, and its caudal pole at thelevel of the rostral pole of the nucleus gracilis. This nucleus is easy to distinguishfrom both, the DVN and LVN, in function of its differences in the fibroarchitec-tonic and neuronal morphology, but at the rostral pole neurons of the MVN canbe confused with the cells of the SVN. Its intermediate third is medially related withthe lateral region of the nucleus praepositus hipoglossi, and a space free of neuronsseparates them.

The MVN is the vestibular nucleus in which the neurons adopt a most compactarrangement. Its neurons have very assorted morphology, from rounded orfusiform to polygonal shape. The neuronal nucleus occupies a central position andhas only one nucleolus (Fig. 1b). The average equivalent diameter of the neuronalnucleus is 9.6 mm. This value ranges from 10.31 mm in the 76-year-old individual to8.3 mm in the 89-year-old individual (Table 1). The MVN is the only vestibularnucleus that shows a significant correlation between the increase in the age and thedecrease of the diameter of the neuronal nucleus (r= −0.64, P=0.044).

The neurons in the MVN accumulate lipofuscin with age although it is not asremarkable as in other vestibular nuclei (Fig. 2c, d).

The MVN is the biggest vestibular nucleus, with an average volume of 29.57mm3. This value ranges from 38.36 mm3 in the 76-year-old individual to 24.82 mm3

in the 82-year-old individual. The average length of this nucleus was 8.85 mm. Thisvalue ranges from 9.9 mm in the 54-year-old individual to 7.2 mm in the89-year-old individual (Table 2). The variations of length and volume were notsignificant.

The MVN has the greater number of neurons, with 122 2419651 in the35-year-old individual. The total number of neurons decreases, with aging, to75 9159453 in 89-year-old individual (Fig. 3c, d). The neuronal decrease inobserved the different ages (Table 3, Fig. 5) is significant (r= −0.786, P=0.01).The neuronal loss related with age seems to affect mainly the intermediate andcaudal thirds of the nucleus.

The MVN shows a distribution, with respect to the neuronal size, very similar tothat found in the DVN. The small neurons represent, in the 35-year-old individual,33.38% of the total, the medium neurons 57.85%, the large neurons 8.51% and thegiant neurons 0.26% (Table 4). The changes related with the aging are similar tothose described in the DVN. The percentage of small size neurons decreases and anincrease in the percentage of medium and large neurons is observed. In the statisticanalysis, we found significance only for the increase in the percentage of mediumsized neurons (r=0.63, P=0.04).


3.3. Lateral 6estibular nucleus (LVN)

The LVN is located in the pons, in a lateral position respect to the MVN, caudalto the SVN and rostral to the DVN. In transverse sections LVN shows always atriangular morphology. Its rostral limit is the caudal pole of the SVN. Distinguish-ing the LVN from the MVN in Nissl stains is sometimes difficult, although thepresence of myelinated fibers in the MVN differentiates them. The ventral surfaceof the LVN is related to the nucleus o6alis, the spinal trigeminal nucleus and thereticular formation. The caudal region of the LVN is located dorsolateral to theDVN. The vestibular nerve penetrates in the brainstem in the groove between thepons and the medulla oblongata and arrives to the ventrolateral aspect of the LVNwhich permits to distinguish both nuclei.

The LVN is characterized by its close relationship with the restiform body and bythe abundance of Deiters’ cells. Attending to the morphometry of its neurons, tworegions can be distinguished in the LVN:1. medial or dorsomedial region: It occupies the rostral third of the nucleus, till the

level of the inferior pole of the nucleus abducens. In this region the neuronsadopt an arrangement more compact than in the lateral region and there arefewer fibers.

2. lateral or ventrolateral region: It occupies the caudal two-thirds of the nucleusand forms its inferior pole. The neurons appear more scattered, and they looklike immersed in the restiform body.

The neurons of the nucleus do not differ from those of the rest of the vestibularnuclear complex, except for the presence of Deiters’ cells. Deiters’ neurons aregenerally pyramidal or elongated in shape. The neuronal nucleus is rounded andlocated in a central position, with a prominent nucleolus (Fig. 1c). The equivalentaverage diameter of the neuronal nucleus was 10.3 mm; this value ranges from 11.1mm observed in the 46-year-old individual to 9.4 mm in the 89-year-old individual(Table 1). With aging there is a slight decrease of this diameter, but the variationsare not significant.

