Persistent postural perceptual dizziness (PPPD) is a common functional vestibular disorder that is triggered and sustained by a complex interaction between physiological and psychological factors affecting spatial orientation and postural control. Past functional neuroimaging research and one recent structural (i.e., voxel-based morphometry-VBM) study have identified alter- ations in vestibular, visuo-spatial, and limbic brain regions in patients with PPPD and anxiety-prone normal individuals. However, no-one thus far has employed surface based morphometry (SBM) to explore whether cortical morphology in patients with PPPD differs from that of healthy people. We calculated SBM measures from structural MR images in 15 patients with PPPD and compared them to those from 15 healthy controls matched for demographics, personality traits known to confer risk for PPPD as well as anxiety and depressive symptoms that are commonly comorbid with PPPD. We tested for associations between SBM measures and dizziness severity in patients with PPPD. Relative to controls, PPPD patients showed significantly decreased local gyrification index (LGI) in multi-modal vestibular regions bilaterally, specifically the posterior insular cortices, supra-marginal gyri, and posterior superior temporal gyri (p < 0.001). Within the PPPD group, dizziness severity positively correlated with LGI in visual areas and negatively with LGI in the right superior parietal cortex. These findings demonstrate abnormal cortical folding in vestibular cortices and correlations between dizziness severity and cortical folding in visual and somatosensory spatial association areas in PPPD patients, which provides new insights into the pathophysiological mechanisms underlying this disorder. . . . . Keywords Persistent postural perceptual dizziness Surface based morphometry Local gyrification index Vestibular cortex Occipital cortex Superior parietal cortex Introduction characterized by persistent dizziness, unsteadiness, and swaying or rocking (non-spinning) vertigo (Staab et al. Persistent postural perceptual dizziness (PPPD) is a chronic 2017). These symptoms may be exacerbated by upright pos- functional vestibular disorder that lies at the interface ture, patients’ own movements, and exposure to environments between neurology, otology, and psychiatry. Clinically, it is containing complex and moving visual stimuli. PPPD may be Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11682-018-9900-6) contains supplementary material, which is available to authorized users. * Luca Passamonti Department of Experimental and Clinical Medicine, University firstname.lastname@example.org MagnaGraecia, Catanzaro, Italy Department of Systems Medicine, University of Rome TorVergata, National Research Council, Institute of Bioimaging and Molecular Rome, Italy Physiology, Catanzaro, Italy Departments of Psychiatry and Psychology and Centre of Space BioMedicine, University of Rome TorVergata, Otorhinolaryngology – Head and Neck Surgery, Mayo Clinic, Rome, Italy Rochester, MN, USA 3 7 Laboratory of Neuromotor Physiology, IRCCS Santa Lucia Department of Clinical Neurosciences, University of Cambridge, Foundation, Rome, Italy Cambridge CB2 0SZ, UK Brain Imaging and Behavior triggered by neurotologic or other medical and psychological extraversion was found in a significantly larger proportion of events that cause vertigo, unsteadiness, or dizziness or disrupt patients with CSD than in a comparison group of patients with balance, including peripheral vestibular disorders, vestibular other vestibular disorders who had similar levels of dizziness, migraine, panic attacks, generalized anxiety disorders, mild anxiety, and depression (67% vs. 25%) (Staab et al. 2014). traumatic brain injury, and hypotensive episodes (Dieterich High levels of neuroticism were also reported in Italian pa- and Staab 2017; Staab et al. 2017). tients with CSD (Chiarella et al. 2016) and Chinese patients In the midst of these events, patients shift posture and gait with PPPD (Yan et al. 2017).On the other hand, German indi- control from a relaxed position to a high-risk strategy of great- viduals with higher ratings of resilience, optimism, and sense er stiffness and shorter strides similar to what normal individ- of coherence experienced a lower incidence of functional diz- uals do in situations of increased postural threat such as stand- ziness after acute vestibular events (Tschan et al. 2011). ing or walking at heights (Brown et al. 2002; Gage et al. Pre-existing anxiety disorders were also linked to the de- 2003). Patients with acute vestibular symptoms also rely more velopment of PPV and CSD after acute neurotologic illnesses strongly on visual or somatosensory cues than vestibular in- and premorbid personal or family histories of anxiety disor- puts for postural control and spatial orientation, a process ders were associated with poorer response to selective seroto- known as visual or somatosensory dependence (Cousins et nin reuptake inhibitors (Staab and Ruckenstein 2005), the al. 2014). Normally, as patients recover from conditions that mainstay of pharmacologic treatment in PPPD. Furthermore, cause vestibular or balance problems, they revert back to nat- five prospective studies showed that high anxiety and body urally relaxed postural control and return to a more cohesive vigilance in the setting of acute vestibular disorders predicted combination of vestibular, visual, and somatosensory cues for persistent PPPD-like dizziness far better than measures of determining spatial orientation. However, patients who devel- structural vestibular deficits, including one Australian investi- op persistent dizziness fail to return to low-risk postural con- gation that demonstrated a durable reduction in symptoms trol and maintain high levels of visual dependence, even if with just three cognitive behavior therapy sessions adminis- they otherwise recover or fully compensate for the events that tered within eight months of the acute illness (i.e., before precipitated their initial symptoms (Staab 2012; Staab et al. chronic symptoms had consolidated) (Best et al. 2009; 2013; Staab and Ruckenstein 2007). These persistent func- Cousins et al. 2017; Edelman et al. 2012; Godemann et al. tional alterations in postural control and spatial orientation 2005; Heinrichs et al. 2007). Together, these studies from four are thought to be key pathophysiologic mechanisms underly- continents indicate that anxiety-related personality traits and a ing PPPD; thus, it is considered to be a chronic functional pre-existing anxiety diathesis are risk factors for PPPD and disorder (Staab 2012). that high anxiety and body vigilance promote its development. A formal definition of PPPD was recently promulgated by In contrast, there is less evidence that anxiety-related factors the World Health Organization (World Health Organization are necessary to sustain PPPD after it is well established. 2016) and the Bárány Society, the international neurotologic Around 40% of patients with PPPD have no active anxiety research organization (Staab et al. 2017). However, observa- disorders (25% have no psychiatric morbidity at all) (Staab tions of similar symptoms may be found in the original de- 2012)and 8–12 sessions of cognitive behavioral therapy con- scription of agoraphobia from 1871 (Westphal 1871) and de- ducted in patients with long-standing PPV offered no lasting bates about the relative contributions of neurologic, otologic, benefit (Holmberg et al. 2006, 2007). and psychologic factors to difficulties that certain individuals Neuroimaging studies are beginning to provide evidence had with locomotion, spatial orientation, and avoidance be- for the brain mechanisms by which anxiety-related personality haviors in the rambunctious marketplaces of nineteenth cen- traits may influence the processing of vestibular and visual tury town squares (Balaban and Jacob 2001). Contemporary information for spatial orientation and locomotion. Two func- predecessors of PPPD include phobic postural vertigo (PPV) tional magnetic resonance imaging (fMRI) studies performed (Brandt and Dieterich 1986), space motion discomfort (Jacob in healthy individuals showed that anxiety-related personality et al. 1989), visual vertigo (Bronstein 1995), and chronic sub- traits affect activity and functional connectivity patterns with- jective dizziness (CSD) (Staab et al. 2004). Epidemiologic in vestibular, visual, and limbic areas of the brain (Indovina et studies of these conditions indicate that PPPD is the second al. 2014; Riccelli et al. 2017a). The first investigation used or third most common cause of dizziness among patients re- vestibular stimulation from a short tone burst that activates ferred to tertiary neurotologic clinics (Staab 2012). the otoliths (Indovina et al. 2014). The second one used visual Earlier studies explored potential etiopathogenic and path- motion stimulation from an immersive virtual reality ophysiological mechanisms of PPPD or its predecessors, find- rollercoaster ride (Riccelli et al. 2017a). In the first study, ing that distinct personality traits confer risk for PPPD or higher levels of neuroticism, measured by the NEO protect against its development (Chiarella et al. 2016; Personality Inventory Revised (NEO-PI-R) (Costa and Indovina et al. 2015; Staab et al. 2014). Specifically, in a study McCrae 1997), correlated positively with activity in the from the USA, a combination of high neuroticism and low brainstem, bilateral cerebellar fastigium, and left visual cortex Brain Imaging and Behavior and negatively with activity in the left supramarginal gyrus. related stimuli (Balaban and Thayer 2001; Staab et al. High levels of introversion (i.e., low extraversion scores) cor- 2013). However, comparing the results from normal individ- related with increased activity in the amygdala. Higher levels uals showing neuroticism-associated increased activity and of neuroticism were also linked to heightened connectivity connectivity in these