WII-2

Multimodal imaging of sensorimotor networks

Principle Investigator:
Univ.-Prof. Dr. med. Peter zu Eulenburg

Objectives:

1. Human cerebral regions homologous to established vestibular areas in non-human primates

2. Vestibular sensation thresholds, their transient network states and the respective neural correlate in functional neuroimaging

3. Functional segregation by means of extrinsic modulation of cortical hubs to delineate effective connectivity in the vestibular cortex

 

Project descriptions:

I.        Human cerebral regions homologous to established vestibular areas in non-human primates

Studies employing neuron recordings and tracer injections in rats, squirrels, java monkeys and macaques have focused on several separate structures in the frontal, temporal and parietal cortex that undoubtedly receive vestibular input: the area 2v at the tip of the intraparietal sulcus, the area 3aV (a vestibular region within area 3a representing neck and trunk) in the central sulcus and an area called the parieto-insular vestibular cortex (PIVC) located posterior to the dorsal end of the insula. Area 2v in the parietal cortex was the first definite cortical vestibular area found in primates. It was initially thought to represent the vestibular area anterior to the suprasylvian sulcus (ASSS) found in the cat (Fredrickson JM et al. 1966). The ASSS had been the first cortical vestibular projection demonstrated in mammals. As early as 1973, Pandya and Sanides had already stressed in their findings that there is a distinctive cytoarchitectonic analogy between the retroinsular parietal cortex in primates and ASSS (Pandya DN and F Sanides 1973). The PIVC as the correlate for this retroinsular region was then discovered by Grüsser and his group in the Java monkey and later also confirmed in the squirrel and marmoset monkey (Grusser OJ et al. 1990). It seemed more likely to represent ASSS in non-human primates than area 2v. Among the regions that have also been shown to receive vestibular information in the monkey are the ventral intraparietal area (VIP), area 7 in the caudal inferior parietal lobe, the primary motor cortex (area 4) and the premotor cortex (area 6). A distinct vestibular cingulate region has been termed though it seems to only receive preprocessed vestibular information from the aforementioned areas 3aV and PIVC (for a more detailed comparative anatomy of the cortical vestibular representations in animals and humans see Lopez and Blanke 2011) (Lopez C and O Blanke 2011). The aim of the present project is to pinpoint and segregate vestibular representations in the human cortex. We also want to follow up on the quest for a primary vestibular cortex (Guldin WO and OJ Grüsser 1998). The use of a wide variety of stimuli (warm and cold caloric irrigation, galvanic vestibular stimulation, short tone bursts as an otolith impulse) as well as multiple imaging modalities (H2O2- and FDG-PET, electrical source and dipole reconstruction in EEG, and fMRI) in the last 30 years of human vestibular research in neuroimaging has led to a variegated and still inhomogeneous level of knowledge about the cortical vestibular network. Most of these artificial vestibular stimulations, despite extensive control conditions in the published studies of vestibular neuroimaging, are possibly also plagued by an array of somatosensory confounders which may have prevented a clearer picture about the cortical vestibular system to date.

The results of a recent ALE meta-analysis from our group (zu Eulenburg P et al. 2012) strongly support the existence of a distinct and unique vestibular cortex in humans with its possible core region in the area OP 2 of the parietal operculum as the homologue to monkey PIVC (Guldin WO and OJ Grüsser 1998). We also found further evidence for a predominant role of the right hemisphere in the cortical processing of vestibular afferents (Dieterich M et al. 2003). At this point in neuroimaging research however, we were not able to allocate a conclusive order or hierarchy within the network for the other temporo-parietal, frontal and cingulate cortex areas also involved in the human processing of vestibular information (e.g. secondary or supplementary). Future studies explicitly testing for neuroanatomical localization, and functional and effective connectivity within a neuroimaging environment as well as an optimisation of vestibular stimulations will have to probe this question in man.

The predominant aim of this project will be to finally localise and delineate all vestibular cortical regions known in non-human primates and make them available as regions of interest to the scientific community. A further goal will be give a definitive answer to the quest for a primary vestibular cortex.

 

II.        Vestibular sensation thresholds, their transient network states and the respective neural correlate in functional neuroimaging

We will use a combined VOG-EEG-fMRI experiment with GVS probing the vestibular sensation thresholds whilst controlling for somatosensory side effects of GVS. Local anesthesia of the mastoid in combination with ultra-low frequency stimuli up to 3mA will be used. GVS-induced ocular responses as detected by VOG will serve as a gold standard and baseline for GVS effects arousing the vestibular system. The different network states (resting-state data without GVS stimulation, subthreshold, individual peri-threshold and clear above vestibular sensation threshold neuroimaging data) of the subjects will enter multivariate pattern analysis (MVPA) to discriminate the different aspects within the vestibular system.