Lipofuscin increases with aging in the neurons of the LVN. This is the vestibularnucleus in which this feature is more striking, due to the presence of Deiters’neurons, since in these cells the accumulation of lipofuscin is greater in the largestneurons. In the case of Deiters’ neurons, there are occasions in which they seem atthe light microscope, as ‘bags’ filled with lipofuscin, since the nucleus cannot beseen (Fig. 2e, f).

The average volume of the LVN was 21.42 mm3. This value ranges from 24.77mm3 in the 76-year-old individual to 19.28 mm3 in the 89-year-old individual (Table2). The average length was 5.58 mm, and this value ranges from 6.6 mm in the35-year-old individual to 4.7 mm in the 89-year-old individual (Table 2). Thevariations related with age were not significant.

The number of neurons of the LVN in the 35-year-old individual was 53 4219651. We have seen a decrease of the number of neurons with age (Fig. 4a, b). Thus,the 89-year-old individual had only 25 6779156 neurons, that represent a 48.1% ofthe 35-year-old individual (Table 3, Fig. 5). The decrease of neurons, related withaging, in the LVN was statically significant (r= −0.636, P=0.045).


In the LVN the regions more affected by the neuronal loss related to aging arethe intermediate and specially the caudal one.

The distribution of the different neuronal groups in the LVN is similar to that ofDVN, but an important proportion is constituted by large neurons, which are alsothose whose percentage decreases more with aging. The 35-year-old individual, had27.89% of small sized neurons, 58.82% medium sized, 11.21% large neurons and2.08% of giant neurons. With aging the medium neurons percentage increases(64.30% in the 89-year-old individual) and the proportion of large (9.86%) andgiant neurons (1.48%) decreases (Table 4). The increase of the medium neuronswith aging it is statistically significant (r=0.63, P=0.045).

3.4. Superior 6estibular nucleus (SVN)

It is the smallest of the vestibular nuclei. Throughout its length, the SVN isexclusively located in the pons extending from the rostral third of the principalsensory nucleus of the trigeminal nerve, to the caudal third of the nucleus abducens.

The SVN it is located lateral to the floor of the IV ventricle and medial to theinferior and superior cerebellar peduncles. Its caudal pole is placed like a wedge

Fig. 4. Comparison of neuronal population in normal and aging subjects. (a) LVN 35 years. (b) LVN89 years. (c) SVN 35 years. (d) SVN 89 years. Bar=90 mm.

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Fig. 5. Variations in the number of neurons of the vestibular nuclei during aging. (A) DVN, (B) MVN, (C) LVN and (D) SVN.


between the medial and lateral regions of the LVN. The intermediate region of theSVN shows a triangular morphology in transverse sections.

The rostral region of the nucleus appears located dorsal to the mesencephalic andprincipal sensory nuclei of the trigeminal nerve. The neuron morphologies of thesenuclei allow to distinguish them easily, since the neurons of the SVN are bigger.The caudal region is lateral located respect to the MVN and dorsal to the LVN.

The neuronal morphology is not uniform, with neurons oval-shaped, rounded orfusiform. The biggest neurons are found mainly in the ventral part of the caudalregion (Fig. 1d). The nucleus is crossed by myelinic fibers that go in a caudal,ventral and medial direction.

The neuronal nucleus is rounded and located in a central position, with aprominent nucleolus. The average equivalent diameter is 9.8 mm and this valueranges from 10.4 mm, in the 72-year-old individual, to 9.3 mm in the 89-year-oldindividual (Table 1). The variations related to age are not significant.

With aging, lipofuscin accumulates in the cytoplasm, specially in larger neurons(Fig. 2g, h).

The average volume of the SVN was 11.05 mm3. This value ranges from 12.39mm3 in the 35-year-old individual to 9.6 mm3 in the 72-years-old individual (Table2). The variations with age are statically significant (r= −0.879, P=0.0245). Theaverage length of the SVN was 4 mm, this value ranges from 4.8 mm, in the46-year-old individual to 3 mm in the 72-year-old individual (Table 2). Thevariations with age are not significant.

The number of neurons in the SVN ranges from 24 5589116 in the 35-year-oldindividual to 22 3739104 in the 46-years-old individual (Table 3, Fig. 5). Thecorrelation analysis does not show any significant difference in the variation of thenumber of neurons (Fig. 4c, d).