brain regions to the findings from pa- between the amygdala and brainstem, amygdala and tients with PPPD showing decreased activity and connectivity, fastigium, left inferior frontal gyrus and left supra-marginal it is clear that more information is needed about how the brain gyrus, and left inferior frontal gyrus and left visual cortex structure and function relate to the development of PPPD. In (Indovina et al. 2014). Introversion correlated negatively with addition, the use of sophisticated structural imaging tech- connectivity between the right amygdala and inferior frontal niques, particularly surface-based morphometry (SBM), may gyrus. In the second study, neuroticism scores correlated pos- allow differentiation of the contributions played by key neu- itively with activity in the left posterior insular cortex (PIC), roanatomical markers (i.e., cortical thickness, surface area, another component of the non-dominant vestibular cortex, and and cortical folding) to alterations in the anatomy of the cor- with increased functional connectivity between the left PIC tical mantle. It also may enable to disentangle among features and right amygdala. Thus, in response to vestibular and visual such as the gray-matter changes recently observed in a VBM motion stimuli, anxiety-related personality traits in normal study of patients with PPPD (Wurthmann et al. 2017). This is individuals were associated with greater reactivity and con- an important issue as cortical thickness, surface area, and cor- nectivity in key brain regions that process vestibular, visual, tical folding are thought to have distinct developmental trajec- and threat-related information and with increased responses in tories and cellular mechanisms (Rakic 2009; Raznahan et al. visual areas (Riccelli et al. 2017a). 2011). More specifically, cortical thickness (CT) depends on Two recent fMRI studies using sound-evoked vestibular the horizontal layers within the cortical columns, while the stimulation and visual motion stimulation compared patients surface area (SA) relates to the number of radial columns with PPPD to a group of normal individuals matched for perpendicular to the pial surface (Dale et al. 1999;Panizzon NEO-PI-R personality traits, anxiety and depression et al. 2009;Rakic 2009). In contrast, the cortical folding re- (Indovina et al. 2015; Riccelli et al. 2017b). Relative to con- sults from the underlying microstructure of the neuronal trols, patients with PPPD showed reduced activation in re- sheets and from the local connectivity within a cortical region sponse to vestibular stimulation of the right posterior insula (Schuez and Miller 2003; White et al. 2010). and adjacent superior temporal gyrus (components of the The purpose of the current study was thus to search for dominant vestibular cortex) as well as in the left anterior insula morphological changes across the cortical mantle in PPPD, extending into the frontal operculum and the left inferior fron- considering the possibility that any identified abnormalities tal gyrus, the left anterior cingulate cortex, and the left hippo- could represent previously undetected structural causes or risk factors for the disorder or secondary structural alterations in- campus. Patients with PPPD also had more negative function- al connectivity between the right superior temporal gyrus and duced by persistent shifts in physiological functioning. We both the left anterior cingulate cortex and left hippocampus as employed well-validated SBM techniques to examine cortical well as between the left anterior insula/inferior frontal gyrus surface anatomy in patients with PPPD relative to a group of and right middle occipital cortex (Indovina et al. 2015). healthy controls. On the basis of previous studies (Balaban Furthermore, patients with PPPD showed alterations in brain and Thayer 2001; Indovina et al. 2015; Staab et al. 2013, networks that affect balance control and reweighting of space- 2014; Wurthmann et al. 2017), we hypothesized that patients motion inputs to favor visual cues (Riccelli et al. 2017b). The with PPPD, relative to healthy people, would show alterations results of a recent resting state fMRI study were consistent in CT, SA, and cortical folding in brain regions belonging to with these findings, showing that patients with PPPD, relative vestibular, visual, and emotional neural networks. to healthy controls, had decreased connectivity between the Specifically, we predicted abnormalities in surface morpholo- left hippocampus and the bilateral temporal, insular, central gy in the vestibular cortex (PIC, parietal operculum, posterior opercular, and occipital cortices (Lee et al. 2018). Similarly, a superior temporal gyrus, and supramarginal gyrus) (Bense et recent structural imaging investigation found that patients al. 2001; Bottini et al. 2001;Lacquanitiet al. 2013; Lopez et with PPPD, relative to healthy controls, had decreased gray al. 2012), visual cortex (Cousins et al. 2014;Indovina et al. matter volume as assessed via