Radiomics in breast cancer classification and prediction.

Breast Cancer (BC) is the common form of cancer in women. Its diagnosis and screening are usually performed through different imaging modalities such as mammography, magnetic resonance imaging and ultrasound. However, mammography and ultrasound-imaging techniques have limited sensitivity and specificity both in identifying lesions and in differentiating malign from benign lesions, especially in presence of dense breast parenchyma. Due to the higher resolution of magnetic resonance images, MRI represents the method with the higher specificity and sensitivity among all the available tools, in both lesions' identification and diagnosis. However, especially for diagnosis, even MRI has limitations that are only partially solved if combined with mammography. Unfortunately, due to the limits of all these imaging tools, in order to have a certain diagnosis, patients often receive painful and costly bioptics procedures. In this context, several computational approaches have been developed to increase sensitivity, while maintaining the same specificity, in BC diagnosis and screening. Amongst these, radiomics has been increasingly gaining ground in oncology to improve cancer diagnosis, prognosis and treatment. Radiomics derives multiple quantitative features from single or multiple medical imaging modalities, highlighting image traits which are not visible to the naked eye and hence significantly augmenting the discriminatory and predictive potential of medical imaging. This review article aims to summarize the state of the art in radiomics-based BC research. The dominating evidence extracted from the literature points towards a high potential of radiomics in disentangling malignant from benign breast lesions, classifying BC types and grades and also in predicting treatment response and recurrence risk. In the era of personalized medicine, radiomics has the potential to improve diagnosis, prognosis, prediction, monitoring, image-based intervention, and assessment of therapeutic response in BC.

Functional connectome of brainstem nuclei involved in autonomic, limbic, pain and sensory processing in living humans from 7 Tesla resting state fMRI.

Despite remarkable advances in mapping the functional connectivity of the cortex, the functional connectivity of subcortical regions is understudied in living humans. This is the case for brainstem nuclei that control vital processes, such as autonomic, limbic, nociceptive and sensory functions. This is because of the lack of precise brainstem nuclei localization, of adequate sensitivity and resolution in the deepest brain regions, as well as of optimized processing for the brainstem. To close the gap between the cortex and the brainstem, on 20 healthy subjects, we computed a correlation-based functional connectome of 15 brainstem nuclei involved in autonomic, limbic, nociceptive, and sensory function (superior and inferior colliculi, ventral tegmental area-parabrachial pigmented nucleus complex, microcellular tegmental nucleus-prabigeminal nucleus complex, lateral and medial parabrachial nuclei, vestibular and superior olivary complex, superior and inferior medullary reticular formation, viscerosensory motor nucleus, raphe magnus, pallidus, and obscurus, and parvicellular reticular nucleus - alpha part) with the rest of the brain. Specifically, we exploited 1.1mm isotropic resolution 7 Tesla resting-state fMRI, ad-hoc coregistration and physiological noise correction strategies, and a recently developed probabilistic template of brainstem nuclei. Further, we used 2.5mm isotropic resolution resting-state fMRI data acquired on a 3 Tesla scanner to assess the translatability of our results to conventional datasets. We report highly consistent correlation coefficients across subjects, confirming available literature on autonomic, limbic, nociceptive and sensory pathways, as well as high interconnectivity within the central autonomic network and the vestibular network. Interestingly, our results showed evidence of vestibulo-autonomic interactions in line with previous work. Comparison of 7 Tesla and 3 Tesla findings showed high translatability of results to conventional settings for brainstem-cortical connectivity and good yet weaker translatability for brainstem-brainstem connectivity. The brainstem functional connectome might bring new insight in the understanding of autonomic, limbic, nociceptive and sensory function in health and disease.

Structural connectivity of autonomic, pain, limbic, and sensory brainstem nuclei in living humans based on 7 Tesla and 3 Tesla MRI.

