Longitudinal changes in human supraspinal processing after RIII-feedback training to improve descending pain inhibition.

The human body has the ability to influence its sensation of pain by modifying the transfer of nociceptive information at the spinal level. This modulation, known as descending pain inhibition, is known to originate supraspinally and can be activated by a variety of ways including positive mental imagery. However, its exact mechanisms remain unknown. We investigated, using a longitudinal fMRI design, the brain activity leading up and in response to painful electrical stimulation when applying positive mental imagery before and after undergoing a previously established RIII-feedback paradigm. Time course analysis of the time preceding painful stimulation shows increased haemodynamic activity during the application of the strategy in the PFC, ACC, insula, thalamus, and hypothalamus. Time course analysis of the reaction to painful stimulation shows decreased reaction post-training in brainstem and thalamus, as well as the insula and dorsolateral PFC. Our work suggests that feedback training increases activity in areas involved in pain inhibition, while simultaneously decreasing the reaction to painful stimuli in brain areas related to pain processing, which points to an activation of decreased spinal nociception. We further suggest that the insula and the thalamus may play a more important role in pain modulation than previously assumed.

Anxiety and physical impairment in patients with central vestibular disorders.

BACKGROUND: There is increasing evidence for close interrelations between vestibular and emotional brain networks. A study in patients with bilateral peripheral vestibulopathy (BVP) showed relatively low vertigo-related anxiety (VRA), despite high physical impairment. The current working hypothesis proposes the integrity of the peripheral vestibular system as a prerequisite for development of VRA. Here we contribute by evaluating VRA and vestibular-related handicap in central vestibular disorders. METHODS: Of 6396 patients presenting in a tertiary vertigo centre, 306 were identified with four clear central vestibular disorders: pure cerebellar ocular motor disorder (COD; 61), cerebellar ataxia (CA; 63), atypical parkinsonian syndromes (APS; 28), vestibular migraine (VM; 154). Their results of the Vertigo Handicap Questionnaire (VHQ), with its subscales for anxiety and handicapped activity, were compared to those of 65 BVP patients. Postural instability was measured on a force-plate. Multivariate linear regression was used to adjust for patient demographics. RESULTS: Patients with chronic central vestibular disorders (COD, CA, APS) had relatively low VRA levels comparable to those in BVP, independent of increased handicapped activity or postural instability. Only VM patients showed significantly higher VRA, although their activity impairment and postural instability were lowest. No significant differences within chronic central vestibular disorders were found for VRA and subjective activity impairment. CONCLUSIONS: Subjective and objective vestibular-related impairment are not necessarily correlated with vestibular-related anxiety in central vestibular disorders. Our findings rather support the hypothesis that, in addition to an intact peripheral, an intact central vestibular system could also serve as a prerequisite to develop specific VRA.

The precuneus as a central node in declarative memory retrieval.

Both, the hippocampal formation and the neocortex are contributing to declarative memory, but their functional specialization remains unclear. We investigated the differential contribution of both memory systems during free recall of word lists. In total, 21 women and 17 men studied the same list but with the help of different encoding associations. Participants associated the words either sequentially with the previous word on the list, with spatial locations on a well-known path, or with unique autobiographical events. After intensive rehearsal, subjects recalled the words during functional magnetic resonance imaging (fMRI). Common activity to all three types of encoding associations was identified in the posterior parietal cortex, in particular in the precuneus. Additionally, when associating spatial or autobiographical material, retrosplenial cortex activity was elicited during word list recall, while hippocampal activity emerged only for autobiographically associated words. These findings support a general, critical function of the precuneus in episodic memory storage and retrieval. The encoding-retrieval repetitions during learning seem to have accelerated hippocampus-independence and lead to direct neocortical integration in the sequentially associated and spatially associated word list tasks. During recall of words associated with autobiographical memories, the hippocampus might add spatiotemporal information supporting detailed scenic and contextual memories.

The human egomotion network.