voxel-based morphometry 2015), and frontal regions that regulate anxiety-related behav- (VBM) in the temporal cortex, cingulate cortex, precentral iors (inferior frontal gyrus, and anterior cingulate cortex). gyrus, hippocampus, dorsolateral prefrontal cortex, caudate Informed by our previous neuroimaging work (Indovina et nucleus, and the cerebellum (Wurthmann et al. 2017). al. 2015), we wanted to minimize the potential confounds of Together, these data strongly suggest that PPPD may be psychological variables on the results of the structural analy- linked to functional and structural alterations in crucial vestib- ses as there is evidence that these factors may be significantly ular, visual, and frontal regulatory regions of the brain, includ- associated with variations in cortical morphology, even in ing those that modulate attention and response to threat- healthy people with no psychiatric disorders (Riccelli et al. Brain Imaging and Behavior 2017c). Therefore, we matched our patients with PPPD to a 120 months with a median of 18 months (see also Table 1). group of healthy controls on standardized measures of person- The severity of impairment due to dizziness was measured in ality traits, anxiety, and depression. patients with PPPD using the Dizziness Handicap Inventory (DHI) (Jacobson and Newman 1990). DHI scores ranged from 10 to 60, indicating a range of low to severe handicap with a Methods mean ± SD of 34 ± 16.1. Generalized Anxiety Disorder (GAD-7) (Spitzer et al. 2006) scores in PPPD patients ranged Participants from 1to18with a mean±SDof8.86±5.2. Only five patients had a score higher than the cut-off of 10. All Fifteen right-handed patients who had developed PPPD after patients were also evaluated with the Mini-International an acute vestibular syndrome (see below for further details) Neuropsychiatric Inventory (MINI) to detect active psychiat- were enrolled in this study. All patients had fully recovered or ric illnesses. In a confirmatory analysis to exclude the effects compensated for their peripheral vestibular conditions at the of active psychiatric disorders, we removed five patients with time of study entry. This cohort overlaps to the one that we PPPD who showed active psychiatric comorbidities when investigated in our previous fMRI study of CSD. Subjects assessed with the MINI (Tables S1 in Supplementary were recruited for that investigation using the diagnostic Materials). Of note, none of the patients with psychiatric co- criteria for CSD, but their clinical histories were verified morbidities were receiving psychoactive drugs. against the definitions of PPPD posted by the World Health We enrolled fifteen healthy volunteers who were Organization (http://www.who.int/classifications/icd/en) and matched to the PPPD group in terms of sex, age, and Bárány Society, specifically: (i) one or more symptoms of scores on self-reports of generalized anxiety (GAD-7) non-vertiginous dizziness, unsteadiness, or swaying-rocking and depression (Patient Health Questionnaire [PHQ-9]) (non-spinning) vertigo lasting 3 months or more, (ii) symp- (Kroenke et al. 2001). We selected healthy controls with toms present most days, throughout the day (though they may overall personality profiles that matched our patients wax and wane), (iii) symptoms exacerbated by upright pos- with PPPD based on a computerized version of the ture, active or passive head motion, and exposure to moving Italian translation of the revised version of the NEO personal- or complex visual stimuli. Exclusion criteria for this study ity inventory (NEO-PI-R) (Costa and McCrae 1997). All par- included active neuro-otologic disorders other than PPPD, ticipants gave written informed consent to participate in this chronic medical illnesses, pregnancy, medication use, study, which was approved by a local ethical committee, in smoking, and history of head injury. accordance with the declaration of Helsinki (http://www.wma. A history of quiescent or fully compensated vestibular pe- net/en/30publications/10policies/b3/). ripheral deficits at the time of study was not an exclusion criterion. This was because otologic illnesses are known to MRI scanning, MRI data quality control be the most common triggers of PPPD (Staab and and processing Ruckenstein 2003, 2007), as was the case in our patient group. In particular, most of our patients with PPPD had a history of MRI brain scans were obtained from all participants using a 3 vestibular neuritis (N = 12), while a few of them had experi- Tesla Unit with an 8-channel head coil (Discovery MR-750, enced benign paroxysmal positional vertigo (N =2)orboth General Electric, Milwaukee, WI). Head movements were (N = 1). These disturbances were localized on the right side in minimized using foam pads around participants’ heads. The seven patients, left side in seven patients, or bilaterally in one MRI protocol included a whole-brain T1-weighted scan patient. Patients with PPPD who had vestibular neuritis [SPGR; Echo Time (ET) 3.7 ms, Repetition Time (TR) underwent caloric testing in the acute stage of their peripheral 9.2 ms, flip angle 12°, voxel size 1.0 × 1.0 × 1.0 mm ]. vestibular disease and 6 months later to evaluate the adequacy Images were first screened for scanner artifacts, motion of their recovery. The percentage of reduced vestibular re- abnormalities, and gross neuroanatomical alterations by a con- sponse on the electronystagmogram was calculated using the sultant neurologist and a consultant neuroradiologist. Next, Jongkees’ formula (Furman and Jacob 1993), which revealed the T1-weighted images were analyzed using Freesurfer soft- mild to moderate unilateral canal paresis (relative vestibular ware (version 5.3.0) (http://www.nmr.mgh.harvard.edu/ reduction in the nystagmus slow-phase velocity peak) across martinos) to create anatomical surface models for statistical patients in the acute stage (mean = 35%, range 25–45%) and analyses (Dale et al. 1999;Fischlet al. 1999;Fischl and return to normal values 6 months later (mean = 13%, range 5– Dale 2000). For each participant, the processing pipeline in- 20%). Patients who experienced benign paroxysmal position- cluded removal of non-brain tissue, transformation to al vertigo as a trigger for PPPD had no symptoms or signs of Talairach space, segmentation of gray and white matter tis- active positional vertigo at the time of entry into the study. The sues, intensity normalization, tessellation of the gray/white duration of illness for patients with PPPD ranged from 8 to matter boundaries, automated topology correction, and Brain Imaging and Behavior Table 1 Demographic, clinical, Demographic and clinical measures PPPD patients Healthy controls Group differences and neuroimaging characteristics in patients with Persistent (n =15) (n = 15) Postural Perceptual Dizziness Mean ± SD Mean ± SD χ ,T, p-values (PPPD) and healthy controls Sex (Number of men & women) 9/6 7/8 χ =0.53; p <0.46 Age (years) 33.4 ± 12.4 30.1 ± 5.6 T = −0.92; p <0.36 Generalized anxiety disorder 8.8 ± 4.8 7.47 ± 4.5 T = −0.82; p <0.42 scale (GAD-7) Patient health questionnaire 8.6 ± 5.2 5.6 ± 5.0 T = −1.59; p <0.12 (PHQ-9) NEO personality inventory – revised (NEO-PI-R) factors Neuroticism 56.2 ± 10.7 55.0 ± 9.8 T = −0.30; p <0.76 Extraversion 51.1 ± 7.9 53.3 ± 10.2 T =0.66; p <0.51 Openness 45.2 ± 10.4 53.0 ± 10.1 T =2.04; p <0.05 Agreeableness 43.4 ± 8.4 47.5 ± 8.4 T =1.31; p <0.20 Conscientiousness 49.7 ± 8.7 49.6 ± 9.2 T = −0.03; p <0.97 Total gray-matter volume (ml) 614.3 ± 62.4 631.8 ± 69.2 T =0.73; p <0.47 Total intracranial volume (ml) 1519.5 ± 185.6 1533.6 ± 227.1 T =0.19; p <0.85 Dizziness handicap inventory (DHI) 34.0 ± 17.1 N/A – Disease duration (months) 32.53 ± 37.2 N/A surface deformation. To map each participant to a common for multiple comparisons, cluster correction was completed space, the surface representing the gray matter–white matter using Monte Carlo simulation (vertex-wise cluster forming boundary was registered to an average cortical surface atlas by threshold of p < 0.05) at a cluster-wise p-value (CWP) of p using a non-linear procedure that optimally aligned sulcal and < 0.05 (Hagler et al. 2006). Age and gender were included as gyral features across participants. covariates of no interest in all analyses. Individual mean CT Cortical thickness was defined by the shortest distance be- values were used as nuisance variables in the CT analysis tween the gray/white matter border and pial surfaces. Vertex- while total intracranial volume was considered as a variable based estimates of SA were obtained by computing the aver- of no interest in analyses that involved SA and cortical volume age of the area of the triangles incident to that vertex (Dale et as outcome measures. Total SA was chosen as a covariate in al. 1999; Fischl et al. 1999; Fischl and Dale 2000). Cortical the LGI analysis as there is an evidence that it has linear volume (CV) was defined as the product of CT and SA. To relationship with gyrification (Luders et al. 2006). In CT, calculate the LGI, an additional outer hull layer that tightly SA, and CV analyses, a smoothing kernel of 5-mm Full wrapped the pial surface was defined. Next, the LGI value at Width at Half Maximum (FWHM) was used. In the each vertex was computed within 25-mm circular regions of gyrification analyses, no smoothing kernel (FWHM = 0 mm) interest and represented by the ratio of the pial to outer hull was employed because the LGI implemented in Freesurfer is surfaces (Schaer et al. 2012). All images were inspected visu- already relatively smoothed by default (Schaer et al. 2012). ally to check for reconstruction errors including skull-strip errors, gross segmentation problems, and inaccuracies in the white-matter and pial surface reconstruction. Surface inaccu- Results racies were corrected manually with Freesurfer’s editing tools. Edited images were re-processed through the Freesurfer pipe- Demographics, clinical variables, and general line. This cycle was repeated until all surface errors were structural