In a preceding work with respect to the recall of a rotation experience as a quantifiable vestibular sensation, we found the majority of the known vestibular cortical regions unresponsive in a vestibular imagery task (zu Eulenburg P et al. 2013). This finding points to a potentially high threshold for actual consciously perceived vestibular arousal in cortical regions. The MVPA results of this project could serve as a basis for ensuing research to look at the causes for the aberrant vestibular sensation processing in patients suffering from prolonged vertigo after e.g. a vestibular neuritis.

 

III.        Functional segregation by means of extrinsic modulation of cortical hubs to delineate effective connectivity in the vestibular cortex

The objective will be twofold. Firstly, can we modify the perception of any artificial vertigo symptom following the vestibular stimulations with preceding virtual lesioning by rTMS? Secondly, which of the selected regions is most effective for such an intervention?

Vertigo is defined as a whirling sensation or the loss of balance. From a neuroscientific point of view the symptom can be described as an uncontrollable detachment of one’s anchoring in a three-dimensional environment leading to the sensation of involuntary egomotion or perceptual motion of the surrounding peripersonal space. Vertigo is one of the cardinal symptoms leading to the consultation of a general practitioner or neurologist. Its high prevalence is associated with an immense long-term effect on the individual´s wellbeing and a considerable economic burden for society (Benecke, Agus et al. 2013). Acute vertigo is typically an indication for the onset of a vestibular disease; chronic vertigo is often a constraint leading to immobility. Present methods of treating vertigo as a disabling symptom independent of the underlying cause consist of a few pharmaceutical agents (e.g. dimenhydrinate, cinnarizine or scopolamine) and plain bed rest. These strategies have remained unchanged for more than 25 years now. With the help of this research project we aim to open a path for the development of a completely new therapeutic field in the treatment of acute and mostly chronic vertigo: repetitive transcranial magnetic stimulation (rTMS). This new treatment should be installed alongside and in addition to the actual handling of the causative disease and physiotherapy. Since 1993 rTMS has been shown to be an effective and safe measure in several disorders in psychiatry (depression, anxiety, addiction and schizophrenia) and neurology (stroke rehabilitation, movement disorders and migraine) (Wassermann and Zimmermann 2012). Chronic pain as an unpleasant and disabling somatosensory symptom very similar to vertigo has also been altered successfully by means of rTMS. The aim of our project is to manipulate several established regions in the human cortex known to be involved in the processing of vestibular information. This manipulation would be performed by temporary virtual lesioning by rTMS. We would then investigate if the perception of vertigo triggered in healthy subjects by three established artificial vestibular stimulations after the prior rTMS intervention is altered. The following obstacles lie ahead. Differently than hypothesized, vertigo as an errant perceptual multisensory integration phenomenon might be represented by a network state in the brain rather than the arousal of a single region. Vertigo may also be generated in a bi-hemispheric interplay making our focus on the right cortex questionable. Both problems would require multi-region rTMS instead of the planned one-target approach. Another potential bottleneck could be that inhibitory rTMS might actually lead to a worsening of the artificial vertigo symptoms induced by the battery of vestibular provocations. In this case, we plan to switch to a protocol inducing facilitatory effects (Hoogendam, Ramakers et al. 2010). Vestibular cortical regions might also be more susceptible to state-dependent or primed rTMS. As a solution we would add blocks of galvanic stimulation just prior to the rTMS sessions.

 

References (*own work):

Afif A, Minotti L, Kahane P, Hoffmann D. 2011. Anatomofunctional organization of the insular cortex: a study using intracerebral electrical stimulation in epileptic patients. Epilepsia 51:2305-2315.

Anteraper SA, Whitfield-Gabrieli S, Keil B, Shannon S, Gabrieli JD, Triantafyllou C. 2013. Exploring functional connectivity networks with multichannel brain array coils. Brain Connect 3:302-315.

Chen L, A TV, Xu J, Moeller S, Ugurbil K, Yacoub E, Feinberg DA. 2015. Evaluation of highly accelerated simultaneous multi-slice EPI for fMRI. Neuroimage 104:452-459.

Dieterich M, Bense S, Lutz S, Drzezga A, Stephan T, Bartenstein P, Brandt T. 2003. Dominance for vestibular cortical function in the non-dominant hemisphere. Cereb Cortex 13:994-1007.

Dieterich M, Brandt T. 2001. Vestibular system: anatomy and functional magnetic resonance imaging. Neuroimaging Clin N Am 11:263-273, ix.