Autonomic, pain, limbic, and sensory processes are mainly governed by the central nervous system, with brainstem nuclei as relay centers for these crucial functions. Yet, the structural connectivity of brainstem nuclei in living humans remains understudied. These tiny structures are difficult to locate using conventional in vivo MRI, and ex vivo brainstem nuclei atlases lack precise and automatic transformability to in vivo images. To fill this gap, we mapped our recently developed probabilistic brainstem nuclei atlas developed in living humans to high-spatial resolution (1.7 mm isotropic) and diffusion weighted imaging (DWI) at 7 Tesla in 20 healthy participants. To demonstrate clinical translatability, we also acquired 3 Tesla DWI with conventional resolution (2.5 mm isotropic) in the same participants. Results showed the structural connectome of 15 autonomic, pain, limbic, and sensory (including vestibular) brainstem nuclei/nuclei complex (superior/inferior colliculi, ventral tegmental area-parabrachial pigmented, microcellular tegmental-parabigeminal, lateral/medial parabrachial, vestibular, superior olivary, superior/inferior medullary reticular formation, viscerosensory motor, raphe magnus/pallidus/obscurus, parvicellular reticular nucleus-alpha part), derived from probabilistic tractography computation. Through graph measure analysis, we identified network hubs and demonstrated high intercommunity communication in these nuclei. We found good (r = .5) translational capability of the 7 Tesla connectome to clinical (i.e., 3 Tesla) datasets. Furthermore, we validated the structural connectome by building diagrams of autonomic/pain/limbic connectivity, vestibular connectivity, and their interactions, and by inspecting the presence of specific links based on human and animal literature. These findings offer a baseline for studies of these brainstem nuclei and their functions in health and disease, including autonomic dysfunction, chronic pain, psychiatric, and vestibular disorders.

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.

Variability and Reproducibility of Directed and Undirected Functional MRI Connectomes in the Human Brain.

A growing number of studies are focusing on methods to estimate and analyze the functional connectome of the human brain. Graph theoretical measures are commonly employed to interpret and synthesize complex network-related information. While resting state functional MRI (rsfMRI) is often employed in this context, it is known to exhibit poor reproducibility, a key factor which is commonly neglected in typical cohort studies using connectomics-related measures as biomarkers. We aimed to fill this gap by analyzing and comparing the inter- and intra-subject variability of connectivity matrices, as well as graph-theoretical measures, in a large (n = 1003) database of young healthy subjects which underwent four consecutive rsfMRI sessions. We analyzed both directed (Granger Causality and Transfer Entropy) and undirected (Pearson Correlation and Partial Correlation) time-series association measures and related global and local graph-theoretical measures. While matrix weights exhibit a higher reproducibility in undirected, as opposed to directed, methods, this difference disappears when looking at global graph metrics and, in turn, exhibits strong regional dependence in local graphs metrics. Our results warrant caution in the interpretation of connectivity studies, and serve as a benchmark for future investigations by providing quantitative estimates for the inter- and intra-subject variabilities in both directed and undirected connectomic measures.

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.

Path integration in 3D from visual motion cues: A human fMRI study.

While neural correlates of path integration on a yaw plane have been studied extensively, much less is known about path integration in three-dimensions (3D). Here we used fMRI during virtual navigation within tunnels in pseudo-3D. We found that the same visual motion stimuli are encoded differently in the brain depending on whether they represent displacements within the yaw plane or within the pitch plane. The yaw plane is more represented in the hippocampus while the pitch plane is more represented in the angular gyrus (AG) and in the posterior inferior temporal gyrus (pITG), known to be involved in 3D space encoding. In addition, a region in pITG, located just above the previous one, showed two different patterns with multi-voxel analysis, separately coding for the pitch and yaw planes. These results suggest that information encoded within pITG about the yaw plane may be exchanged with the hippocampus, while information about the pitch plane may be exchanged with the AG.

Visual gravity cues in the interpretation of biological movements: neural correlates in humans.

Our visual system takes into account the effects of Earth gravity to interpret biological motion (BM), but the neural substrates of this process remain unclear. Here we measured functional magnetic resonance (fMRI) signals while participants viewed intact or scrambled stick-figure animations of walking, running, hopping, and skipping recorded at normal or reduced gravity. We found that regions sensitive to BM configuration in the occipito-temporal cortex (OTC) were more active for reduced than normal gravity but with intact stimuli only. Effective connectivity analysis suggests that predictive coding of gravity effects underlies BM interpretation. This process might be implemented by a family of snapshot neurons involved in action monitoring.

Sound-evoked vestibular stimulation affects the anticipation of gravity effects during visual self-motion.

Humans anticipate the effects of gravity during visually simulated self-motion in the vertical direction. Here we report that an artificial vestibular stimulation consisting of short-tone bursts (STB) suppresses this anticipation. Participants pressed a button upon entering a tunnel during virtual-reality roller coaster rides in downward or forward directions. In different trials, we delivered STB, pulsed white noise (WN), or no sound (NO). In the control conditions (WN, NO), participants responded earlier during downward than forward motion irrespective of true kinematics, consistent with the a priori expectation that downward but not forward motion is accelerated by gravity. STB canceled the difference in response timing between the two directions, without affecting overall task performance. Thus, we argue that vestibular signals play a role in the anticipation of visible gravity effects during self-motion.