neuroimaging data corrected. Table 1 summarizes the demographics, clinical variables, and Statistical analyses general structural neuroimaging data (e.g. total intracranial volume) for the PPPD and healthy control groups. There were A general linear model (GLM) was used to identify between- no significant differences in mean age, sex distribution, or group differences in CT, SA, cortical volume, and LGI. For mean scores on the GAD-7, PHQ-9, or in four of the five the PPPD group, correlations between subject specific SBM NEO-PI-R personality factors. Although scores for openness measures at each vertex and individual DHI scores and illness differed statistically between groups, both patients and con- duration were also assessed for each hemisphere. To control trols had mean scores within the normative range for the Brain Imaging and Behavior general population (standardized scores of 45–55). This im- Discussion plies that the NEO-PI-R profiles of both groups was reason- ably matched for personality traits. Likewise, there were In this study, we used SBM methods to measure cortical mor- no significant differences in total gray matter volume or phology in patients with PPPD and to examine relationships intracranial volume between patients with PPPD and among cortical thickness, surface area, local gyrification index healthy controls indicating a good match between sub- (cortical folding), and severity and duration of dizziness. We ject groups on these demographic, psychological, and general found that patients with PPPD, relative to healthy controls, anatomical variables. had decreased cortical folding in key brain regions that com- prise the posterior insula, superior temporal gyrus and sulcus, Relationship between cortical morphology and supra-marginal gyrus. Decreased cortical folding extend- ed to parietal and temporo-occipital association areas, specif- and dizziness severity or disease duration ically the inferior and superior parietal gyrus, pre-cuneus, cuneus, inferior and middle temporal gyri, and lateral occipital Relative to healthy controls, patients with PPPD had signifi- cantly decreased mean values for the LGI in the posterior gyrus, in the right hemisphere, which is the dominant hemi- insular cortex, superior temporal gyrus, superior temporal sul- sphere for vestibular function in right-handed individuals. The cus, supra-marginal gyrus, precentral gyrus bilaterally, as well regions surrounding the posterior Sylvian fissure and extend- as in the inferior and superior parietal gyri, pre-cuneus, ing into adjacent temporal, parietal and occipital association cuneus, inferior and middle temporal gyri and lateral occipital areas have been strongly implicated in processing and inte- gyrus in the right hemisphere, and finally in the post-central grating multi-sensory inputs from vestibular, visual, and so- gyrus and parietal operculum in the left hemisphere (Fig. 1, matosensory systems (Brandt 1999; Guldin and Grüsser 1998; Table 2). Most of these results were confirmed when remov- Indovina et al. 2005;Lacquaniti etal. 2013; Lopez et al. 2012; Lopez and Blanke 2011; zu Eulenburg et al. 2012). They also ing the PPPD patients with psychiatric comorbidities from the main analyses. In particular, PPPD patients without psychiat- play important roles in processing data related to motion of self, body posture, location, and movements of external ob- ric comorbidities continued to show decreased LGI in the superior and middle temporal pole gyri, supra-marginal jects (Panizzon et al. 2009; Schuez and Miller 2003;White et gyrus and lateral occipital gyrus in the right hemisphere al. 2010), allowing highly mobile animals like humans to con- (see Table S1, Supplementary Materials). There were no struct coherent, internal maps of spatial orientation and motion significant differences between groups in CT, SA, or of self and objects in the environment (Indovina et al. 2013, cortical volumes. In the PPPD group, DHI scores corre- 2016; Lacquaniti et al. 2013; Riccelli et al. 2017a, b;Schuez lated positively with the LGI in the right lingual gyrus and Miller 2003; White et al. 2010). and right lateral occipital gyrus and negatively with the We observed no effects for CT and SA which suggests that LGI in the right superior parietal lobule (Fig. 2, Table 3). cortical folding alterations may be the primary structural marker of PPPD. There may also be an important relationship Disease duration correlated positively with the LGI in the right lateral orbitofrontal gyrus, right superior parietal gyrus, right between areas with decreased LGI that we identified in this study and regions with reduced functional connectivity that inferior frontal gyrus (pars opercularis), left lateral occipital gyrus, left fusiform gyrus, and left superior parietal gyrus we found in our previous fMRI study of this same patient (Fig. 3). cohort. Structural and functional abnormalities corresponded Fig. 1 Cortical areas showing significantly decreased local Superior Temporal Gyrus (posterior