Structural connectome and connectivity lateralization of the multimodal vestibular cortical network.

Unlike other sensory systems, the structural connectivity patterns of the human vestibular cortex remain a matter of debate. Based on their functional properties and hypothesized centrality within the vestibular network, the 'core' cortical regions of this network are thought to be areas in the posterior peri-sylvian cortex, in particular the retro-insula (previously named the posterior insular cortex-PIC), and the subregion OP2 of the parietal operculum. To study the vestibular network, structural connectivity matrices from n=974 healthy individuals drawn from the public Human Connectome Project (HCP) repository were estimated using multi-shell diffusion-weighted data followed by probabilistic tractography and spherical-deconvolution informed filtering of tractograms in combination with subject-specific grey-matter parcellations. Weighted graph-theoretical measures, modularity, and 'hubness' of the multimodal vestibular network were then estimated, and a structural lateralization index was defined in order to assess the difference in fiber density of homonym regions in the right and left hemisphere. Differences in connectivity patterns between OP2 and PIC were also estimated. We found that the bilateral intraparietal sulcus, PIC, and to a lesser degree OP2, are key 'hub' regions within the multimodal vestibular network. PIC and OP2 structural connectivity patterns were lateralized to the left hemisphere, while structural connectivity patterns of the posterior peri-sylvian supramarginal and superior temporal gyri were lateralized to the right hemisphere. These lateralization patterns were independent of handedness. We also found that the structural connectivity pattern of PIC is consistent with a key role of PIC in visuo-vestibular processing and that the structural connectivity pattern of OP2 is consistent with integration of mainly vestibular somato-sensory and motor information. These results suggest an analogy between PIC and the simian visual posterior sylvian (VPS) area and OP2 and the simian parieto-insular vestibular cortex (PIVC). Overall, these findings may provide novel insights to the current models of vestibular function, as well as to the understanding of the complexity and lateralized signs of vestibular syndromes.

White matter microstructure of the extended limbic system in male and female youth with conduct disorder.

BACKGROUND: Previous studies of conduct disorder (CD) have reported structural and functional alterations in the limbic system. However, the white matter tracts that connect limbic regions have not been comprehensively studied. The uncinate fasciculus (UF), a tract connecting limbic to prefrontal regions, has been implicated in CD. However, CD-related alterations in other limbic tracts, such as the cingulum and the fornix, have not been investigated. Furthermore, few studies have examined the influence of sex and none have been adequately powered to test whether the relationship between CD and structural connectivity differs by sex. We examined whether adolescent males and females with CD exhibit differences in structural connectivity compared with typically developing controls. METHODS: We acquired diffusion-weighted magnetic resonance imaging data from 101 adolescents with CD (52 females) and 99 controls (50 females). Data were processed for deterministic spherical deconvolution tractography. Virtual dissections of the UF, the three subdivisions of the cingulum [retrosplenial cingulum (RSC), parahippocampal and subgenual cingulum], and the fornix were performed and measures of fractional anisotropy (FA) and hindrance-modulated orientational anisotropy (HMOA) were analysed. RESULTS: The CD group had lower FA and HMOA in the right RSC tract relative to controls. Importantly, these effects were moderated by sex - males with CD significantly lower FA compared to male controls, whereas CD and control females did not differ. CONCLUSIONS: Our results highlight the importance of considering sex when studying the neurobiological basis of CD. Sex differences in RSC connectivity may contribute to sex differences in the clinical presentation of CD.

Functional activity changes in memory and emotional systems of healthy subjects with déjà vu.