All volitional movement in a three-dimensional space requires multisensory integration, in particular of visual and vestibular signals. Where and how the human brain processes and integrates self-motion signals remains enigmatic. Here, we applied visual and vestibular self-motion stimulation using fast and precise whole-brain neuroimaging to delineate and characterize the entire cortical and subcortical egomotion network in a substantial cohort (n=131). Our results identify a core egomotion network consisting of areas in the cingulate sulcus (CSv, PcM/pCi), the cerebellum (uvula), and the temporo-parietal cortex including area VPS and an unnamed region in the supramarginal gyrus. Based on its cerebral connectivity pattern and anatomical localization, we propose that this region represents the human homologue of macaque area 7a. Whole-brain connectivity and gradient analyses imply an essential role of the connections between the cingulate sulcus and the cerebellar uvula in egomotion perception. This could be via feedback loops involved updating visuo-spatial and vestibular information. The unique functional connectivity patterns of PcM/pCi hint at central role in multisensory integration essential for the perception of self-referential spatial awareness. All cortical egomotion hubs showed modular functional connectivity with other visual, vestibular, somatosensory and higher order motor areas, underlining their mutual function in general sensorimotor integration.

A virtual reality time reproduction task for rodents.

Estimates of the duration of time intervals and other magnitudes exhibit characteristic biases that likely result from error minimization strategies. To investigate such phenomena, magnitude reproduction tasks are used with humans and other primates. However, such behavioral tasks do not exist for rodents, one of the most important animal orders for neuroscience. We, therefore, developed a time reproduction task that can be used with rodents. It involves an animal reproducing the duration of a timed visual stimulus by walking along a corridor. The task was implemented in virtual reality, which allowed us to ensure that the animals were actually estimating time. The hallway did not contain prominent spatial cues and movement could be de-correlated from optic flow, such that the animals could not learn a mapping between stimulus duration and covered distance. We tested the reproduction of durations of several seconds in three different stimulus ranges. The gerbils reproduced the durations with a precision similar to experiments on humans. Their time reproductions also exhibited the characteristic biases of magnitude estimation experiments. These results demonstrate that our behavioral paradigm provides a means to study time reproduction in rodents.

Persistent horizontal and vertical, MR-induced nystagmus in resting state Human Connectome Project data.

OBJECTIVE: Strong magnetic fields from magnetic resonance (MR) scanners induce a Lorentz force that contributes to vertigo and persistent nystagmus. Prior studies have reported a predominantly horizontal direction for healthy subjects in a 7 Tesla (T) MR scanner, with slow phase velocity (SPV) dependent on head orientation. Less is known about vestibular signal behavior for subjects in a weaker, 3T magnetic field, the standard strength used in the Human Connectome Project (HCP). The purpose of this study is to characterize the form and magnitude of nystagmus induced at 3T. METHODS: Forty-two subjects were studied after being introduced head-first, supine into a Siemens Prisma 3T scanner. Eye movements were recorded in four separate acquisitions over 20 min. A biometric eye model was fitted to the recordings to derive rotational eye position and then SPV. An anatomical template of the semi-circular canals was fitted to the T2 anatomical image from each subject, and used to derive the angle of the B0 magnetic field with respect to the vestibular apparatus. RESULTS: Recordings from 37 subjects yielded valid measures of eye movements. The population-mean SPV ± SD for the horizontal component was -1.38 ± 1.27 deg/sec, and vertical component was -0.93 ± 1.44 deg/sec, corresponding to drift movement in the rightward and downward direction. Although there was substantial inter-subject variability, persistent nystagmus was present in half of subjects with no significant adaptation over the 20 min scanning period. The amplitude of vertical drift was correlated with the roll angle of the vestibular system, with a non-zero vertical SPV present at a 0 degree roll. INTERPRETATION: Non-habituating vestibular signals of varying amplitude are present in resting state data collected at 3T.

Distributed coding of duration in rodent prefrontal cortex during time reproduction.

As we interact with the external world, we judge magnitudes from sensory information. The estimation of magnitudes has been characterized in primates, yet it is largely unexplored in nonprimate species. Here, we use time interval reproduction to study rodent behavior and its neural correlates in the context of magnitude estimation. We show that gerbils display primate-like magnitude estimation characteristics in time reproduction. Most prominently their behavioral responses show a systematic overestimation of small stimuli and an underestimation of large stimuli, often referred to as regression effect. We investigated the underlying neural mechanisms by recording from medial prefrontal cortex and show that the majority of neurons respond either during the measurement or the reproduction of a time interval. Cells that are active during both phases display distinct response patterns. We categorize the neural responses into multiple types and demonstrate that only populations with mixed responses can encode the bias of the regression effect. These results help unveil the organizing neural principles of time reproduction and perhaps magnitude estimation in general.