Simulated self-motion in a visual gravity field: sensitivity to vertical and horizontal heading in the human brain.

Multiple visual signals are relevant to perception of heading direction. While the role of optic flow and depth cues has been studied extensively, little is known about the visual effects of gravity on heading perception. We used fMRI to investigate the contribution of gravity-related visual cues on the processing of vertical versus horizontal apparent self-motion. Participants experienced virtual roller-coaster rides in different scenarios, at constant speed or 1g-acceleration/deceleration. Imaging results showed that vertical self-motion coherent with gravity engaged the posterior insula and other brain regions that have been previously associated with vertical object motion under gravity. This selective pattern of activation was also found in a second experiment that included rectilinear motion in tunnels, whose direction was cued by the preceding open-air curves only. We argue that the posterior insula might perform high-order computations on visual motion patterns, combining different sensory cues and prior information about the effects of gravity. Medial-temporal regions including para-hippocampus and hippocampus were more activated by horizontal motion, preferably at constant speed, consistent with a role in inertial navigation. Overall, the results suggest partially distinct neural representations of the cardinal axes of self-motion (horizontal and vertical).

Anticipating the effects of visual gravity during simulated self-motion: estimates of time-to-passage along vertical and horizontal paths.

By simulating self-motion on a virtual rollercoaster, we investigated whether acceleration cued by the optic flow affected the estimate of time-to-passage (TTP) to a target. In particular, we studied the role of a visual acceleration (1 g = 9.8 m/s(2)) simulating the effects of gravity in the scene, by manipulating motion law (accelerated or decelerated at 1 g, constant speed) and motion orientation (vertical, horizontal). Thus, 1-g-accelerated motion in the downward direction or decelerated motion in the upward direction was congruent with the effects of visual gravity. We found that acceleration (positive or negative) is taken into account but is overestimated in module in the calculation of TTP, independently of orientation. In addition, participants signaled TTP earlier when the rollercoaster accelerated downward at 1 g (as during free fall), with respect to when the same acceleration occurred along the horizontal orientation. This time shift indicates an influence of the orientation relative to visual gravity on response timing that could be attributed to the anticipation of the effects of visual gravity on self-motion along the vertical, but not the horizontal orientation. Finally, precision in TTP estimates was higher during vertical fall than when traveling at constant speed along the vertical orientation, consistent with a higher noise in TTP estimates when the motion violates gravity constraints.

Interception of vertically approaching objects: temporal recruitment of the internal model of gravity and contribution of optical information.

Introduction: Recent views posit that precise control of the interceptive timing can be achieved by combining on-line processing of visual information with predictions based on prior experience. Indeed, for interception of free-falling objects under gravity's effects, experimental evidence shows that time-to-contact predictions can be derived from an internal gravity representation in the vestibular cortex. However, whether the internal gravity model is fully engaged at the target motion outset or reinforced by visual motion processing at later stages of motion is not yet clear. Moreover, there is no conclusive evidence about the relative contribution of internalized gravity and optical information in determining the time-to-contact estimates. Methods: We sought to gain insight on this issue by asking 32 participants to intercept free falling objects approaching directly from above in virtual reality. Object motion had durations comprised between 800 and 1100 ms and it could be either congruent with gravity (1 g accelerated motion) or not (constant velocity or -1 g decelerated motion). We analyzed accuracy and precision of the interceptive responses, and fitted them to Bayesian regression models, which included predictors related to the recruitment of a priori gravity information at different times during the target motion, as well as based on available optical information. Results: Consistent with the use of internalized gravity information, interception accuracy and precision were significantly higher with 1 g motion. Moreover, Bayesian regression indicated that interceptive responses were predicted very closely by assuming engagement of the gravity prior 450 ms after the motion onset, and that adding a predictor related to on-line processing of optical information improved only slightly the model predictive power. Discussion: Thus, engagement of a priori gravity information depended critically on the processing of the first 450 ms of visual motion information, exerting a predominant influence on the interceptive timing, compared to continuously available optical information. Finally, these results may support a parallel processing scheme for the control of interceptive timing.

Mal de Debarquement Syndrome explained by a vestibulo-cerebellar oscillator.

