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Brain Advance Access published online on September 4, 2008
Brain, doi:10.1093/brain/awn201
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

An ipsilateral vestibulothalamic tract adjacent to the medial lemniscus in humans

Andreas Zwergal1, Jean Büttner-Ennever2, Thomas Brandt1 and Michael Strupp1

1Department of Neurology and 2Department of Anatomy Ludwig-Maximilians-University, Klinikum Grosshadern, Munich, Germany

Correspondence to: Andreas Zwergal, MD, Department of Neurology, University of Munich, Klinikum Grosshadern, Marchioninistrasse 15, D-81377 Munich, Germany E-mail: andreas.zwergal{at}med.uni-muenchen.de


   Summary
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 Summary
Introduction
 Methods and patients
 Results
 Discussion
 References
 
We examined 14 patients with acute anteromedial pontomesencephalic infarctions for signs of vestibular and ocular motor dysfunction. In all cases, an isolated ipsilateral deviation of the subjective visual vertical (mean: 4.1, range: 2.7– 6.6) was found without any further signs of vestibular or eye movement disorders like ocular torsion or skew deviation. Distinct lesions in thin-slice brainstem MRI showed an overlap zone in the medial portion of the medial lemniscus. The finding of putative ipsilateral vestibular projections running adjacent to or within the medial lemniscus was subsequently confirmed by a reanalysis of an anterograde tracer labelling study in the primate after tracer injection in the vestibular nucleus complex. The major conclusions of this study are as follows: (i) there is evidence for an ipsilateral graviceptive pathway running from the vestibular nuclei close to and within the medial lemniscus to the posterolateral thalamus [ipsilateral vestibulothalamic tract (IVTT)], (ii) this pathway might be the human homologue of the three-neuron sensory vestibulocortical tract described in primates and (iii) unilateral lesions of this pathway cause only vestibulo-perceptive dysfunction in the roll plane in contrast to lesions of the crossed graviceptive pathways (in the medial longitudinal fascicle), which were described earlier and which manifest as a combination of tilt of the subjective visual vertical, ocular torsion and skew deviation.

Key Words: vestibular system; imaging; information processing

Abbreviations: IVTT, ipsilateral vestibulo-thalamic tract; INC, interstitial nucleus of Cajal; MLF, medial longitudinal fascicle; SVV, subjective visual vertical

Received May 6, 2008. Revised July 24, 2008. Accepted July 31, 2008.


   Introduction
Top
 Summary
 Introduction
Methods and patients
 Results
 Discussion
 References
 
The vestibular system processes information by means of a multilevel sensorimotor network that subserves postural, ocular motor and perceptual functions. The two major functions of the vestibular system at the cortical level are motion perception and spatial orientation. According to brain activation studies in animals and humans, these functions are mediated by several areas in the parietal and temporal lobes (e.g. parietoinsular vestibular cortex, area 3a in the central sulcus and area 7 at the inferior parietal cortex) (Bense et al., 2001Go; Dieterich et al., 2003Go), which receive multisensory inputs (vestibular, somatosensory and visual) (Brandt et al., 2002Go). It is still unclear, however, how vestibular input is transmitted from the vestibular nuclei to the cortex. One potential candidate is the crossed graviceptive pathway within the medial longitudinal fascicle (MLF), which has multisynaptic projections running via the integration centres for eye movements in the roll plane to the thalamus (Dieterich et al., 1993a). Unilateral damage of these pathways first appears clinically as ocular motor symptoms (ocular torsion, skew deviation) and vestibular–perceptive symptoms [i.e. false-cortical representation of verticality as measured by deviation of the subjective visual vertical (SVV)]. An uncrossed graviceptive pathway with a direct thalamic projection has been described in animal experiments (vestibulothalamic tract) (Boisacq-Schepens, 1972; Lang et al., 1979Go; Meng et al., 2001Go). The existence of a human homologue has been suggested by functional imaging studies, which show a predominantly ipsilateral ascending projection of vestibular information to the cortex (Dieterich et al., 2003Go). However, the anatomical course of such a projection was not known.

The present study was prompted by the incidental finding in single cases that patients with distinct anteromedial pontomesencephalic infarctions, which affected the medial lemniscus, show an isolated ipsilateral deviation of the SVV. This indicates an ipsilateral deficit of vestibulocortical graviceptive input, if there were no other ocular motor dysfunctions in the roll plane, in particular no ocular torsion or skew deviation. On the basis of this observation, we systematically investigated the vestibular and ocular motor functions in patients with this type of brainstem lesion involving the medial lemniscus.