Déjà vu (DV) is a fascinating and mysterious human experience that has attracted interest from psychologists and neuroscientists for over a century. In recent years, several studies have been conducted to unravel the psychological and neurological correlates of this phenomenon. However, the neural mechanisms underlying the DV experience in benign manifestations are still poorly understood. Thirty-three healthy volunteers completed an extensive neuropsychiatric and neuropsychological battery including personality evaluation. The presence of DV was assessed with the Inventory for Deja vu Experiences Assessment. Participants underwent episodic memory learning test, and 2 days later during event-related functional magnetic resonance imaging (fMRI), they are asked to rate old and new pictures as a novel, moderately/very familiar, or recollected. We identified 18 subjects with DV (DV+) and 15 without DV (DV-) matched for demographical, neuropsychological, and personality characteristics. At a behavioral level, no significant difference was detected in the episodic memory tasks between DV+ and DV-. Functional magnetic resonance imaging analysis revealed that DV+, independently from task conditions, were characterized by increased activity of the bilateral insula coupled with reduced activation in the right parahippocampal, both hippocampi, superior/middle temporal gyri, thalami, caudate nuclei, and superior frontal gyri with respect to DV-. Our study demonstrates that individuals who experienced DV are not characterized by different performance underlying familiarity/recollection memory processes. However, fMRI results provide evidence that the physiological DV experience is associated with the employment of different neural responses of brain regions involved in memory and emotional processes.

Sex differences in risk-based decision making in adolescents with conduct disorder.

Altered decision making processes and excessive risk-seeking behaviours are key features of conduct disorder (CD). Previous studies have provided compelling evidence of abnormally increased preference for risky options, higher sensitivity to rewards, as well as blunted responsiveness to aversive outcomes in adolescents with CD. However, most studies published to date have focused on males only; thus, it is not known whether females with CD show similar alterations in decision making. The current study investigated potential sex differences in decision making and risk-seeking behaviours in adolescents with CD. Forty-nine adolescents with CD (23 females) and 51 control subjects (27 females), aged 11-18 years, performed a computerised task assessing decision making under risk-the Risky Choice Task. Participants made a series of decisions between two gamble options that varied in terms of their expected values and probability of gains and losses. This enabled the participants' risk preferences to be determined. Taking the sample as a whole, adolescents with CD exhibited increased risk-seeking behaviours compared to healthy controls. However, we found a trend towards a sex-by-group interaction, suggesting that these effects may vary by sex. Follow-up analyses showed that males with CD made significantly more risky choices than their typically developing counterparts, while females with CD did not differ from typically developing females in their risk-seeking behaviours. Our results provide preliminary evidence that sex may moderate the relationship between CD and alterations in risk attitudes and reward processing, indicating that there may be sex differences in the developmental pathways and neuropsychological deficits that lead to CD.

Neuroticism modulates brain visuo-vestibular and anxiety systems during a virtual rollercoaster task.

Different lines of research suggest that anxiety-related personality traits may influence the visual and vestibular control of balance, although the brain mechanisms underlying this effect remain unclear. To our knowledge, this is the first functional magnetic resonance imaging (fMRI) study that investigates how individual differences in neuroticism and introversion, two key personality traits linked to anxiety, modulate brain regional responses and functional connectivity patterns during a fMRI task simulating self-motion. Twenty-four healthy individuals with variable levels of neuroticism and introversion underwent fMRI while performing a virtual reality rollercoaster task that included two main types of trials: (1) trials simulating downward or upward self-motion (vertical motion), and (2) trials simulating self-motion in horizontal planes (horizontal motion). Regional brain activity and functional connectivity patterns when comparing vertical versus horizontal motion trials were correlated with personality traits of the Five Factor Model (i.e., neuroticism, extraversion-introversion, openness, agreeableness, and conscientiousness). When comparing vertical to horizontal motion trials, we found a positive correlation between neuroticism scores and regional activity in the left parieto-insular vestibular cortex (PIVC). For the same contrast, increased functional connectivity between the left PIVC and right amygdala was also detected as a function of higher neuroticism scores. Together, these findings provide new evidence that individual differences in personality traits linked to anxiety are significantly associated with changes in the activity and functional connectivity patterns within visuo-vestibular and anxiety-related systems during simulated vertical self-motion. Hum Brain Mapp 38:715-726, 2017. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Individual differences in depression are associated with abnormal function of the limbic system in multiple sclerosis patients.