Mal de Debarquement Syndrome (MdDS) is a puzzling central vestibular disorder characterized by a long-lasting perception of oscillatory postural instability that may occur after sea travels or flights. We have postulated that MdDS originates from the post-disembarking persistence of an adaptive internal oscillator consisting of a loop system, involving the right and left vestibular nuclei, and the Purkinje cells of the right and left flocculonodular cerebellar cortex, connected by GABAergic and glutamatergic fibers. We have formulated here a mathematical model of the vestibulo-cerebellar loop system and carried out a computational analysis based on a set of differential equations describing the interactions among the loop elements and containing Hill functions that model input-output firing rates relationships among neurons. The analysis indicates that the system acquires a spontaneous and permanent oscillatory behavior for a decrease of threshold and an increase of sensitivity in neuronal input-output responses. These results suggest a role for synaptic plasticity in MdDS pathophysiology, thus reinforcing our previous hypothesis that MdDS may be the result of excessive synaptic plasticity acting on the vestibulo-cerebellar network during its entraining to an oscillatory environment. Hence, our study points to neuroendocrine pathways that lead to increased synaptic response as possible new therapeutic targets for the clinical treatment of the disorder.

A case report of agoraphobia following right parietal lobe surgery: changes in functional and structural connectivities of the multimodal vestibular network.

Agoraphobia is a visuo-vestibular-spatial disorder that may involve dysfunction of the vestibular network, which includes the insular and limbic cortex. We sought to study the neural correlates of this disorder in an individual who developed agoraphobia after surgical removal of a high-grade glioma located in the right parietal lobe, by assessing pre- and post-surgery connectivities in the vestibular network. The patient underwent surgical resection of the glioma located within the right supramarginal gyrus. The resection interested also portions of the superior and inferior parietal lobe. Structural and functional connectivities were assessed through magnetic resonance imaging before and 5 and 7 months after surgery. Connectivity analyses focused on a network comprising 142 spherical regions of interest (4 mm radius) associated with the vestibular cortex: 77 in the left and 65 in the right hemisphere (excluding lesioned regions). Tractography for diffusion-weighted structural data and correlation between time series for functional resting-state data were calculated for each pair of regions in order to build weighted connectivity matrices. Graph theory was applied to assess post-surgery changes in network measures, such as strength, clustering coefficient, and local efficiency. Structural connectomes after surgery showed a decrease of strength in the preserved ventral portion of the supramarginal gyrus (PFcm) and in a high order visual motion area in the right middle temporal gyrus (37dl), and decrease of the clustering coefficient and of the local efficiency in several areas of the limbic, insular cortex, parietal and frontal cortex, indicating general disconnection of the vestibular network. Functional connectivity analysis showed both a decrease in connectivity metrics, mainly in high-order visual areas and in the parietal cortex, and an increase in connectivity metrics, mainly in the precuneus, parietal and frontal opercula, limbic, and insular cortex. This post-surgery reorganization of the vestibular network is compatible with altered processing of visuo-vestibular-spatial information, yielding agoraphobia symptoms. Specifically, post-surgical functional increases of clustering coefficient and local efficiency in the anterior insula and in the cingulate cortex might indicate a more predominant role of these areas within the vestibular network, which could be predictive of the fear and avoiding behavior characterizing agoraphobia.

Watching the Effects of Gravity. Vestibular Cortex and the Neural Representation of "Visual" Gravity.

Gravity is a physical constraint all terrestrial species have adapted to through evolution. Indeed, gravity effects are taken into account in many forms of interaction with the environment, from the seemingly simple task of maintaining balance to the complex motor skills performed by athletes and dancers. Graviceptors, primarily located in the vestibular otolith organs, feed the Central Nervous System with information related to the gravity acceleration vector. This information is integrated with signals from semicircular canals, vision, and proprioception in an ensemble of interconnected brain areas, including the vestibular nuclei, cerebellum, thalamus, insula, retroinsula, parietal operculum, and temporo-parietal junction, in the so-called vestibular network. Classical views consider this stage of multisensory integration as instrumental to sort out conflicting and/or ambiguous information from the incoming sensory signals. However, there is compelling evidence that it also contributes to an internal representation of gravity effects based on prior experience with the environment. This a priori knowledge could be engaged by various types of information, including sensory signals like the visual ones, which lack a direct correspondence with physical gravity. Indeed, the retinal accelerations elicited by gravitational motion in a visual scene are not invariant, but scale with viewing distance. Moreover, the "visual" gravity vector may not be aligned with physical gravity, as when we watch a scene on a tilted monitor or in weightlessness. This review will discuss experimental evidence from behavioral, neuroimaging (connectomics, fMRI, TMS), and patients' studies, supporting the idea that the internal model estimating the effects of gravity on visual objects is constructed by transforming the vestibular estimates of physical gravity, which are computed in the brainstem and cerebellum, into internalized estimates of virtual gravity, stored in the vestibular cortex. The integration of the internal model of gravity with visual and non-visual signals would take place at multiple levels in the cortex and might involve recurrent connections between early visual areas engaged in the analysis of spatio-temporal features of the visual stimuli and higher visual areas in temporo-parietal-insular regions.

