Author response: Lying in a 3T MRI scanner induces neglect-like spatial attention bias
2021-09-02

Article Figures and data Abstract Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract The static magnetic field of MRI scanners can induce a magneto-hydrodynamic stimulation of the vestibular organ (MVS). In common fMRI settings, this MVS effect leads to a vestibular ocular reflex (VOR). We asked whether – beyond inducing a VOR – putting a healthy subject in a 3T MRI scanner would also alter goal-directed spatial behavior, as is known from other types of vestibular stimulation. We investigated 17 healthy volunteers, all of which exhibited a rightward VOR inside the MRI-scanner as compared to outside-MRI conditions. More importantly, when probing the distribution of overt spatial attention inside the MRI using a visual search task, subjects scanned a region of space that was significantly shifted toward the right. An additional estimate of subjective straight-ahead orientation likewise exhibited a rightward shift. Hence, putting subjects in a 3T MRI-scanner elicits MVS-induced horizontal biases of spatial orienting and exploration, which closely mimic that of stroke patients with spatial neglect. Introduction Roberts et al., 2011 observed that healthy subjects who were exposed to the static magnetic field of 3T and 7T MRI scanners developed a persistent horizontal nystagmus in complete darkness. Since then, this effect was replicated by various groups (e.g. Mian et al., 2013; Boegle et al., 2016) and was shown to be present for standard fMRI settings at 1.5T and 3T (Boegle et al., 2016). Moreover, these studies have further corroborated the initial conclusion by Roberts et al., 2011 that the nystagmus is caused by Lorentz forces that result from the interaction of the static magnetic field of the scanner and ionic currents in the endolymph fluid of the subject's labyrinth (see Ward et al., 2019 for review). This force acts upon the cupulae of the horizontal and anterior semicircular canals, inducing a mixed horizontal and torsional nystagmus (Otero-Millan et al., 2017). The stronger horizontal component comprises of a slow horizontal vestibular ocular reflex (VOR) that is accompanied by fast resetting saccades in the opposite direction. In natural settings, a stimulation of the horizontal canals occurs, for instance, when our head is accelerated to the left or to the right. The resulting VOR then smoothly moves our eyes in the direction opposite to the head rotation. The VOR thus supports – together with the visually induced optokinetic reflex – the stabilization of the retinal image despite head-motion (for review e.g. see Ilg, 1997; Angelaki and Cullen, 2008). Roberts et al., 2011 (p.1638) pointed out that the fake head-motion signal induced by magneto-hydrodynamic vestibular stimulation (MVS) 'carries important ramifications and caveats for functional MRI studies, not only of the vestibular system but of cognition, motor control, and perception in general'. For instance, Boegle et al., 2016 observed that MVS does indeed modulate fMRI-signal fluctuations. This modulation affected the default mode network as a function of the strength of the magnetic field and mainly in areas associated with vestibular and oculomotor function. Thus, MVS induces balance shifts in resting-state network dynamics that might be 'like a "special patient group with a vestibular imbalance" but without lesions in the inner ear or central nervous system' (Boegle et al., 2016; p.420). However, do these functional modulations by MVS also alter behavioral responses? Would the mere exposure to the uniform magnetic field within a 3T MRI scanner already produce the characteristic biases of spatial orientation and exploration that we know to occur with vestibular stimulation? For example, in healthy subjects, caloric vestibular stimulation (CVS) of one external auditory canal not only induces a VOR but also provokes 'neglect-like' behavioral phenomena. Stroke patients with spatial neglect show a tonic deviation of head and eyes towards the ipsilesional side and no longer explore or orient towards large parts of space contralateral to their lesion and therefore neglect contralesionally located people or objects (Heilman et al., 1983; Karnath, 2015, for a review). In healthy volunteers, CVS induces a tonic bias of head orientation around the yaw axis (Karnath et al., 2003) and a tonic shift of the average horizontal eye position (Abderhalden, 1926; Jung, 1953). Both of these orientation biases resemble those observed in neurological patients suffering from spatial neglect (cf. Fruhmann-Berger and Karnath, 2005): already at rest, that is when doing nothing, these patients' head and eyes are tonically deviated towards the ipsilesional side. Moreover, CVS in darkness even induces a bias in subjective straight-ahead (SSA) in healthy subjects, mimicking the bias of the SSA in neglect patients towards their ipsilesional side (e.g. Karnath et al., 1994c; Chokron and Imbert, 1995; Kapoor et al., 2001). Finally, CVS biases healthy subjects' scan path during visual search (Karnath et al., 1996): when exploring their surroundings for possible targets subjects' eye