BACKGROUND: Depression is common in patients with multiple sclerosis (MS), although the brain mechanisms of this psychiatric condition in MS are poorly understood. Specifically, it remains to be determined whether depression in MS is related to altered activity and functional connectivity patterns within limbic circuits. METHODS: Seventy-seven MS patients with variable levels of depression (as assessed via the Beck Depression Inventory) underwent functional magnetic resonance imaging while performing an emotional processing task. To conduct the functional connectivity analyses, the bilateral amygdala and hippocampus, two areas critically involved in the pathophysiology of depression, were chosen as 'seed' regions. Multiple regression models were used to assess how depression in MS patients was correlated with the activity and functional connectivity patterns within the limbic system. RESULTS: Depression scores in MS patients were negatively correlated: (1) with the activity in the subgenual cingulate cortex; (2) with the functional connectivity between the hippocampus and orbitofrontal cortex as well as the dorsolateral prefrontal cortex, and (3) with the functional connectivity between the amygdala and dorsolateral prefrontal cortex. CONCLUSIONS: Our study showed that individual differences in depression in MS patients were significantly associated with altered regional activity and functional connectivity patterns within the limbic system.

Structural 'connectomic' alterations in the limbic system of multiple sclerosis patients with major depression.

BACKGROUND: Major depression (MD) is a common psychiatric disorder in multiple sclerosis (MS). Despite the negative impact of MD on the quality of life of MS patients, little is known about its underlying brain mechanisms. OBJECTIVE: We studied the whole-brain connectivity patterns that were associated with MD in MS. Alterations were mainly expected within limbic circuits. METHODS: Diffusion tensor imaging data were collected in 20 MS patients with MD, 22 non-depressed MS patients and 16 healthy controls. We used deterministic tractography and graph analysis to study the white-matter connectivity patterns that characterized MS patients with MD. RESULTS: We found that MD in MS was associated with increased local path length in the right hippocampus and right amygdala. Further analyses revealed that these effects were driven by an increased shortest distance between both the right hippocampus and right amygdala and a series of regions including the dorsolateral and ventrolateral prefrontal cortex, orbitofrontal cortex, sensory-motor cortices and supplementary motor area. CONCLUSION: Our data provide strong support for neurobiological accounts positing that MD in MS is mediated by abnormal 'communications' within limbic circuits. We also found evidence that MD in MS may be linked with connectivity alterations at the limbic-motor interface, a group of regions that translates emotions into survival-oriented behaviors.

Reduced cortical folding in multi-modal vestibular regions in persistent postural perceptual dizziness.

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 alterations 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.

Brain responses to virtual reality visual motion stimulation are affected by neurotic personality traits in patients with persistent postural-perceptual dizziness.

OBJECTIVE: Persistent postural perceptual dizziness (PPPD) is a common vestibular disorder of persistent dizziness and unsteadiness, exacerbated by upright posture, self-motion, and exposure to complex or moving visual stimuli. Previous functional magnetic resonance imaging (fMRI) studies found dysfunctional activity in the visual-vestibular cortices in patients with PPPD. Clinical studies showed that the anxiety-related personality traits of neuroticism and introversion may predispose individuals to PPPD. However, the effects of these traits on brain function in patients with PPPD versus healthy controls (HCs) have not been studied. METHODS: To investigate potential differential effects of neuroticism and introversion on functioning of their visuo-vestibular networks, 15 patients with PPPD and 15 HCs matched for demographics and motion sickness susceptibility underwent fMRI during virtual reality simulation of a rollercoaster ride in vertical and horizontal directions. RESULTS: Neuroticism positively correlated with activity in the inferior frontal gyrus (IFg), and enhanced connectivity between the IFg and occipital regions in patients with PPPD relative to HCs during vertical versus horizontal motion comparison. CONCLUSIONS: In patients with PPPD, neuroticism increased the activity and connectivity of neural networks that mediate attention to visual motion cues during vertical motion. This mechanism may mediate visual control of balance in neurotic patients with PPPD.

Surface-based morphometry reveals the neuroanatomical basis of the five-factor model of personality.