   Methods and patients
Top
 Summary
 Introduction
 Methods and patients
Results
 Discussion
 References
 
Fourteen patients with anterior paramedian pontomesencephalic infarctions were included (retrospectively: n = 8, prospectively: n = 6; 8 males; mean age 60.1 ± 13.4 years). Thin-slice MRI (3 mm) of the brainstem was performed in all patients (T1-, T2-, diffusion-, FLAIR-weighted images). Brainstem lesions were mapped after spatial normalization to brainstem levels and regions (posterior paramedian, lateral, anterior paramedian) and projected onto standardized sections of a stereotactic atlas of the brainstem (Kretschmann, 2007Go). All patients underwent complete neurological and neuroophthalmological examinations. The latter included evaluation for spontaneous nystagmus with Frenzel's goggles in primary position, gaze-evoked nystagmus, smooth pursuit (horizontally and vertically), saccades, optokinetic nystagmus by means of a rolling drum, visual fixation suppression of the vestibuloocular reflex, rebound nystagmus, head-shaking nystagmus, head-impulse test as described by Halmagyi and Curthoys (Halmagyi et al., 1988) and the range of ocular motion. Vertical deviation of the visual axis (skew deviation) was measured by the cover test using prisms. All of these standardized clinical examinations were performed by experienced neuroophthalmologists (Brandt et al., 2005).

Psychophysical determination of the visual vertical was performed by measuring the subject's adjustment of a bar to the perceived vertical without any spatial orientation clues in a dotted hemispherical dome, as described earlier (Dieterich et al., 1993a). Under these conditions, the normal range of SVV was defined as 0 ± 2.5° (positive values: rightward tilt, negative values: leftward tilt). The degree of ocular torsion was measured by fundus photographs taken in a scanning laser ophthalmoscope, with the head upright. In the prospectively analysed group, the following additional examinations were performed: three-dimensional sway path analysis by posturography, somatosensory-evoked potentials (median nerve, tibial nerve) and vestibular-evoked myogenic potentials. Somatosensory-evoked potentials were obtained by delivering 0.2 msec square wave electrical stimuli at 4.5 Hz transcutaneously to the medial/tibial nerves via bipolar electrodes (1500 trials). Recording electrodes were placed on the skin at the seventh cervical vertebra and at C3 and C4 (International 10-20 System). Data were collected and evaluated by means of Excel (Microsoft, Redmont, WA, USA) spreadsheet software and SPSS (SPSS Inc, Chicago, IL, USA).


   Results
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 Summary
 Introduction
 Methods and patients
 Results
Discussion
 References
 
The most frequent symptoms and clinical findings at the patients’ initial presentation were hemihypesthesia (11 of 14) and mild hemiparesis (11 of 14) contralateral to the lesion. In the three patients without sensory dysfunction, only the medial-most part of the medial lemniscus was affected; thus, no apparent sensory symptoms were caused. None of the patients had double vision, oscillopsia or vertigo. The sway path analysis in the six patients in the prospective group was normal (Table 1).


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  		Table 1 Patients’ characteristics

 
Deviation of the SVV and ocular motor function
All patients had a pathological SVV deviation (mean: 4.1, range: 2.7–6.6, normal range 0–2.5 [mean ± 2-fold SD)] to the side of the lesions (ipsiversive) (Fig. 1). Ocular motor functions were normal compared with age-matched controls (no gaze-holding deficit, no saccadic smooth pursuit, no saccadic dysmetria or slowing), except for mild symmetric cerebellar ocular motor signs in four cases. The origin of these signs was most probably not related to the acute ischaemia: two patients had a personal and family history of severe migraine (60% of patients with migraine exhibit mild ocular motor disorders in the attack-free interval), the third took valproate at a dose of 2 g for epileptic seizures and the fourth had a history of alcohol abuse with signs of mild cerebellar atrophy on MRI. In particular, pathological ocular torsion or skew deviation was not found in any of the 14 patients. There was no difference in the degree of SVV deviation between patients with left- and right-sided lesions. Subgroup analysis of prospectively and retrospectively examined patients revealed no difference as to the mean of SVV and localization of the lesions. Follow-up examination in single cases showed rapid normalization of the SVV deviation (7–14 days).


Figure 1
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  		Fig. 1 Box plot charts of values of SVV measured in unilateral anteromedial pontomesencephal infarctions (n = 14). Positive SVV values indicate tilt to the right and negative values, tilt to the left (the normal range is defined as ±2.5°, grey zone). In the box plot charts, the horizontal lines indicate the 25, 50 and 75th percentile and the bars above and below, the smallest and largest outlier.