Fredrickson JM, Scheid P, Figge U, Kornhuber HH. 1966. Vestibular nerve projection to the cerebral cortex of the rhesus monkey. Exp Brain Res 2:318-327.

Grusser OJ, Pause M, Schreiter U. 1990. Localization and responses of neurones in the parieto-insular vestibular cortex of awake monkeys (Macaca fascicularis). The Journal of physiology 430:537-557.

Guldin WO, Grüsser OJ. 1998. Is there a vestibular cortex? Trends Neurosci 21:254-259.

Kahane P, Hoffmann D, Minotti L, Berthoz A. 2003. Reappraisal of the human vestibular cortex by cortical electrical stimulation study. Ann Neurol 54:615-624.

Kaza E, Klose U, Lotze M. 2011. Comparison of a 32-channel with a 12-channel head coil: are there relevant improvements for functional imaging? J Magn Reson Imaging 34:173-183.

Keil B, Blau JN, Biber S, Hoecht P, Tountcheva V, Setsompop K, Triantafyllou C, Wald LL. 2013. A 64-channel 3T array coil for accelerated brain MRI. Magn Reson Med 70:248-258.

Lopez C, Blanke O. 2011. The thalamocortical vestibular system in animals and humans. Brain Res Rev.

Pandya DN, Sanides F. 1973. Architectonic parcellation of the temporal operculum in rhesus monkey and its projection pattern. Z Anat Entwicklungsgesch 139:127-161.

Stephan T, Deutschländer A, Nolte A, Schneider E, Wiesmann M, Brandt T, Dieterich M. 2005. Functional MRI of galvanic vestibular stimulation with alternating currents at different frequencies. NeuroImage 26:721-732.

Wiggins GC, Polimeni JR, Potthast A, Schmitt M, Alagappan V, Wald LL. 2009. 96-Channel receive-only head coil for 3 Tesla: design optimization and evaluation. Magn Reson Med 62:754-762.

Xu J, Moeller S, Auerbach EJ, Strupp J, Smith SM, Feinberg DA, Yacoub E, Ugurbil K. 2013. Evaluation of slice accelerations using multiband echo planar imaging at 3 T. Neuroimage 83:991-1001.

*zu Eulenburg P, Caspers S, Roski C, Eickhoff SB. 2012. Meta-analytical definition and functional connectivity of the human vestibular cortex. Neuroimage 60:162-169.

*zu Eulenburg P, Muller-Forell W, Dieterich M. 2013. On the recall of vestibular sensations. Brain Struct Funct 218:255-267.

 

Relevant publications:

zu Eulenburg, P., Baumgärtner, U., Treede, R.D., Dieterich, M., 2013. Interoceptive and multimodal functions of the operculo-insular cortex: tactile, nociceptive and vestibular representations. NeuroImage 83,75-86

zu Eulenburg, P., Müller-Forell, W., Dieterich M., 2013. On the recall of vestibular sensations. Brain Structure & Function 218(1):255-267

zu Eulenburg, P., Caspers, S., Roski, C., Eickhoff, S.B., 2012. Meta-analytical definition and functional connectivity of the human vestibular cortex. NeuroImage 60:162-169.

        NeuroWiss - Grundlagenpreis 2012 Frankfurt/Main

zu Eulenburg, P., Stoeter, P., Dieterich, M., 2010. Voxel-based morphometry depicts central compensation after vestibular neuritis. Ann Neurol 68(2):241-249.

Schlindwein, P., 2009. Die elektrophysiologische Untersuchung des vestibulo-collischen        Reflexes (VCR). Klinische Neurophysiologie 40, 170-176.

Schlindwein, P., Mueller, M., Bauermann, T., Brandt, T., Stoeter, P., Dieterich, M., 2008.

Cortical representation of saccular vestibular stimulation: VEMPs in fMRI. NeuroImage 39, 19-31.

Dieterich, M., Bauermann, T., Best, C., Stoeter, P., Schlindwein, P., 2007.

Evidence for cortical visual substitution of chronic bilateral vestibular failure (an fMRI study). Brain130, 2108-2116.

 

 

Team:

peter platzhalter

Univ.-Prof. Dr. med.
Peter zu Eulenburg

Dr. med. Maxine Ria Rühl

Contact:

Univ.-Prof. Dr. med. Peter zu Eulenburg

German Center for Vertigo & Dizziness

Feodor-Lynen-Straße 19 81377 Munich, Germany

Tel: + 49 (0) 89 4400 74822

Fax: + 49 (0) 89 4400 74801

Email: Peter.zu.Eulenburg@med.uni-muenchen.de