The five-factor model (FFM) is a widely used taxonomy of human personality; yet its neuro anatomical basis remains unclear. This is partly because past associations between gray-matter volume and FFM were driven by different surface-based morphometry (SBM) indices (i.e. cortical thickness, surface area, cortical folding or any combination of them). To overcome this limitation, we used Free-Surfer to study how variability in SBM measures was related to the FFM in n = 507 participants from the Human Connectome Project.Neuroticism was associated with thicker cortex and smaller area and folding in prefrontal-temporal regions. Extraversion was linked to thicker pre-cuneus and smaller superior temporal cortex area. Openness was linked to thinner cortex and greater area and folding in prefrontal-parietal regions. Agreeableness was correlated to thinner prefrontal cortex and smaller fusiform gyrus area. Conscientiousness was associated with thicker cortex and smaller area and folding in prefrontal regions. These findings demonstrate that anatomical variability in prefrontal cortices is linked to individual differences in the socio-cognitive dispositions described by the FFM. Cortical thickness and surface area/folding were inversely related each others as a function of different FFM traits (neuroticism, extraversion and consciousness vs openness), which may reflect brain maturational effects that predispose or protect against psychiatric disorders.

Altered Insular and Occipital Responses to Simulated Vertical Self-Motion in Patients with Persistent Postural-Perceptual Dizziness.

BACKGROUND: Persistent postural-perceptual dizziness (PPPD) is a common functional vestibular disorder characterized by persistent symptoms of non-vertiginous dizziness and unsteadiness that are exacerbated by upright posture, self-motion, and exposure to complex or moving visual stimuli. Recent physiologic and neuroimaging data suggest that greater reliance on visual cues for postural control (as opposed to vestibular cues-a phenomenon termed visual dependence) and dysfunction in central visuo-vestibular networks may be important pathophysiologic mechanisms underlying PPPD. Dysfunctions are thought to involve insular regions that encode recognition of the visual effects of motion in the gravitational field. METHODS: We tested for altered activity in vestibular and visual cortices during self-motion simulation obtained via a visual virtual-reality rollercoaster stimulation using functional magnetic resonance imaging in 15 patients with PPPD and 15 healthy controls (HCs). We compared between groups differences in brain responses to simulated displacements in vertical vs horizontal directions and correlated the difference in directional responses with dizziness handicap in patients with PPPD. RESULTS: HCs showed increased activity in the anterior bank of the central insular sulcus during vertical relative to horizontal motion, which was not seen in patients with PPPD. However, for the same comparison, dizziness handicap correlated positively with activity in the visual cortex (V1, V2, and V3) in patients with PPPD. CONCLUSION: We provide novel insight into the pathophysiologic mechanisms underlying PPPD, including functional alterations in brain processes that affect balance control and reweighting of space-motion inputs to favor visual cues. For patients with PPPD, difficulties using visual data to discern the effects of gravity on self-motion may adversely affect balance control, particularly for individuals who simultaneously rely too heavily on visual stimuli. In addition, increased activity in the visual cortex, which correlated with severity of dizziness handicap, may be a neural correlate of visual dependence.

Sex Differences in the Relationship Between Conduct Disorder and Cortical Structure in Adolescents.

OBJECTIVE: Previous studies have reported reduced cortical thickness and surface area and altered gyrification in frontal and temporal regions in adolescents with conduct disorder (CD). Although there is evidence that the clinical phenotype of CD differs between males and females, no studies have examined whether such sex differences extend to cortical and subcortical structure. METHOD: As part of a European multisite study (FemNAT-CD), structural magnetic resonance imaging (MRI) data were collected from 48 female and 48 male participants with CD and from 104 sex-, age-, and pubertal-status-matched controls (14-18 years of age). Data were analyzed using surface-based morphometry, testing for effects of sex, diagnosis, and sex-by-diagnosis interactions, while controlling for age, IQ, scan site, and total gray matter volume. RESULTS: CD was associated with cortical thinning and higher gyrification in ventromedial prefrontal cortex in both sexes. Males with CD showed lower, and females with CD showed higher, supramarginal gyrus cortical thickness compared with controls. Relative to controls, males with CD showed higher gyrification and surface area in superior frontal gyrus, whereas the opposite pattern was seen in females. There were no effects of diagnosis or sex-by-diagnosis interactions on subcortical volumes. Results are discussed with regard to attention-deficit/hyperactivity disorder, depression, and substance abuse comorbidity, medication use, handedness, and CD age of onset. CONCLUSION: We found both similarities and differences between males and females in CD-cortical structure associations. This initial evidence that the pathophysiological basis of CD may be partly sex-specific highlights the need to consider sex in future neuroimaging studies and suggests that males and females may require different treatments.