Brain Correlates of Persistent Postural-Perceptual Dizziness: A Review of Neuroimaging Studies.

Persistent postural-perceptual dizziness (PPPD), defined in 2017, is a vestibular disorder characterized by chronic dizziness that is exacerbated by upright posture and exposure to complex visual stimuli. This review focused on recent neuroimaging studies that explored the pathophysiological mechanisms underlying PPPD and three conditions that predated it. The emerging picture is that local activity and functional connectivity in multimodal vestibular cortical areas are decreased in PPPD, which is potentially related to structural abnormalities (e.g., reductions in cortical folding and grey-matter volume). Additionally, connectivity between the prefrontal cortex, which regulates attentional and emotional responses, and primary visual and motor regions appears to be increased in PPPD. These results complement physiological and psychological data identifying hypervigilant postural control and visual dependence in patients with PPPD, supporting the hypothesis that PPPD arises from shifts in interactions among visuo-vestibular, sensorimotor, and emotional networks that overweigh visual over vestibular inputs and increase the effects of anxiety-related mechanisms on locomotor control and spatial orientation.

Processing of targets in smooth or apparent motion along the vertical in the human brain: an fMRI study.

Neural substrates for processing constant speed visual motion have been extensively studied. Less is known about the brain activity patterns when the target speed changes continuously, for instance under the influence of gravity. Using functional MRI (fMRI), here we compared brain responses to accelerating/decelerating targets with the responses to constant speed targets. The target could move along the vertical under gravity (1g), under reversed gravity (-1g), or at constant speed (0g). In the first experiment, subjects observed targets moving in smooth motion and responded to a GO signal delivered at a random time after target arrival. As expected, we found that the timing of the motor responses did not depend significantly on the specific motion law. Therefore brain activity in the contrast between different motion laws was not related to motor timing responses. Average BOLD signals were significantly greater for 1g targets than either 0g or -1g targets in a distributed network including bilateral insulae, left lingual gyrus, and brain stem. Moreover, in these regions, the mean activity decreased monotonically from 1g to 0g and to -1g. In the second experiment, subjects intercepted 1g, 0g, and -1g targets either in smooth motion (RM) or in long-range apparent motion (LAM). We found that the sites in the right insula and left lingual gyrus, which were selectively engaged by 1g targets in the first experiment, were also significantly more active during 1g trials than during -1g trials both in RM and LAM. The activity in 0g trials was again intermediate between that in 1g trials and that in -1g trials. Therefore in these regions the global activity modulation with the law of vertical motion appears to hold for both RM and LAM. Instead, a region in the inferior parietal lobule showed a preference for visual gravitational motion only in LAM but not RM.

Mal de Debarquement Syndrome: A Matter of Loops?

Introduction: Mal de Debarquement Syndrome (MdDS) is a poorly understood neurological disorder affecting mostly perimenopausal women. MdDS has been hypothesized to be a maladaptation of the vestibulo-ocular reflex, a neuroplasticity disorder, and a consequence of neurochemical imbalances and hormonal changes. Our hypothesis considers elements from these theories, but presents a novel approach based on the analysis of functional loops, according to Systems and Control Theory. Hypothesis: MdDS is characterized by a persistent sensation of self-motion, usually occurring after sea travels. We assume the existence of a neuronal mechanism acting as an oscillator, i.e., an adaptive internal model, that may be able to cancel a sinusoidal disturbance of posture experienced aboard, due to wave motion. Thereafter, we identify this mechanism as a multi-loop neural network that spans between vestibular nuclei and the flocculonodular lobe of the cerebellum. We demonstrate that this loop system has a tendency to oscillate, which increases with increasing strength of neuronal connections. Therefore, we hypothesize that synaptic plasticity, specifically long-term potentiation, may play a role in making these oscillations poorly damped. Finally, we assume that the neuromodulator Calcitonin Gene-Related Peptide, which is modulated in perimenopausal women, exacerbates this process thus rendering the transition irreversible and consequently leading to MdDS. Conclusion and Validation: The concept of an oscillator that becomes noxiously permanent can be used as a model for MdDS, given a high correlation between patients with MdDS and sea travels involving undulating passive motion, and an alleviation of symptoms when patients are re-exposed to similar passive motion. The mechanism could be further investigated utilizing posturography tests to evaluate if subjective perception of motion matches with objective postural instability. Neurochemical imbalances that would render individuals more susceptible to developing MdDS could be investigated through hormonal profile screening. Alterations in the connections between vestibular nuclei and cerebellum, notably GABAergic fibers, could be explored by neuroimaging techniques as well as transcranial magnetic stimulation. If our hypothesis were tested and verified, optimal targets for MdDS treatment could be found within both the neural networks and biochemical factors that are deemed to play a fundamental role in loop functioning and synaptic plasticity.