part) and PIC, Posterior gyrification index in PPPD patients relative to healthy controls. Insular Cortex. Color bar represents -log (P value). R, L, Labels refer to peaks: SMGg, Supra-marginal gyrus; STG, right/left hemisphere Brain Imaging and Behavior Table 2 Cortical areas displaying Local gyrification index significantly decreased local gyrification index in patients with HCs > PPPD Persistent Postural Perceptual Dizziness (PPPD) relative to Hemisphere Max Size CWP Regions healthy controls (HCs). Whole- brain local gyrification index Left 4.29 3461.1 <0.001 Superior Temporal Gyrus results derived from FreeSurfer. Superior Temporal Sulcus Correction for multiple Posterior insula comparisons was performed using Monte Carlo simulation Post-central Gyrus (vertex-wise cluster forming Supra-marginal Gyrus threshold of p < 0.05) at a cluster- 2.44 545.7 0.025 Pre-central Gyrus wise p-value (CWP) of p <0.05. Post-central Gyrus Age and gender were included as covariates of no interest. CWP, Inferior Frontal Gyrus (pars opercularis) cluster-wise P corrected level Hemisphere Max Size CWP Regions Right 4.06 8919.1 <0.001 Supra-marginal Gyrus Pre-central Gyrus Superior Temporal Gyrus Superior Temporal Sulcus Posterior insula Inferior Parietal Cortex Superior Parietal Cortex Pre-cuneus Cuneus Inferior Temporal Gyrus 2.42 696.8 <0.001 Middle Temporal Gyrus Lateral Occipital Gyrus in the right vestibular cortex, specifically in the right superior Alternatively, the SBM changes in PPPD that we identified temporal gyrus. The significance of these parallel results lies in this study may develop as a result of changes in physiolog- in the tension-based theory of morphogenesis, which posits ical functioning that are hypothesized to be key mechanisms that folding of the cortical mantle is a consequence of mechan- of PPPD, that is, areas of brain plasticity resulting from altered ical tension along the axons that connect different brain re- postural control and changes in multi-sensory space-motion gions (Van Essen 1997). Hence, reduced cortical folding may information processing. result from weakening of network connectivity across poste- The significant correlations between LGI and clinical fea- rior temporo-parietal cortical areas centered around the supe- tures such as the DHI scores and disease duration in patients rior temporal gyrus. Our findings of both reduced gyrification with PPPD offer further clues regarding the additional neural and altered connectivity in this key component of the domi- mechanisms that may contribute to the core symptoms of the nant vestibular cortex amplifies our previous suggestion that disorder and their exacerbation by moving or complex visual alterations in activity and connectivity in this region may un- stimuli. DHI scores positively related with the cortical folding derlie the core symptoms of persistent unsteadiness and dizzi- in the right lingual gyrus and the lateral occipital gyrus, while ness as well as their exacerbation by upright posture in pa- they were negatively related to cortical folding in the right tients with PPPD (Staab 2012). The folding alterations ob- superior parietal lobule. These results are consistent with served in the superior temporal gyrus, middle temporal gyrus physiologic studies of patients with persistent visually in- and right precentral gyrus also confirm the gray matter alter- duced dizziness triggered by various structural vestibular dis- ations reported in these regions in a recent VBM study orders (Bronstein 2005, 2004; Bronstein et al. 2013; Cousins (Wurthmann et al. 2017). et al. 2014; Guerraz et al. 2001) and with computerized dy- It is not possible to determine from a cross-sectional study namic posturographic measurements in patients with PPPD (Ödman and Maire 2008; Söhsten et al. 2016), which demon- whether the changes in cortical folding are a primary or sec- ondary phenomena. In the case they predate the onset of strated over reliance on visual stimuli for perception of verti- PPPD, they may represent a structural risk factor, that is, an cality and control of posture (i.e., visual dependence). Thus, area of vulnerability in the brain that limits healthy recovery structural and functional alterations in the multimodal vestib- following exposure to factors that precipitate PPPD. ular cortex coupled with structural changes in opposite Brain Imaging and Behavior Fig. 2 Cortical areas showing significantly negative (in blue) and positive (in red) correlation between Dizziness Handicap Inventory (DHI) and local gyrification index in Persistent Postural Perceptual Dizziness (PPPD) patients. Residual (Res_) scores are shown in the Y and X axes Table 3 Cortical areas showing significantly positive and negative multiple comparisons was performed using Monte Carlo simulation correlation between local gyrification index (LGI) and clinical variables (vertex-wise cluster forming threshold of p < 0.05) at a cluster-wise p- (Dizziness Handicap Inventory (DHI) and illness duration) in Persistent