Role of the Insula and Vestibular System in Patients with Chronic Subjective Dizziness: An fMRI Study Using Sound-Evoked Vestibular Stimulation.

Chronic subjective dizziness (CSD) is a common vestibular disorder characterized by persistent non-vertiginous dizziness, unsteadiness, and heightened sensitivity to motion stimuli that may last for months to years after events that cause acute vestibular symptoms or disrupt balance. CSD is not associated with abnormalities of basic vestibular or oculomotor reflexes. Rather, it is thought to arise from persistent use of high-threat postural control strategies and greater reliance on visual cues for spatial orientation (i.e., visual dependence), long after triggering events resolve. Anxiety-related personality traits confer vulnerability to CSD. Anomalous interactions between the central vestibular system and neural structures related to anxiety may sustain it. Vestibular- and anxiety-related processes overlap in the brain, particularly in the insula and hippocampus. Alterations in activity and connectivity in these brain regions in response to vestibular stimuli may be the neural basis of CSD. We examined this hypothesis by comparing brain activity from 18 patients with CSD and 18 healthy controls measured by functional magnetic resonance imaging during loud short tone bursts, which are auditory stimuli that evoke robust vestibular responses. Relative to controls, patients with CSD showed reduced activations to sound-evoked vestibular stimulation in the parieto-insular vestibular cortex (PIVC) including the posterior insula, and in the anterior insula, inferior frontal gyrus, hippocampus, and anterior cingulate cortex. Patients with CSD also showed altered connectivity between the anterior insula and PIVC, anterior insula and middle occipital cortex, hippocampus and PIVC, and anterior cingulate cortex and PIVC. We conclude that reduced activation in PIVC, hippocampus, anterior insula, inferior frontal gyrus, and anterior cingulate cortex, as well as connectivity changes among these regions, may be linked to long-term vestibular symptoms in patients with CSD. Furthermore, altered connectivity between the anterior insula and middle occipital cortex may underlie the greater reliance on visual cues for spatial orientation in CSD patients relative to controls.

Personality traits modulate subcortical and cortical vestibular and anxiety responses to sound-evoked otolithic receptor stimulation.

OBJECTIVE: Strong links between anxiety, space-motion perception, and vestibular symptoms have been recognized for decades. These connections may extend to anxiety-related personality traits. Psychophysical studies showed that high trait anxiety affected postural control and visual scanning strategies under stress. Neuroticism and introversion were identified as risk factors for chronic subjective dizziness (CSD), a common psychosomatic syndrome. This study examined possible relationships between personality traits and activity in brain vestibular networks for the first time using functional magnetic resonance imaging (fMRI). METHODS: Twenty-six right-handed healthy individuals underwent fMRI during sound-evoked vestibular stimulation. Regional brain activity and functional connectivity measures were correlated with personality traits of the Five Factor Model (neuroticism, extraversion-introversion, openness, agreeableness, consciousness). RESULTS: Neuroticism correlated positively with activity in the pons, vestibulo-cerebellum, and para-striate cortex, and negatively with activity in the supra-marginal gyrus. Neuroticism also correlated positively with connectivity between pons and amygdala, vestibulo-cerebellum and amygdala, inferior frontal gyrus and supra-marginal gyrus, and inferior frontal gyrus and para-striate cortex. Introversion correlated positively with amygdala activity and negatively with connectivity between amygdala and inferior frontal gyrus. CONCLUSIONS: Neuroticism and introversion correlated with activity and connectivity in cortical and subcortical vestibular, visual, and anxiety systems during vestibular stimulation. These personality-related changes in brain activity may represent neural correlates of threat sensitivity in posture and gaze control mechanisms in normal individuals. They also may reflect risk factors for anxiety-related morbidity in patients with vestibular disorders, including previously observed associations of neuroticism and introversion with CSD.