Network changes in patients with phobic postural vertigo.

INTRODUCTION: Functional dizziness comprises a class of dizziness disorders, including phobic postural vertigo (PPV), that cause vestibular symptoms in the absence of a structural organic origin. For this reason, functional brain mechanisms have been implicated in these disorders. METHODS: Here, functional network organization was investigated in 17 PPV patients and 18 healthy controls (HCs) during functional magnetic resonance imaging with a visual motion stimulus, data initially collected and described by Popp et al. (2018). Graph theoretical measures (degree centrality [DC], clustering coefficient [CC], and eccentricity) of 160 nodes within six functional networks were compared between HC and PPV patients during visual motion and static visual patterns. RESULTS: Graph theoretical measures analyzed during the static condition revealed significantly different DC in the default-mode, sensorimotor, and cerebellar networks. Furthermore, significantly different group differences in network organization changes between static visual and visual motion stimulation were observed. In PPV, DC and CC showed a significantly stronger increase in the sensorimotor network during visual stimulation, whereas cerebellar network showed a significantly stronger decrease in DC. CONCLUSION: These results suggest that the altered visual motion processing seen in PPV patients may arise from a modified state of sensory and cerebellar network connectivity.

Synchronization between instructor and observer when learning a complex bimanual skill.

While learning from an instructor by watching a 'how-to' video has become common practice, we know surprisingly little about the relation between brain activities in instructor and observers. In this fMRI study we investigated the temporal synchronization between instructor and observers using intersubject correlation in the naturalistic setting of learning to fold origami. Brain activity of the blindfolded instructor during action production was compared to the observers while they viewed the instructor's video-taped actions. We demonstrate for the first time that the BOLD activity in the instructor's and observer's brain are synchronized while observing and learning a manual complex task with the goal of reproducing it. We can rule out that this synchrony originates from visual feedback. Observers exhibiting higher synchrony with the instructor in the ventral premotor cortex, while viewing the video for the first time, were more successful in reproducing the origami afterwards. Furthermore, changes in instructor-observer synchrony across observational learning sessions occur in cerebellar areas, as well as differences in instructor-observer synchrony between learning and the counting folds, our non-learning control. Not only known cerebellar motor production areas show synchrony, shedding new light on the involvement of the cerebellum in action observation and learning.

A bedside application-based assessment of spatial orientation and memory: approaches and lessons learned.

Spatial orientation and memory deficits are an often overlooked and potentially powerful early marker for pathological cognitive decline. Pen-and-paper tests for spatial abilities often do not coincide with actual navigational performance due to differences in spatial perspective and scale. Mobile devices are becoming increasingly useful in a clinical setting, for patient monitoring, clinical decision-making, and information management. The same devices have positional information that may be useful for a scale appropriate point-of-care test for spatial ability. We created a test for spatial orientation and memory based on pointing within a single room using the sensors in mobile phone. The test consisted of a baseline pointing condition to which all other conditions were compared, a spatial memory condition with eyes-closed, and two body rotation conditions (real or mental) where spatial updating were assessed. We examined the effectiveness of the sensors from a mobile phone for measuring pointing errors in these conditions in a sample of healthy young individuals. We found that the sensors reliably produced appropriate azimuth and elevation pointing angles for all of the 15 targets presented across multiple participants and days. Within-subject variability was below 6° elevation and 10° azimuth for the control condition. The pointing error and variability increased with task difficulty and correlated with self-report tests of spatial ability. The lessons learned from the first tests are discussed as well as the outlook of this application as a scientific and clinical bedside device. Finally, the next version of the application is introduced as an open source application for further development.

DeepVOG: Open-source pupil segmentation and gaze estimation in neuroscience using deep learning.