 
MRI findings
Thin-slice MRI images of the brainstem showed lesions in the anterior paramedian pontomesencephalic brainstem ipsilateral to the SVV deviation in all patients. In all cases the lesions were caused by infarction. This infarction territory was attributed to an anterior perforating artery (Fig. 2A). The infarction zone extended to the ventral tegmental area but did not affect the vestibular nuclei, the ocular motor nuclei or the MLF. Lesions were localized from the level of the lower pons to the mesencephalon. The overlap zone of all infarctions was allocated to the medial ventral tegmental area, which corresponded to the medial portion of the medial lemniscus (Fig. 2B).


Figure 2
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  		Fig. 2 Graphic representation of the brainstem lesions as depicted on thin-slice MRI images (3 mm). (A) Representative images of patients with an anteromedial pontomesencephalic infarction (diffusion-weighted and FLAIR images). (B) Brainstem lesions were mapped according to standardized sections of a stereotactic brainstem atlas (Kretschmann, 2007Go). Right-sided lesions were flipped to the left to analyse for overlap. Some of the lesions extended over several levels and are therefore presented twice on different slices. Three different brainstem levels are representatively shown [at the pontomedullary junction (bottom), midpons level (middle) and the pontomesencephalic junction (top)]. The level of section is indicated on the brainstem schemes, wherein the topography of the medial lemniscus (blue colour) and the vestibular nucleus complex (grey circle) is also depicted (modified from Kretschmann, 2007Go). The overlap zone (red colour) projects onto the medial portion of the medial lemniscus (blue colour). LM = medial lemniscus; PT = pyramidal tract. Asterisk denotes crossing graviceptive pathways in the MLF; 1, nucleus vestibularis; 2, nucleus nervi facialis; 3, nervus facialis; 4, nervus vestibulocochlearis; 5, nervus abducens; 6, pedunculus cerebellaris inferior; 7, arteria basilaris; 8, nervus trigeminus; 9, nucleus nervi abducentis; 10, nucleus principalis nervi trigemini; 11, pedunculus cerebellaris superior (brachium conjunctivum); 12, lemniscus lateralis; 13, tractus spinothalamicus.

 
Electrophysiological examinations
Somatosensory-evoked potentials on contralateral stimulation of the tibial nerve were pathological in four of six patients (prospective group: P37 was absent in one; P31–P37 latency delayed in three patients), on contralateral stimulation of the median nerve, in three of six patients (N13–N20 latency was delayed). The somatosensory-evoked potentials on ipsilateral stimulation were within the normal range in all patients. Vestibular-evoked myogenic potentials were bilaterally normal.


   Discussion
Top
 Summary
 Introduction
 Methods and patients
 Results
 Discussion
References
 
The major findings of this study were as follows. First, deviations of SVV are caused by lesions of the medial lemniscus or areas adjacent to it. These deviations indicate an impairment of graviceptive perception in the roll plane. Second, deviation of the SVV was always ipsilateral to the side of the lesion as opposed to contralateral deviations, which were previously described to result from lesions of the crossed graviceptive pathways running along the MLF (Dieterich et al., 1993a; Zwergal et al., 2008Go). Third, lesions of the medial lemniscus area are purely perceptual disturbances in the roll plane in contrast to perceptual and ocular motor disturbances due to lesions of the crossed fibres (Dieterich et al., 1993a).

We will now focus on the concept of ipsilateral and contralateral graviceptive pathways with respect to their different functional relevance in vestibular processing at the thalamic and cortical levels. Furthermore, we will discuss data from a reanalysis of an anterograde tracer injection study of the vestibular nucleus in primates (Lang et al., 1979Go), which serve as confirmatory evidence for the concept of an ipsilateral vestibulothalamic tract (IVTT) adjacent to and within the medial lemniscus.

There is strong evidence that graviceptive signals from the otoliths and vertical semicircular canals subserve vestibular function in the roll plane (Halmagyi et al., 1979Go; Dieterich et al., 1993a; Strupp et al., 2003Go). First, eye–head coordination in the roll plane is driven by crossed graviceptive projections running via the MLF to the contralateral interstitial nucleus of Cajal (INC), which represents the integration centre for eye movements in the roll and pitch planes (Dieterich et al., 1993a; Zwergal et al., 2008Go). Unilateral damage of these fibres regularly causes tilt of the SVV, ocular torsion, and skew deviation (ocular tilt reaction) (Dieterich et al., 1993a). Second, the internal representation of verticality is mediated by graviceptive vestibulocortical projections. The anatomical localization of the underlying pathways is ambiguous. The posterolateral thalamus has been shown to be a target to ascending fibres carrying vestibular–perceptive information (Hassler, 1959Go; Lang et al., 1979Go; Tasker et al., 1992; Dieterich et al., 1993b). A projection from the INC to the posterolateral thalamus has been hypothesized (Dieterich et al., 1993b). Lesions of the INC or the ascending crossed graviceptive pathways to the INC cause deviation of the SVV to the contralateral side (Dieterich et al., 1993b).