movements are no longer symmetrically distributed in the horizontal dimension but biased towards one side of the body's midsaggital plane. Also this CVS-induced horizontal bias in spatial attention is resembled by the spontaneous, asymmetrical, spatially biased exploratory behavior of neglect patients (Karnath et al., 1996; Karnath et al., 1998), leading to 'spatial neglect' of one side of the surrounding scene. Conversely, it is possible to compensate the spontaneous biases of neglect patients through CVS (Rubens, 1985; Karnath, 1994b; Vallar et al., 1995; Karnath et al., 1996; Rode et al., 1998; for review e.g. see Rossetti and Rode, 2002). In the present study, we asked whether these behavioral effects on spatial orientation and exploration known from CVS are likewise induced by MVS through exposure to a static magnetic field of a 3T MRI scanner. We hypothesized that MVS should induce a horizontal bias in both the exploratory scan path during visual search and in the SSA of healthy subjects, resembling the horizontal biases of neglect patients. Results To address our research question we analyzed oculomotor behavior of 17 healthy subjects inside and outside a standard 3T MRI scanner (Siemens MAGNETOM Prisma). All subjects provided their informed consent according to the guidelines of our institutional ethics board. Parts of our procedures resembled that of typical fMRI experiments (compare Figure 1—figure supplement 1 and Materials and methods for further details): We placed our subjects with their back on the scanner table and their head rested inside a 20-channel head-coil. A mirror was mounted on top of the head-coil to provide subjects with an indirect view on our custom-made black 'visual search-screen'. The screen was placed behind the coil inside the scanner bore at about 110 cm viewing distance. Various glass-fiber-cables penetrated the screen at discrete locations and allowed us presenting small visual stimuli by feeding these cables with LED light signals. Maximal target distance from the screen center amounted to ±12° visual angle in the horizontal direction and to –5° to 6° in the vertical direction. An IR-video-camera unit was mounted next to the mirror to record a video-signal of subjects' right eye. The study was conducted in complete darkness by extinguishing all light sources and covering subjects with a black blanket. This was important, as any visible stimulus that would be present in subjects' visual field, could help them to suppress a MVS-induced VOR as well as to explore the visual scene and to perform the SSA task in an unbiased fashion. To probe for the putative MVS-effects on spatial orienting and exploration we designed an experiment comprising of three consecutive phases: (i) an initial 'outside 1' phase with our subjects on the scanner-table at its maximal horizontal displacement from the scanner center (head coil at ~125 cm horizontal [0 cm vertical] displacement); the strength of the magnetic field in this position is roughly 10 times smaller than at the scanner center (compare Figure 1—figure supplement 1); (ii) a subsequent 'inside' phase with the subject's head being in the center of the scanner bore where the strength of the uniform magnetic field is 3 Tesla; (iii) as well as a final 'outside 2' phase that was identical to outside 1. Accordingly, any MVS effect on behavior or attention that we would observe during these three phases should be stronger for inside as compared to the two outside phases. Each phase started with an initial 'calibration task' for eye-tracking (see Materials and methods section for details). We next instructed subjects to fixate at a dim light-point presented in the center of their visual field for 5 s. Then the dim light-point was switched off and the subjects had to 'look straight ahead' for 60 s in complete darkness ('looking straight-ahead task'). Finally, we asked subjects to find and fixate transient light stimuli. During this 'visual search task', we presented six search targets (each slowly fading-in over a period of 5 s). Locations of search targets were pseudorandomized across phases and between participants. The presentation of these stimuli only served to maintain the subjects' motivation to search for possible targets. Our interest was the spatial distribution of subjects' overt spatial attention, as assessed by their exploratory scan path in the absence of any visual targets. Thus, for most of the time (i.e. 140 s; total duration of visual search task: 172 s), no visible target was present and subjects were searching in complete darkness. For data analysis we discarded the time periods with targets present (plus an additional grace period of 5 s after a light stimulus was turned off; this was done to prevent carry-over effects from prior target-fixation). The search task always ended with a central light stimulus presented during the last 2 s (also not considered for data analysis). Please refer to Materials and methods for detailed information on the time-course of our experiment. Figure 1 illustrates the resulting eye-data of an exemplary subject throughout all tasks and phases. It shows that during the inside phase the typical saw-tooth-like