BACKGROUND: A prerequisite for many eye tracking and video-oculography (VOG) methods is an accurate localization of the pupil. Several existing techniques face challenges in images with artifacts and under naturalistic low-light conditions, e.g. with highly dilated pupils. NEW METHOD: For the first time, we propose to use a fully convolutional neural network (FCNN) for segmentation of the whole pupil area, trained on 3946 VOG images hand-annotated at our institute. We integrate the FCNN into DeepVOG, along with an established method for gaze estimation from elliptical pupil contours, which we improve upon by considering our FCNN's segmentation confidence measure. RESULTS: The FCNN output simultaneously enables us to perform pupil center localization, elliptical contour estimation and blink detection, all with a single network and with an assigned confidence value, at framerates above 130 Hz on commercial workstations with GPU acceleration. Pupil centre coordinates can be estimated with a median accuracy of around 1.0 pixel, and gaze estimation is accurate to within 0.5 degrees. The FCNN is able to robustly segment the pupil in a wide array of datasets that were not used for training. COMPARISON WITH EXISTING METHODS: We validate our method against gold standard eye images that were artificially rendered, as well as hand-annotated VOG data from a gold-standard clinical system (EyeSeeCam) at our institute. CONCLUSIONS: Our proposed FCNN-based pupil segmentation framework is accurate, robust and generalizes well to new VOG datasets. We provide our code and pre-trained FCNN model open-source and for free under www.github.com/pydsgz/DeepVOG.

Who gets lost and why: A representative cross-sectional survey on sociodemographic and vestibular determinants of wayfinding strategies.

When we think of our family and friends, we probably know someone who is good at finding their way and someone else that easily gets lost. We still know little about the biological and environmental factors that influence our navigational ability. Here, we investigated the frequency and sociodemographic determinants of wayfinding and their association with vestibular function in a representative cross-sectional sample (N = 783) of the adult German-speaking population. Wayfinding was assessed using the Wayfinding Strategy Scale, a self-report scale that produces two scores for each participant representing to what degree they rely on route-based or orientation (map-based) strategies. We were interested in the following research questions: (1) the frequency and determinants of wayfinding strategies in a population-based representative sample, (2) the relationship between vestibular function and strategy choice and (3) how sociodemographic factors influence general wayfinding ability as measured using a combined score from both strategy scores. Our linear regression models showed that being male, having a higher education, higher age and lower regional urbanization increased orientation strategy scores. Vertigo/dizziness reduced the scores of both the orientation and the route strategies. Using a novel approach, we grouped participants by their combined strategy scores in a multinomial regression model, to see whether individuals prefer one strategy over the other. The majority of individuals reported using either both or no strategy, instead of preferring one strategy over the other. Young age and reduced vestibular function were indicative of using no strategy. In summary, wayfinding ability depends on both biological and environmental factors; all sociodemographic factors except income. Over a third of the population, predominantly under the age of 35, does not successfully use either strategy. This represents a change in our wayfinding skills, which may result from the technological advances in navigational aids over the last few decades.

Cognitive conflict and restructuring: The neural basis of two core components of insight.

Sometimes, the solution to a difficult problem simply pops into mind. Such a moment of sudden comprehension is known as "insight". This fundamental cognitive process is crucial for problem solving, creativity and innovation, yet its true nature remains elusive, despite one century of psychological research. Typically, insight is investigated by using spatial puzzles or verbal riddles. Broadening the traditional approach, we propose to tackle this question by presenting magic tricks to participants and asking them to find out the secret method used by the magician. Combining this approach with cueing in an fMRI experiment, we were able to break down the insight process into two underlying components: cognitive conflict and restructuring. During cognitive conflict, problem solvers identify incongruent information that does not match their current mental representation. In a second step this information is restructured, thereby allowing them to correctly determine how the magic trick was done. We manipulated the occurrence of cognitive conflict by presenting two types of cues that lead participants to either maintain their perceptual belief (congruent cue) or to change their perceptual belief (incongruent cue) for the mechanism behind the magic trick. We found that partially overlapping but distinct networks of brain activity were recruited for cognitive conflict and restructuring. Posterior, predominantly visual brain activity during cognitive conflict reflected processes related to prediction error, attention to the relevant cue-specific sensory domain, and the default brain state. Restructuring on the other hand, showed a highly distributed pattern of brain activity in regions of the default mode, executive control networks, and salience networks. The angular gyrus and middle temporal gyrus were active in both cognitive conflict and restructuring, suggesting that these regions are important throughout the insight problem solving process. We believe this type of approach towards understanding insight will give lead to a better understanding of this complex process and the specific role that different brain regions play in creative thought.