In the present study, we report for the first time on an isolated ipsilateral deviation of the SVV in anteromedial pontomesencephalic brainstem infarctions. In contrast to the projections described above, it is not accompanied by ocular motor dysfunction in the roll plane. Overlap analysis showed that the medial part of the medial lemniscus was involved in all cases. Therefore, an ipsilateral graviceptive projection is assumed, which directly runs close to and within the medial lemniscus and possibly to the posterolateral thalamus, thereby bypassing the centres for eye–head coordination in the midbrain tegmentum (INC). This may be a correlate of the vestibulothalamic tract, which has been previously described in animals. Electrophysical recording and autoradiographical labelling studies in cats have shown otolithic projections running ipsilaterally from the vestibular nuclei through the paramedian pontine ventral tegmentum (anterior to the ascending tract of Deiters and the MLF) at the medial edge of the medial lemniscus to the thalamus (nucleus ventralis posterolateralis/posteromedialis) (Deecke et al., 1974Go; Kotchabhakdi et al., 1980Go; Meng et al., 2001Go).

Vestibulothalamic projections have also been studied in primates by injecting an anterograde tracer substance (radioactive leucine) in the vestibular nuclear complex (Lang et al., 1979Go). Several ascending pathways were labelled in this way, for example, the MLF (mostly crossed), the ascending tract of Deiters (crossed and uncrossed) and the crossed ventral tegmental tract. Prompted by this finding, we reanalysed the original sections of the Lang et al. study to look for projections in the region of the medial lemniscus. A bundle of labelled uncrossed fibres was found on the medial edge and also a few fibres within the medial lemniscus (Fig. 3). The localization of these projections fits the overlap zone in the patients described in our study and supports the concept of IVTT adjacent or within the medial lemnicus following its course to the posterolateral thalamus. An ipsilateral vestibulothalamic projection has been hypothesized in humans to travel via the superior vestibular nucleus and a contralateral graviceptive projection, via the medial vestibular nucleus (Dieterich et al., 2005aGo).


Figure 3
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  		Fig. 3 Combined dark- and bright-field photomicrograph of the anterograde labelled fibres at the level of the pons produced by injections of radioactive proline and leucine into the ipsilateral vestibular nucleus complex in a maquague monkey (for method see Lang et al., 1979Go). The level of section and area of magnification is shown in the figure inlay. The labelled fibres are indicated by arrows. A bundle of fibres (fat-dashed circle) can be seen on the medial edge and a few fibres within the medial lemnicus. In comparison, the known fibre projections in the crossed ventral tegmental tract are shown in the upper part of the picture (fine-dashed circle). The inset is modified from the study of Lang et al. and shows the pontomesencephalic region from which the photograph was taken. BC = brachium conjunctivum (superior cerebellar peduncle); LM = medial lemniscus; NRTP = nucleus reticularis tegmenti pontis.

 
The concept of both ipsi- and contralateral graviceptive projections to the thalamus allows to explain the observation described earlier, namely that patients with infarction in the posterolateral vestibular thalamus present with either ipsilateral or contralateral deviations of the SVV (Dieterich et al., 1993b), depending on which tract is affected mainly. Brain activation studies in patients with infarctions of the posterolateral thalamus showed evidence that the ipsilateral and contralateral vestibulocortical projections were interrupted (Hassler, 1959Go; Dieterich et al., 2005bGo).

A trisynaptic vestibulo-thalamo-cortical projection in humans was assumed on the basis of recordings of cortical short latency vestibular potentials following repetitive galvanic stimulation of the vestibular nerve (Fukushima, 1997Go; de Waele et al., 2001Go). These studies showed a mean latency of about 10 ms for the first cortical response following a vestibular stimulus. The ipsilateral temporoparietal cortex, the supplementary motor area and the (pre-) frontal lobe were activated first (multisensory areas of the inner circle of vestibular cortical representations) (de Waele et al., 2001Go). We show clinical evidence of direct sensory vestibulo-thalamo-cortical projections running with the medial lemniscus and thus bypassing the ocular motor system. These projections might represent a fast vestibular track having the following functional implications. First, the fast transition of graviceptive information to the cortex during head or body movements would synchronize the cortical multisensory (visual, vestibular and perceptive) representation of space and the subcortical integration in ocular motor and postural systems (vestibulo-perceptive efference copy). Second, movement-induced vestibular information would reach the cortex before visual information. This would allow the multisensory cortex to discriminate optic flow induced by self-motion from surround-motion, which is crucial for spatial orientation and control of posture within the graviceptive field.


   Acknowledgement
 
We thank Judy Benson for copyediting the manuscript.


   References
Top
 Summary
 Introduction
 Methods and patients
 Results
 Discussion
 References
 
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