The medium sized neurons constitute the most abundant neuronal group(62.78%), followed by large neurons (19.22%), small neurons (15.95%), and giantneurons (2.05%), in the man 35-years-old (Table 4). With aging there is an increasein the small neurons (27.71% at 89 years), and a decrease of the other groups. Noneof these changes was significant.

4. Discussion

The effects of aging in the central nervous system have been studied by manyauthors for more than a century, but only a few works published deal specificallywith its effects in the vestibular nuclei. Aging does not affect equally all the areasof the encephalon (Terry et al., 1987) and its effects, on the different nuclei of thehuman brainstem, are not the same (Moatamed 1966; Konigsmark and Murphy,1972; Monagle and Brody, 1974; Boseila et al., 1975; Vijayashankar and Brody,1977a).

One of the most striking effects of aging is the accumulation of lipofuscin in thecytoplasm of the neurons, specially in larger ones. This fact is remarkable in theLVN due to the presence of the Deiters’ neurons while the SVN seems to


accumulate less pigment. Sturrock (1989b) in the LVN of mice finds lipofuscin inthe large neurons, but we have found lipofuscin, in human, in small neurons too.

We are going to discuss our results by comparing them with the data of literatureand we will try to elucidate the consequences of our findings according to theconnectivity and physiology of every nucleus.

4.1. Descending 6estibular nucleus

The DVN constitutes the caudal pole of the vestibular nuclear complex. Thisnucleus receives primary vestibular afferents in all its length, but regional differ-ences in those afferents have been reported (Naito et al., 1995). The spinal afferentsare minimal and arrive to the caudal region (Rubertone and Haines, 1982). Thecerebellar afferents are distributed all over the nucleus, intermingled with thevestibular ones (Baloh and Honrubia, 1990). The afferences from other areas arevery scarce.

Most of its efferents go toward the reticular formation and the cerebellum(Carleton and Carpenter, 1983), issuing many commissural fibers toward thecontralateral vestibular nuclei (Brodal, 1972).

The average volume of the DVN is 15.9 mm3. This agrees with the data of Lopezet al. (1997) and Suarez et al. (1997). On the other hand, the volume calculatedfrom the neuron density and number of neurons shown by Blinkov and Ponomarev(1965) is smaller (9.4 mm3). These authors warn in the discussion of their work thatthey have not taken into account the effect of the tissue retraction. Blinkov andPonomarev employ for their study celloidin embedded material, and it could bethat there is an important tissue retraction due to the chloroform (Haug, 1986).

The number of neurons in our series reduces with aging, being this decreasestatistically significant. Lopez et al. (1997) find also a significant decrease, but thevalues of the number of neurons are larger than ours. Blinkov and Ponomarev(1965) and Suarez et al. (1997) find more neurons in the DVN of not aging subjects.

Middle sized neurons are most abundant, followed by small, large and giantneurons, as has already been shown by Suarez et al. (1997). These data are similarto those of the rat (Suarez et al., 1993).

The neuronal loss with aging is apparently uniform throughout the nucleus andwe have not found differences in different levels of the DVN that could be relatedto differences of afferent or efferent fiber distribution.

The decrease of the number of neurons with aging can be due to transneuronaldegeneration related to the cell loss of vestibular neuroepithelium. It is possible thatthe decrease in the number of its neurons contributes to vestibular impairment ofthe elderly as this nucleus could be an integrative center of labyrinthine andcerebellar signals (Baloh and Honrubia, 1990).

4.2. Medial 6estibular nucleus

The MVN, also called Nucleus of Schwalbe, is the largest of the main vestibularnuclei and has the highest neuronal density of all the nuclei studied (4250.38neurons/mm3 in the 35-year-old individual).


The MVN receives primary vestibular afferents throughout its length but they aremore numerous in the rostral region (Carleton and Carpenter, 1984; Naito et al.,1995). Spinal afferents go to the caudal region (Pompeiano and Brodal, 1957a;Prihoda et al., 1991).

The efferent connections arising from the rostral region are most of themcontralateral and go, included in the medial longitudinal fascicle, toward theoculomotor nuclei (MacCrea et al., 1987). The MVN is, with the SVN and theDVN, the principal origin of the commissural connections that coordinate thefunction of the vestibular nuclei (Carleton and Carpenter, 1983).