eye movement pattern, which is characteristic for a vestibular nystagmus, was observed (also compare Video 1). It consisted of a slow rightward VOR that was accompanied by fast resetting saccades in the opposite leftward direction. This prototypical nystagmus-pattern was largely reduced for the outside 1 phase and it was practically absent for the outside 2 phase. To express the strength of the VOR quantitatively, we calculated the median de-saccaded horizontal eye-velocity (starting 5 s after the offset of the central light stimulus). This estimate is reflected by the blue lines in the respective horizontal eye-velocity time-courses shown in the middle column of Figure 1. Figure 1 with 2 supplements see all Download asset Open asset MVS-induced oculomotor behavior. The figure provides exemplary data from an individual subject. The three task phases are represented by individual rows. Horizontal eye position data from the looking straight-ahead task are shown in the left column. The figure inset additionally expands parts of the inside time course to better illustrate the alternation between the slow phase VOR toward the right and the fast resetting saccades directed in the opposite direction. Saccade endpoints are depicted by the cyan circles and the blue lines reflect the respective SSA estimates. Corresponding horizontal eye velocity traces of the looking straight ahead-task are shown in the middle column. Note that the cyan peaks in these time-courses refer to individual saccades, which have been removed from the eye velocity records to allow estimation of slow-phase velocity in isolation (the blue lines indicate the respective horizontal VOR-estimates). Finally, 2D eye-position eye data from the visual search task are depicted in the rightmost column (time periods with search targets plus 5 s are excluded). The horizontal center of visual search is depicted by the blue vertical lines, reflecting the median of horizontal saccade endpoints (cyan circles). Positive values indicate the rightward/upward direction. Video 1 Download asset This video cannot be played in place because your browser does support HTML5 video. You may still download the video for offline viewing. Download as MPEG-4 Download as WebM Download as Ogg This video was taken after completion of our experiment. It serves to illustrate the MVS-induced effects on eye movements in complete darkness. There was no obvious horizontal nystagmus when the subject was outside the scanner (at a position identical to outside 1 and 2 phases). A pronounced horizontal nystagmus was present inside the scanner (and already when the subject was being moved into the scanner). The horizontal nystagmus was alleviated when moving the subject outside the scanner. At the outside position virtually no nystagmus was present. Note that longer exposure times to the magnetic field inside the MRI-scanner would typically lead to an aftereffect of the VOR in the opposite direction (e.g. compare Roberts et al., 2011). The same qualitative effects were present in all of our 17 subjects, as is shown in Figure 2. The average slow eye velocity for the outside 1 phase was 0.30°/s on average ( ± 0.49°/s standard deviation [SD]) and increased to 1.42°/s ( ± 1.49°/s SD) for the inside phase. After removing the subjects from the scanner bore to outside 2, average slow eye velocity decreased to –0.01°/s ( ± 0.40°/s SD). The within-subject differences in velocity between outside 1 and inside and between inside and outside 2 were significant (one-tailed paired t-test: t(16)=6.62, p < 0.001, g1[CI95%] = 1.60 [0.87, 2.32] and t(16)=6.69, p < 0.001, g1[CI95%] = 1.62 [0.88, 2.35], respectively). Average horizontal eye velocity during outside 1 was also slightly larger as compared to outside 2 (two-tailed paired t-test: t(16)=3.08, p = 0.007, g1[CI95%] = 0.75 [0.20, 1.28]). As expected (Otero-Millan et al., 2017), the MVS effects affected only horizontal eye movements of our 2D eye movement recordings and were absent in the vertical direction (outside 1: –0.29°/s ± 0.56°/s SD; inside: –0.29°/s ± 0.60°/s SD; outside 2: –0.21°/s ± 0.58°/s SD; statistical comparisons with two-tailed paired t-tests yielded no significant differences in vertical eye velocity between any of the three task phases [p > 0.20]). In summary, these data agree with earlier observations of an MVS-induced horizontal VOR (for review see Ward et al., 2019) and provide additional evidence for the consistent presence of this effect while being inside a 3T MRI scanner (Boegle et al., 2016). Figure 2 with 2 supplements see all Download asset Open asset MVS-induced increase in de-saccaded horizontal eye velocity towards the right. Horizontal eye velocity of individual subjects (circles, N = 17) are shown for all three task phases. Positive values denote rightward motion. The blue lines and the boxes reflect across subjects mean and standard error (SE; to account for our within-subject design, we removed the between-subject variance for calculation of the SE according to the procedure described by Masson and Loftus, 2003). The p-values of pairwise statistical comparisons are indicated in grey boxes. We next asked whether MVS also affects the