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Boegle, Rainer E. (2017): Modulation of the central vestibular networks through aging and high-strength magnetic fields: Implications for studies of vestibular function with functional magnetic resonance imaging. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)
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Abstract

The importance of the vestibular system usually goes unnoticed in our daily lives and its significance is only experienced by patients suffering from vestibular diseases. The vestibular system is essential for orientation in space, and perception of motion, as well as keeping balance, and maintaining stable visual perception while moving in a three-dimensional world. Functional imaging has long been used to study the multisensory vestibular network in healthy subjects, as well as in patients with diseases of the vestibular system. The majority of these previous studies sought to associate brain areas with vestibular processing, by evaluating increases or decreases in blood-oxygen-level dependent signal (BOLD-signal) during application of artificial vestibular stimulations. However, many basic network properties of the multisensory vestibular cortical network still remain unknown. Since it is now possible to infer networks from functional connectivity analysis, that associates areas into networks based on their spatiotemporal signal behavior, a few of the remaining questions can be addressed. The dynamics of the vestibular networks and other co-activated networks in regard to the processing of a multisensory stimulation remain largely unknown. Do subjects of different ages respond differently to a vestibular challenge? Furthermore, a new form of vestibular stimulation, termed magnetic vestibular stimulation (MVS), has recently been discovered. It occurs in strong magnetic fields (≥1.5 tesla), that are commonly used in functional magnetic resonance imaging (fMRI), and raises questions about a possible modulation of vestibular networks during fMRI, potentially biasing functional neuroimaging results. The purpose of this thesis is to develop suggestions for studying the multisensory vestibular network and the influence of vestibular modulations on resting-state networks with fMRI. The focus lies on basic scientific investigations of (1) the influence of aging on the ability of subjects to respond to a challenge of the multisensory vestibular network and (2) the modulatory influence of magnetic fields (the MR environment) on functional imaging and resting-state networks in general. To this end, we carried out two studies. The first study was a cross-sectional aging study investigating the modulation of vestibular, somatosensory and motor networks in healthy adults (N=39 of 45 in total, age 20 to 70 years, 17 males). We used galvanic vestibular stimulation (GVS) to stimulate all afferences of the peripheral vestibular end organs or vestibular nerve in order to activate the entire multisensory vestibular network, as age-associated changes might be specific to sensory processing. We also controlled for changes of the motor network, structural fiber integrity (fractional anisotropy – FA), and volume changes to simultaneously compare the effects of aging across structure and function. The second study investigated the influence of the static magnetic field of the MR environment in a group of healthy subjects (N=27 of 30 in total, age 21 to 38 years, 19 females), as it was recently shown that a strong magnetic field produces a vestibular imbalance in healthy subjects. We examined MVS at field strengths of 1.5 tesla and 3 tesla. The associated spontaneous nystagmus, the scaling of the nystagmus’ slow phase velocity (SPV) across field strengths, the between subject variance of the SPV were analysed, and the analogous scaling relationship was identified in the modulation of resting-state network amplitudes, like the default mode network (DMN), between 1.5 tesla and 3 tesla to reveal its effect on fMRI results. Aging and MVS modulated networks associated with vestibular function and resting-state networks known for vestibular interactions. The results from our aging study imply that the dynamics of vestibular networks is limited by the influence of aging even in healthy adults without any noticeable vestibular deficit. Vestibular networks show a decline of functional connectivity with age and an increase of temporal variability (in excess of stimulation induced changes) with age. In contrast somatosensory and motor networks did not show any significant linear relationship with age or any significant changes between the youngest and oldest participants. Age-associated structural changes (gray matter volume changes or structural connectivity changes) did not explain the decline in functional connectivity or increase in temporal variability. Furthermore, stimulation thresholds did not change with age (nor did they correlate with the functional connectivity amplitudes or temporal variability), indicating that the age-associated changes that were found for the vestibular network, were not dependent on peripheral decline, as GVS is thought to directly stimulate the vestibular nerve. The results from our study of the influence of the static magnetic field of the MR environment showed that MVS was already present at a field strength of 1.5 tesla, as evident from the induced nystagmus, indicating a state of vestibular imbalance. Furthermore, MVS scaled linearly with field strength between 1.5 tesla and 3 tesla, and identified the effects of MVS in the scaling of functional resting-state network fluctuations, showing that MVS does indeed influence resting-state networks due to vestibular imbalance. Specifically, MVS does influence DMN resting-state network dynamics in accordance with the predicted scaling of MVS based on the Lorentz-force model for MVS. These results taken together not only imply that subjects were in a vestibular state of imbalance, but also that the extent and direction of the state of imbalance showed more variance between subjects with increasing field strength. In summary, the following suggestions for vestibular research can be delineated to extend the kind of questions that can be answered by functional MRI experiments and to improve these investigations for the benefit of clinically relevant research of healthy controls and patients. Regarding the influence of age, we suggest that researchers comparing patients with vestibular deficits and healthy controls should separate the age-matched group into age-strata (non-overlapping subgroups with different age spans, e.g. 20-40 years, 40-60 years and above 60 years of age). Each stratum should be compared and interpreted separately given that different age-groups have different levels of vestibular network dynamics available for compensation (or responding to a challenge). This is particularly relevant when patients show a wide age-distribution, e.g. in the case of vestibular neuritis patients. With respect to the influence of magnetic fields, we suggest that MVS should be seen as a new way of manipulating networks that either process vestibular information or show vestibular interactions, by using strong magnetic fields (≥1.5 tesla), as commonly used in MRI. The potential of modulating vestibular influences on networks via MVS lies in being able to induce or manipulate vestibular imbalances. In the healthy this can be used to create states that are similar to the diseased state, but without peripheral or central lesions. In patients this will allow to extend or reduce vestibular imbalances. In both cases this can be done while performing functional MRI simply by using the magnetic field of the MRI scanner and adjusting the head position of the subject in question. In studies that need to avoid vestibular perturbations MVS should be controlled by adjusting the head position of the subject and measuring the resulting eye movements. This should then be seen as an effort to remove unwanted variance, i.e., as an effort to homogenize the group, and achieve better statistical results due to less (uncontrolled) MVS interference that increases bias and variance with increasing field strength. In summary, these suggestions result in three short questions that researchers could ask themselves when thinking about vestibular research projects in the future. Age-grouping: “Is the response to a challenge different for younger adults than older adults, i.e., does each age-group compensate differently?” MVS modulation: “Can a manipulation of the imbalance state of our subjects with MVS help us to reveal more about the vestibular network’s response to a challenge or should we avoid interference by MVS in the imbalance state of our subjects?” Sensitivity: “Is the measure that I want to use sensitive enough to show the differences that I am looking for?” Connectivity and temporal variability might be sensitive enough, but many clinical tests might not be sufficient.