Sensitivity of occipito-temporal cortex, premotor and Broca's areas to visible speech gestures in a familiar language.

When looking at a speaking person, the analysis of facial kinematics contributes to language discrimination and to the decoding of the time flow of visual speech. To disentangle these two factors, we investigated behavioural and fMRI responses to familiar and unfamiliar languages when observing speech gestures with natural or reversed kinematics. Twenty Italian volunteers viewed silent video-clips of speech shown as recorded (Forward, biological motion) or reversed in time (Backward, non-biological motion), in Italian (familiar language) or Arabic (non-familiar language). fMRI revealed that language (Italian/Arabic) and time-rendering (Forward/Backward) modulated distinct areas in the ventral occipito-temporal cortex, suggesting that visual speech analysis begins in this region, earlier than previously thought. Left premotor ventral (superior subdivision) and dorsal areas were preferentially activated with the familiar language independently of time-rendering, challenging the view that the role of these regions in speech processing is purely articulatory. The left premotor ventral region in the frontal operculum, thought to include part of the Broca's area, responded to the natural familiar language, consistent with the hypothesis of motor simulation of speech gestures.

Lower Functional Connectivity in Vestibular-Limbic Networks in Individuals With Subclinical Agoraphobia.

Background: Agoraphobia was described in 1871 as a condition of fear-related alterations in spatial orientation and locomotor control triggered by places or situations that might cause a patient to panic and feel trapped. In contemporary nosology, however, this original concept of agoraphobia was split into two diagnostic entities, i.e., the modern anxiety disorder of agoraphobia, consisting solely of phobic/avoidant symptoms in public spaces, and the recently defined vestibular disorder of persistent postural perceptual dizziness (PPPD), characterized by dizziness, and unsteadiness exacerbated by visual motion stimuli. Previous neuroimaging studies found altered brain activity and connectivity in visual-vestibular networks of patients with PPPD vs. healthy controls. Neuroticism and introversion, which pre-dispose to both agoraphobia and PPPD, influenced brain responses to vestibular and visual motion stimuli in patients with PPPD. Similar neuroimaging studies have not been undertaken in patients with agoraphobia in its current definition. Given their shared history and pre-disposing factors, we sought to test the hypotheses that individuals with agoraphobic symptoms have alterations in visual-vestibular networks similar to those of patients with PPPD, and that these alterations are influenced by neuroticism and introversion. Methods: Drawing from the Human Connectome Project (HCP) database, we matched 52 participants with sub-clinical agoraphobia and 52 control subjects without agoraphobic symptoms on 19 demographic and psychological/psychiatric variables. We then employed a graph-theoretical framework to compare resting-state functional magnetic resonance images between groups and evaluated the interactive effects of neuroticism and introversion on the brain signatures of agoraphobia. Results: Individuals with subclinical agoraphobia had lower global clustering, efficiency and transitivity relative to controls. They also had lower connectivity metrics in two brain networks, one positioned to process incoming visual space-motion information, assess threat, and initiate/inhibit behavioral responses (visuospatial-emotional network) and one positioned to control and monitor locomotion (vestibular-navigational network). Introversion interacted with agoraphobic symptoms to lower the connectivity of the visuospatial-emotional network. This contrasted with previous findings describing neuroticism-associated higher connectivity in a narrower visual-spatial-frontal network in patients with PPPD. Conclusion: Functional connectivity was lower in two brain networks in subclinical agoraphobia as compared to healthy controls. These networks integrate visual vestibular and emotional response to guide movement in space.