distribution of overt attention in our visual search task. The rightmost column in Figure 1 demonstrates a 2D-plot of our exemplary subject's eye position during search, including only those time epochs when no target stimulus was presented. While the area of visual search for both outside phases was centered on the middle of the screen (which was aligned to the subject's body midline), the search space clearly deviated to the right when the subject was inside, while parts on the far left of the search-space were now neglected. This horizontal bias in our subject's exploratory eye movements was not a mere consequence of the rightward VOR inside the scanner but was likewise reflected by the distribution of overt attention, that is the endpoints of the saccades guiding visual search: the mean horizontal position of these saccade endpoints (indicated by the blue vertical lines in the rightmost plots in Figure 1) almost perfectly resembled the center of the search screen for the outside 1 and 2 phases, while it was clearly shifted to the right for the inside phase. Across our 17 subjects, statistical analysis of subjects' exploratory spatial behavior (Figure 3) revealed that the average horizontal mean of visual search was at 1.65° ( ± 4.40° SD) and at 1.01° ( ± 3.98° SD) for the outside 1 and 2 phases, respectively, while inside this measure was significantly shifted to 4.69° ( ± 4.61°) towards the right (one-tailed paired t-tests; outside 1 vs. inside: t(16)=-5.12, p < 0.001, g1[CI95%] = 1.24 [0.59, 1.87]; inside vs. outside 2: t(16)=4.38, p < 0.001, g1[CI95%] = 1.06 [0.45, 1.65]). The measures did not significantly differ between phases outside 1 and 2 (two-tailed paired t-test: t(16)=0.76, p = 0.46, g1[CI95%] = −0.18 [-0.66, 0.30]). Figure 3 with 1 supplement see all Download asset Open asset MVS-induced rightward bias in visual search. Individual subjects' horizontal mean saccade endpoints during visual search (in the absence of targets) are depicted as individual circles and for all three task phases (N = 17; positive values = right). The blue lines and the boxes reflect across subjects mean and SE (to account for our within-subject design, we removed the between-subject variance for calculation of the SE according to the procedure described by Masson and Loftus, 2003). The p-values of pairwise statistical comparisons are indicated in grey boxes. Finally, we asked whether the MVS-induced spatial bias would also affect the looking straight ahead task. To this end, we again focused on the horizontal distribution of saccade endpoints during this task, as they reflected subjects' voluntary attempt to continue looking straight ahead. For each subject and for each task phase, we calculated the median horizontal position of saccade endpoints (starting 5 s after the offset of the central light stimulus) as a proxy for the subjective straight-ahead (SSA). This measure is illustrated by the blue lines in the leftward column of Figure 1 for our exemplary subject. Similar to the horizontal shift of exploratory search behavior across task phases, also the looking straight ahead measure shifted. Initially, the SSA was close to the midline during the outside 1 phase. It shifted to the right for the inside phase and then back towards the left (with some overshoot) for the outside 2 phase. Across our 17 subjects, the SSA likewise exhibited a significant rightward shift from the outside 1 (1.79° ± 5.39° SD) to the inside (4.76° ± 4.02° SD) phase (one-tailed paired t-test: t(16)=-2.38, p = 0.015, g1[CI95%] = 0.58 [0.05, 1.08]; compare Figure 4). This effect vanished after removing subjects from the scanner in the outside 2 phase (0.26° ± 4.37° SD; one-tailed paired t-test: t(16)=3.56, p = 0.001, g1[CI95%] = 0.86 [0.29, 1.42]). There was no significant difference between the SSA for phases outside 1 and 2 (two-tailed paired t-test: t(16)=1.17, p = 0.26, g1[CI95%] = −0.28 [-0.76, 0.21]). Figure 4 with 1 supplement see all Download asset Open asset MVS-induced rightward bias in subjective straight-ahead (SSA). Individual subjects' SSA, namely the median horizontal saccade endpoint when to straight is depicted by individual circles for all three task phases (N = 17; positive values = right). The blue lines and the boxes reflect across subjects mean and SE (to account for our within-subject design, we removed the between-subject variance for calculation of the SE according to the procedure described by Masson and Loftus, 2003). The p-values of pairwise statistical comparisons are indicated in grey boxes. may whether being inside an MRI scanner might have to a in subjects' and that this – than the static magnetic field – could be the of the rightward biases in spatial attention (cf. et al., et al., 2019 for a and the perception of To out possible of as well as any other effect on subjects' behavior that could result from to we the of our experiment in six subjects, now the scanner in the that is with their The behind this was that the is when is with to the static magnetic field of the MRI-scanner (e.g. compare Roberts et al., while is no in or as compared to our experiment. In to the now we expected that the behavioral effects are as that is show