This nucleus is supposed to be a coordination center of the eye, head and neckmovements (Ohgaki et al., 1988; Baloh and Honrubia, 1990). Its commissuralconnections are probably important in the vestibular compensation (Baloh andHonrubia, 1990).

The average volume of this nucleus is 29.57 mm3, similar to the findings of Lopezet al. (1997) and Suarez et al. (1997), and bigger than the 20.9 mm3 of Blinkov andPonomarev (1965). The changes of volume and length that appear with aging arenot significant. The MVN is the only vestibular nucleus with a significant decreaseof the diameter of the neuronal nucleus with aging.

The MVN has more neurons than the rest of the vestibular nuclei. Our findingscoincide with those of Blinkov and Ponomarev (1965), Dıaz et al. (1996), Suarez etal. (1997), Lopez et al. (1997). Neuron decrease with aging is significant, speciallyafter the sixth decade of life, arriving to 60% of the initial number, at the end of thelife. Lopez et al. (1997) also report a decrement in the number of neurons but nonstatically significant. We have obtained a good correlation between aging andneuron decrease in our work (r= −0.786).

The most abundant neuron group in the MVN is that of middle sized neurons,followed by the small ones. With aging there is an increase in the proportion of themedium and large sized neurons, and a slight decreases in the proportion of smallneurons, but these changes are not significant.

Lin and Carpenter (1993) showed that in the MVN there are neurons with aspontaneous discharge rate of high frequency (5–35 Hz), and therefore they aresupposed to act as a sort of pacemaker. The unilateral destruction of labyrinthcauses a decrement in the spontaneous discharge rate in the affected side (MacCabeet al., 1972) that originates a series of oculomotor and postural alterations. Thesealterations relate to with the lack of balance of the excitatory stimuli from bothvestibular nuclear complexes (for a review of the topic see Smith and Curthoys,1989). The vestibular compensation is the recovery process that makes thesesymptoms disappear gradually and it is related with the return of the restingactivity in the vestibular nuclei. The recovery of balance is particularly notable inthe MVN (DeWaele et al., 1988; Maeda, 1988; Smith and Curthoys, 1988;Newlands and Perachio, 1990).

Compensation occurs at different times depending on the species; thus, theguinea pig is compensated in 2 days (DeWaele et al., 1988; Smith and Curthoys,1988), while in the frog it delays for 40–70 days (Flohr et al., 1981). Although thevestibular nerve, and even the neuroepithelium, can regenerate in the guinea pig


(Forge et al., 1993; Rubel et al., 1995), the return of the normal activity may berelated to the synaptic plasticity within the central nervous system. Anatomicaland physiological studies have been made in mammals concerning vestibularcompensation with contradictory results; for some authors the section of com-missural fibers does not cause decompensation (Newlands and Perachio, 1986)while, for other authors, the vestibular compensation depends on an intact com-missural system (Dieringer and Precht, 1979; Keller and Precht, 1979; Galiana etal., 1984; Galiana, 1985), including the cerebellar and reticular formation connec-tions (Maeda, 1988). Gacek et al. (1988), think that compensation has to dowith postsynaptic changes that increase the efficiency of these synapses. Smith etal. (1991) think that the receptors of excitatory neurotransmitters, specially gluta-mate NMDA-receptors, influence the commissural interaction between bothvestibular nuclear complexes, although it is not clear which nuclei are involved.

Barion and Andretta (1988), studying patients with an acute unilateral vestibu-lar function loss, observed that in those younger than 40 years the nystagmusdisappeared by the 8th day, while in those older than 40 years, it persisted for atleast 15 days. On the other hand, 1 year after the onset of the process, only 8%of those younger than 40 years complained of dizziness, while 87% of thoseolder than 40 years had dizziness. The authors consider that this can be inrelation with the changes produced by aging in the inferior olive nucleus andwith the alteration of some neurotransmitters. We believe that the decrease ob-served in the number of neurons of MVN could relate to the difficulties thathave the elders to compensate the vestibular deficits after an injury.

