Neuroimaging Markers of Mal de Débarquement Syndrome

Abstract

Mal de débarquement syndrome (MdDS) is a motion-induced disorder of oscillating vertigo that persists after the motion has ceased. The neuroimaging characteristics of the MdDS brain state have been investigated with studies on brain metabolism, structure, functional connectivity, and measurements of synchronicity. Baseline metabolism and resting-state functional connectivity studies indicate that a limbic focus in the left entorhinal cortex and amygdala may be important in the pathology of MdDS, as these structures are hypermetabolic in MdDS and exhibit increased functional connectivity to posterior sensory processing areas and reduced connectivity to the frontal and temporal cortices. Both structures are tunable with periodic stimulation, with neurons in the entorhinal cortex required for spatial navigation, acting as a critical efferent pathway to the hippocampus, and sending and receiving projections from much of the neocortex. Voxel-based morphometry measurements have revealed volume differences between MdDS and healthy controls in hubs of multiple resting-state networks including the default mode, salience, and executive control networks. In particular, volume in the bilateral anterior cingulate cortices decreases and volume in the bilateral inferior frontal gyri/anterior insulas increases with longer duration of illness. Paired with noninvasive neuromodulation interventions, functional neuroimaging with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and simultaneous fMRI-EEG have shown changes in resting-state functional connectivity that correlate with symptom modulation, particularly in the posterior default mode network. Reduced parieto-occipital connectivity with the entorhinal cortex and reduced long-range fronto-parieto-occipital connectivity correlate with symptom improvement. Though there is a general theme of desynchronization correlating with reduced MdDS symptoms, the prediction of optimal stimulation parameters for noninvasive brain stimulation in individuals with MdDS remains a challenge due to the large parameter space. However, the pairing of functional neuroimaging and noninvasive brain stimulation can serve as a probe into the biological underpinnings of MdDS and iteratively lead to optimal parameter space identification.

Keywords: functional MRI; independent component phase coherence; mal de débarquement syndrome; noninvasive brain stimulation; persistent oscillating vertigo; positron emission tomography; voxel-based morphometry.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Cha, Ding and Yuan.

Figures

Figure 1

18F-FDG PET contrasts between mal de débarquement syndrome (MdDS) and controls (Ctrl) with differences of z > 3.3. Clusters are shown at z > 2.57 for the MdDS > Ctrl contrast and at z > 1.96 for the Ctrl > MdDS contrast for better visualization. Coordinates of peak significance are indicated in parentheses. In SPM, negative X-values are on the left and positive on the right. (A) MdDS > Ctrl: left entorhinal cortex/amygdala [Montreal Neurological Institute (MNI): −14, −8, −22], (a) sagittal view and (b) coronal view. (B) Ctrl > MdDS: (a) left superior medial gyrus (MNI: −8, 52, 36), (b) left middle frontal gyrus (MNI: −32, 18, 30), (c) left middle temporal gyrus (MNI: −50, −52, 8), (d) right insula/amygdala (MNI: 30, −2, −26 and 40, 2, −8), (e) left inferior temporal gyrus (MNI: −52, −38, −24), and (f) left superior temporal gyrus (MNI: −52, 0, −14). Figure adapted from Cha YH et al., PLOS One 2012 (4).

Figure 2

Resting-state functional connectivity reflected by Pearson correlation coefficients converted to z-scores (A) between the left entorhinal cortex/amygdala seed of hypermetabolism [entorhinal cortex/amygdala (EC/AG)] and regions of hypometabolism [left superior medial gyrus (SMG), left middle frontal gyrus (MFG), left superior temporal gyrus (STG), left inferior temporal gyrus (ITG), right insula (Insula), right amygdala (Amyg), and left middle temporal gyrus (MTG)], functionally defined frontal eye fields (FEF), motion-sensitive area V5 (V5), primary visual cortex V1 (V1), and anatomically defined superior parietal lobule (SPL). Connectivity for MdDS is shown in red; Controls (Ctrl) in blue. Connectivity differences of anterior to posterior nodes between MdDS and Ctrl participants are shown pictorially in (B). Figure adapted from Cha YH et al., PLOS One 2012 (4).

Figure 3

Baseline resting-state functional connectivity between the left and right dorsolateral prefrontal cortices (DLPFCs) and the ipsilateral entorhinal cortex as a function of symptom severity change after repetitive transcranial magnetic stimulation (rTMS) to the DLPFC. Individuals with higher baseline connectivity between the DLPFC and ipsilateral entorhinal cortex responded better to rTMS (A). The location of each DLPFC was determined from individualized neuronavigation targets aiming for the anterior portion of the middle of the middle frontal gyrus (B). Coordinates of the entorhinal cortex were determined from individual structural scans. Figure adapted from Yuan et al., Brain Connectivity 2017 (49).

Figure 4

Percent change in vertigo intensity measured as a visual analog scale change from pre to post stimulation. Negative deflections represent a decrease in symptoms; positive deflections, an increase in symptoms. (A) Participants in the dorsolateral prefrontal cortex (DLPFC) repetitive transcranial magnetic stimulation (rTMS) study (24 at baseline with one dropout). (B) Participants in the occipital/cerebellar theta burst study (26 participants with one dropout). Figure adapted from Cha YH et al., Brain Stimulation 2016 (50). and Cha YH et al., Otology Neurotology 2019 (51).

Figure 5

Coronal view of a selection of brain regions with volume changes as a function of duration of illness of mal de débarquement syndrome (MdDS). Blue indicates volume decrease with duration of illness; red indicates volume increase with duration of illness. Coordinates of peak significance are indicated in parentheses. In SPM, negative X-values are on the left and positive on the right. ACC, anterior cingulate cortex [Montreal Neurological Institute (MNI): ±2, 40, 13). IFG/AI: inferior frontal gyrus/anterior insula (MNI: −26, 30, −3 and 27, 24, 4). MFG: middle frontal gyrus (MNI: −42, 15, 43). Lob I–IV: cerebellar lobules I–IV (MNI: −6, −38, −17 and 8, −50, −27). Lob VIII: cerebellar lobule VIII (18, −66, −55). Images are shown at the Y coordinate indicated above each image. Figure adapted from Cha YH and Chakrapani S, PLOS One 2015 (53).

Figure 6

Independent component phase coherence (ICPC) changes reflected as increases (blue) and decreases (red) of ICPC as a function of treatment response to repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) (A). As a function of treatment response, connectivity in the high alpha, beta, and gamma, and delta bands decrease, while connectivity in the low alpha band increases with treatment response. Changes in the theta frequency are mixed. Baseline connectivity as a function of treatment response (blue represents high, and red represents low) in (B). Baseline connectivity is high across all frequency bands in treatment responders. Lines connecting independent components are weighted for higher statistical significance. Dashed lines indicate connectivity that both changes and predicts treatment response. Figure adapted from Cha YH et al., Brain Connectivity 2018 (70).