value (CWP) of p < 0.05. Age and gender were included as covariates of Postural Perceptual Dizziness (PPPD) patients. Whole-brain local no interest. CWP, cluster-wise P corrected level gyrification index results derived from FreeSurfer. Correction for LGI – DHI Positive correlation Hemisphere Max Size (mm ) CWP Regions Right 2.72 966.3 0.002 Lateral Occipital Gyrus 2.33 1978.7 <0.001 Lingual Gyrus Negative correlation Hemisphere Max Size (mm ) CWP Regions Right −2.22 874.6 0.004 Superior parietal Lobule LGI – Illness duration Positive correlation Hemisphere Max Size (mm ) CWP Regions Right 3.697 1073.9 <0.001 Inferior frontal Gyrus, pars opercularis 3.010 1109.2 <0.001 Lateral Orbitofrontal Gyrus 2.401 2734.0 <0.001 Superior parietal Lobule Left 3.848 1519.6 <0.001 Lateral Occipital Gyrus 3.589 2608.4 <0.001 Fusiform Gyrus 2.321 1064.2 0.002 Superior parietal Lobule Brain Imaging and Behavior Fig. 3 Cortical areas showing significantly negative (in blue) and positive (in red) correlation between illness duration and local gyrification index in Persistent Postural Perceptual Dizziness (PPPD) patients. Residual (Res_) scores are shown in the Y and X axes directions in visual and somatosensory association areas patients with PPPD which implies that replication in which are important for processing spatial information may larger samples is warranted. Third, our groups were underlie the phenomenon of visual dependence and its clinical not perfectly matched on age and sex although there manifestation as hypersensitivity to complex or moving visual were no statically significant differences in these demo- stimuli in patients with PPPD. graphic variables. Fourth, this is a cross-sectional study Curiously, we found no differences in cortical mor- which means that future research will have to examine phology between PPPD and healthy controls in anterior patients with PPPD prospectively to ascertain when the regions of the brain that are involved in modulating brain morphological changes identified here develop, anxiety or threat-related behaviors. This can be due to i.e., if they are primary or secondary alterations to the the fact that our PPPD and control groups were closely initial event that triggers PPPD. It will also be impor- matched on psychological variables so that our between tant to assess in longitudinal studies the extent to which group analyses would not have detected abnormalities in the brain structural or function alterations in PPPD can cortical structure if they were related solely to these be modified by available treatments for PPPD. Last but psychological variables. not least, forthcoming studies should include groups of Some limitations of this study should also be acknowl- patients with psychiatric and neuro-otological disorders edged. First, SBM metrics do not allow characterization of who have not developed PPPD to confirm and extend gray matter abnormalities that might be present at the subcor- the current findings and demonstrate their specificity to tical level. 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Central set influences on gait. Experimental Brain Research, 084-R.0). Luca Passamonti is funded by the Medical Research Council 145(3), 286–296. https://doi.org/10.1007/s00221-002-1082-0. (MRC) (MR/P01271X/1) at the University of Cambridge, UK. Chiarella, G., Petrolo, C., Riccelli, R., Giofrè, L., Olivadese, G., Gioacchini, F. M., Scarpa, A., Cassandro, E., & Passamonti, L. (2016). Chronic subjective dizziness: Analysis of underlying per- Compliance with ethical standards sonality factors. Journal of Vestibular Research: Equilibrium & Orientation, 26(4), 403–408. https://doi.org/10.3233/VES-160590. Conflict of interest The authors declare that there is no conflict of inter- Costa, P. T., & McCrae, R. R. (1997). Stability and change in personality est regarding the publication of this article. assessment: The revised NEO personality inventory in the year 2000. Journal of Personality Assessment, 68(1), 86–94. https://doi. Ethical approval All procedures performed in studies involving human org/10.1207/s15327752jpa6801_7. participants were in accordance with the ethical standards of the institu- Cousins, S., Cutfield, N. J., Kaski, D., Palla, A., Seemungal, B. M., tional and/or national research committee and with the 1964 Helsinki Golding, J. F., Staab, J. P., & Bronstein, A. M. (2014). Visual de- declaration and its later amendments or comparable ethical standards. pendency and dizziness after vestibular neuritis. PLoS One, 9(9), e105426. https://doi.org/10.1371/journal.pone.0105426. Informed consent Informed consent was obtained from all individual Cousins, S., Kaski, D., Cutfield, N., Arshad, Q., Ahmad, H., Gresty, M. participants included in the study. A., Seemungal, B. M., Golding, J., & Bronstein, A. M. (2017). Predictors of clinical recovery from vestibular neuritis: A prospec- Open Access This article is distributed under the terms of the Creative tive study. 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