4.3. Lateral 6estibular nucleus

The LVN or nucleus of Deiters is located ventromedially respect to the infe-rior pole of the SVN, which is introduced like a wedge between its medial andlateral regions (Sadjadpour and Brodal, 1968; Dıaz et al., 1993; Suarez et al.,1997). Its caudal limit is more difficult to determine since at this level it isreplaced gradually by the DVN. The medial region of the LVN is related withthe MVN. These nuclei are easy to identify due to the differences that they showin their cytoarchitecture. In some animals the boundary is yet clearer because ofthe interposition of the acoustic stria between both nuclei (Gstoettner andBurian, 1987; Naito et al., 1995) which, according to some authors, does notappear in the man (Sadjadpour and Brodal, 1968; Dıaz et al., 1993).

The rostral region of the LVN has been divided into a medial and a lateralregion, which has more fibers and more giant neurons (Sadjadpour and Brodal,1968). Coinciding with Suarez et al. (1997) and Dıaz et al. (1993) we think thatthere is a similar quantity of giant neurons in both areas of the rostral region.

The afferent fibers seem to arrive mostly to the ventral region of the LVN andthey come mainly from the utricle (Siegborn and Grant, 1983; Carleton andCarpenter, 1984; Naito et al., 1995) and, in smaller quantity, from the semicircu-


lar canals (Cowie and Carpenter, 1985; Naito et al., 1995). On the other hand, thedorsal and caudal regions receive no primary vestibular afferents (Cowie andCarpenter, 1985; Suarez et al., 1989; Naito et al., 1995). The dorsocaudal regionreceives afferent input originating from the spinal cord (Pompeiano and Brodal,1957a; Henkel and Martin, 1977b; Rubertone and Haines, 1982) and from thecerebellum (Henkel and Martin, 1977b; Carleton and Carpenter, 1983).

Excitatory fibers originated in the rostroventral region of the LVN go toward thenucleus oculomotorius (Steiger and Buttner-Ennever, 1979). The spinal projection ofthe LVN is designated classically as lateral vestibulospinal fascicle or fascicle ofDeiters. This nucleus may be to be an important center for the vestibulo-spinalreflexes, specially those that affect the hindlimb (Carleton and Carpenter, 1983).For Rose et al. (1992), the vestibular stimuli have greater importance in the controlof the forelimb.

The volume average of the LVN that we have found is larger than that found byDıaz et al. (1993), Lopez et al. (1997), and that of Blinkov and Ponomarev (1965).The average length that we observed agrees with the study of Dıaz et al. (1993). Themodifications in the volume and the length of the LVN, related to the aging, arenot statistically significant.

In the present study a significant decrease in the number of neurons of the LVNwith aging was observed, specially in the caudal region. Lopez et al. (1997) do notfind a significant decrease in the neuronal population of the LVN. Sturrock (1989b)finds a significant decrement in the number of large neurons in the LVN of mice,but not in the small ones.

When it is compared with the other vestibular nuclei, the LVN has more largeand giant neurons, specially in the caudal pole, what coincides with the observa-tions of other authors (Henkel and Martin, 1977a; Gstoettner and Burian, 1987).

Elderly persons have problems in recovering balance when something alters theirstanding position. Factors that contribute to this condition are the decrease of theneural conduction velocity, the slower reaction time, the muscular weakness or thevestibular alterations in the elders (Kenshalo, 1979).

Norre et al. (1987), in their study on patients with unilateral vestibular deficitscould observe, with posturography, that the compensation of the vestibulospinalreflexes was achieved in 71% of patients younger than 40 years. On the contrary,only 30% of those older than 60 years achieved this compensation.

An important proportion of the neurons of the LVN are large neurons whoseaxons go into the vestibulospinal tract (Carpenter, 1988). Large neurons reduce inpercentage in the old age and they can contribute to the alteration of vestibu-lospinal reflexes. The neuron loss is more significant in the caudal third of thenucleus and we believe that it can be related with the fact that the axons of theseneurons go toward the lumbar spinal cord (Pompeiano and Brodal, 1957a,b). Thealteration of the vestibular nuclei, especially the LVN, can produce a disturbance ofthis circuit of control of the balance, the muscular tone and the coordination of themovements.


4.4. Superior 6estibular nucleus

The SVN is the most rostral of the vestibular nuclear complex and lies lateral tothe fourth ventricle. Our findings, with respect to the cytoarchitecture of the nucleuscoincide with preceding studies (Sadjadpour and Brodal, 1968; Suarez et al., 1997).