a bias to the left of to the right side. We provide a detailed of this experiment in Figure 1—figure supplement 2. In subjects now exhibited a leftward VOR inside the scanner ± SD) as compared to both outside 1 and 2 phases ± 0.30°/s 0.49°/s ± SD) (see Figure supplement 1). the biases in overt spatial attention (outside 1: ± SD; inside: ± SD; outside 2: ± SD; see Figure supplement 1) and the perception of SSA (outside 1: ± SD; inside: ± SD; outside 2: ± SD; see Figure supplement 1) as In other the spatial biases were now toward the left side and thus in the direction by Finally, we exploratory to whether the MVS-induced in VOR would the observed in visual search and SSA across our the average in VOR velocity for the inside phase as compared to both outside 1 and 2 phases respective in both visual search = p < and in subjects' SSA = p < (also compare Figure supplement Discussion studies (for review see Ward et al., we observed a MVS-induced tonic horizontal VOR when inside a 3T MRI scanner. As compared to the outside 1 and 2 phases, this effect was present in subject. The velocity of the VOR inside the amounted to 1.42°/s during our looking straight-ahead task. Our task to an namely into the direction of a target LED in the reduced by about as compared to a without (cf. et al., et al., this our estimate well to the roughly VOR in an earlier MVS study, which a at 3T but without (Boegle et al., 2016). Our experiment further revealed that inside the 3T MRI scanner (in the common position in with head also to a spatially biased behavior when subjects were to straight ahead and when they were visual search. of we would to out that the respective biases in the looking straight ahead task and the visual search task were not a mere of the tonic of subjects' eyes toward the right. The behavioral measure in both tasks to the distribution of endpoints of subjects' voluntary saccades while they were to task The of subjects' eyes to the MVS-induced VOR does not this measure of spatial behavior (for further also Karnath et al., Hence, the shifts inside the scanner reflect a spatial bias in overt spatial attention and goal-directed (i) in the visual search task the center of subjects' visual (in the absence of any visible was shifted by roughly to the (ii) in the looking straight ahead task, the average endpoint of subjects' saccades in darkness likewise deviated toward the namely by about The MVS-induced in VOR that we observed in our study did the in visual search and in the SSA across experiments (compare Figure supplement we also revealed a significant of the rightward VOR from the outside 1 phase to the outside 2 phase. also the center of visual search as well as the SSA did differ between outside 1 and 2 phases, while being to midline for the outside 2 phase. these were not The in VOR from the outside 1 phase to the outside 2 phase could be the result of a VOR that been shown to occur for longer exposure to MVS at in the presence of spatial as from the the nervous system the MVS-induced tonic as is obvious from a slow but of the VOR over the course of to et al., 2016). or not the biases in the center of visual search and in the SSA could likewise be subjects to is an question for Our task was to qualitative effects of MVS on these measures (compare and does not their time-course of All well resemble the known effects of caloric vestibular stimulation on spatial exploration and After healthy subjects' about SSA, by orientation of a into this shifted (e.g. Karnath et al., 1994c; Karnath et al., Moreover, CVS likewise leads to a horizontal shift of healthy subjects' scan path during visual search (Karnath et al., known CVS-induced roughly between and and thus were slightly larger than the MVS-induced spatial bias observed in the present experiment. the CVS-induced biases in spatial behavior also when to straight ahead et al., and during spatial exploration (Karnath et al., This that CVS and also MVS does induce in spatial for goal-directed that are of spatial behavior are most of no vestibular in the but an system' with the vestibular at its (e.g. see and 1998; Karnath and and 2011 for The areas that this system further parts in the as well as in the anterior and in the and 1998; et al., Karnath and et al., et al., et al., and in of these areas have been shown to vestibular with and information about eye in a that them to visual in to the body (e.g. et al., and et al., This of spatial information for example, the of our goal-directed behavior including saccades, or (see Karnath, for review). also been in functional studies (e.g. et al., et al., and 2013; et al., It thus is that tonic MVS well as biases in these spatial leading to the of subjective straight ahead and spatial exploration (also compare and body was to the horizontal shifts in spatial behavior present in spatial neglect see Karnath, for a review). Moreover, the of lesions exhibited by patients with spatial neglect is largely with the system and a common (Karnath and Karnath and and Hence, MVS induces of spatial behavior in healthy subjects and these are to its with the the same system that is typically affected in patients suffering from spatial neglect. the the question