Most of its afferent fibers come from the peripheral vestibular organs, mainlyfrom the semicircular canals (Brodal, 1974). In humans larger cells are located inthe ventrocaudal region of the nucleus (Suarez et al., 1997).

The SVN mainly projects, in the cat, toward the oculomotor nuclei by the mediallongitudinal fascicle and the ipsilateral brachium conjuncti6um. Their efferencesinnervate the nucleus trochlearis and the nucleus oculomotorius, and its action onthese nuclei is excitatory (Mitsacos et al., 1983a). It is striking the absence ofcontralateral inhibiting stimuli of the vestibulo-ocular neurons (Mitsacos et al.,1983a). Some fibers are sent to the contralateral SVN, the MVN and to the DVNfor the synergistic function of both sides (Brodal, 1974).

The SVN is considered the center of the vestibulo-ocular reflexes. Due to theconnections of the rostral regions of both, the MVN and the LVN, these nucleiprobably also influence those reflexes.The average volume of the SVN reported inour study agrees with the study of Suarez et al. (1997). Blinkov and Ponomarev(1965) find a higher volume while the maximum value reported by Lopez et al.(1997) smaller than ours. We cannot find an explanation for the differencesreported in the literature if not due to the differences in the processing of thehistologic material. This is the only nucleus where we have seen a decrement in thevolume with age. The average length of the SVN in our series agrees with thatcalculated by Suarez et al. (1997) and the differences observed with age are notsignificant.

In the SVN we have not found alterations in the number of neurons with aging,obtaining an average number of all the studied ages around 23 000–24 000 neuronswhich agrees with the data from Suarez et al. (1997) and is lower than the resultsof Lopez et al. (1997). On the other hand Blinkov and Ponomarev (1965) find thatthere are a much larger number of neurons. This difference could be explained bythe counting method that these authors use, based in the density of neurons and thevolume of the nucleus.

We have not found significant differences in the number of neurons with agingwhile Lopez et al. (1997) find a significant decrease. It is remarkable that in theirdata the decrease appears only in the oldest people, being the rest of the datasimilar to ours.

Aging does not affect compensation of the vestibulo-ocular reflex as shown byNorre et al. (1987). This author, studying patients with unilateral vestibular injuryobserved that the rotatory test is symmetrical in 57% of patients independently ofage.

The SVN can be the principal integrative center for the ocular reflexes elicited bythe semicircular canals due to its connections (Ito et al., 1973; Baloh and Honrubia,1990). There has not been found a decrease of the number of neurons neither in thenucleus abducens (Vijayashankar and Brody, 1977a), nor in the nucleus trochlearis


(Vijayashankar and Brody, 1977b) of the man, and also remains constant thenumber of neurons in the nucleus abducens (Sturrock, 1989a), the nucleus troch-learis and nucleus oculomotorius of mice (Sturrock, 1991). The extraocular musclesare very active throughout the life, what means that the corresponding nuclei havea great activity. Perhaps this muscular activity prevents the loss of neurons in theoculomotor nuclei, since activity can delay the appearance of the cellular death insome neuronal groups (Vogt and Vogt, 1946). The preservation of neurons of theoculomotor nuclei could maintain the number of neurons of the SVN constant. Thefinding that there is no neuron loss in the rostral region of the MVN and the LVN,whose neurons project to the oculomotor nuclei, favors also this hypothesis. Theobservations of Sturrock (1989b) regarding the preservation of the number of smallneurons in the LVN of mice are also consistent with this hypothesis.

As a conclusion, we think that a moderate vestibular dysfunction, that would notto cause problems in a young adult, could produce symptoms and signs in theelderly, when there are also poor sight and loss of proprioception and neuromuscu-lar function. Belal and Glorig (1986) coined the term ‘presbystasis’ to refer to multisensorial dizziness as a differentiated entity, which is common in older persons. Forsome authors, multiple neurosensory deficits are the most important cause ofdizziness in this group of age (Drachman and Hart, 1972). A normal aging processonly produces a discreet loss of function, and most elders should only walk slowlyand turn with greater care, because their balance is less firm that in the youth. It ispossible that loss of balance appears only when more than one system is affected.We believe that the cellular decrease observed in the cited vestibular nuclei is aconsequence of the normal aging and it is not cause of dizziness per se.

Acknowledgements

This work was supported by a FISS (93/0634; 99/1316) grant.

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Aging and the human vestibular nuclei: morphometric analysis

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