Human Exploration of Enclosed Spaces through Echolocation.

Some blind humans have developed echolocation, as a method of navigation in space. Echolocation is a truly active sense because subjects analyze echoes of dedicated, self-generated sounds to assess space around them. Using a special virtual space technique, we assess how humans perceive enclosed spaces through echolocation, thereby revealing the interplay between sensory and vocal-motor neural activity while humans perform this task. Sighted subjects were trained to detect small changes in virtual-room size analyzing real-time generated echoes of their vocalizations. Individual differences in performance were related to the type and number of vocalizations produced. We then asked subjects to estimate virtual-room size with either active or passive sounds while measuring their brain activity with fMRI. Subjects were better at estimating room size when actively vocalizing. This was reflected in the hemodynamic activity of vocal-motor cortices, even after individual motor and sensory components were removed. Activity in these areas also varied with perceived room size, although the vocal-motor output was unchanged. In addition, thalamic and auditory-midbrain activity was correlated with perceived room size; a likely result of top-down auditory pathways for human echolocation, comparable with those described in echolocating bats. Our data provide evidence that human echolocation is supported by active sensing, both behaviorally and in terms of brain activity. The neural sensory-motor coupling complements the fundamental acoustic motor-sensory coupling via the environment in echolocation.SIGNIFICANCE STATEMENT Passive listening is the predominant method for examining brain activity during echolocation, the auditory analysis of self-generated sounds. We show that sighted humans perform better when they actively vocalize than during passive listening. Correspondingly, vocal motor and cerebellar activity is greater during active echolocation than vocalization alone. Motor and subcortical auditory brain activity covaries with the auditory percept, although motor output is unchanged. Our results reveal behaviorally relevant neural sensory-motor coupling during echolocation.

Rapid and independent memory formation in the parietal cortex.

Previous evidence indicates that the brain stores memory in two complementary systems, allowing both rapid plasticity and stable representations at different sites. For memory to be established in a long-lasting neocortical store, many learning repetitions are considered necessary after initial encoding into hippocampal circuits. To elucidate the dynamics of hippocampal and neocortical contributions to the early phases of memory formation, we closely followed changes in human functional brain activity while volunteers navigated through two different, initially unknown virtual environments. In one condition, they were able to encode new information continuously about the spatial layout of the maze. In the control condition, no information could be learned because the layout changed constantly. Our results show that the posterior parietal cortex (PPC) encodes memories for spatial locations rapidly, beginning already with the first visit to a location and steadily increasing activity with each additional encounter. Hippocampal activity and connectivity between the PPC and hippocampus, on the other hand, are strongest during initial encoding, and both decline with additional encounters. Importantly, stronger PPC activity related to higher memory-based performance. Compared with the nonlearnable control condition, PPC activity in the learned environment remained elevated after a 24-h interval, indicating a stable change. Our findings reflect the rapid creation of a memory representation in the PPC, which belongs to a recently proposed parietal memory network. The emerging parietal representation is specific for individual episodes of experience, predicts behavior, and remains stable over offline periods, and must therefore hold a mnemonic function.

Beyond Dizziness: Virtual Navigation, Spatial Anxiety and Hippocampal Volume in Bilateral Vestibulopathy.

Bilateral vestibulopathy (BVP) is defined as the impairment or loss of function of either the labyrinths or the eighth nerves. Patients with total BVP due to bilateral vestibular nerve section exhibit difficulties in spatial memory and navigation and show a loss of hippocampal volume. In clinical practice, most patients do not have a complete loss of function but rather an asymmetrical residual functioning of the vestibular system. The purpose of the current study was to investigate navigational ability and hippocampal atrophy in BVP patients with residual vestibular function. Fifteen patients with BVP and a group of age- and gender- matched healthy controls were examined. Self-reported questionnaires on spatial anxiety and wayfinding were used to assess the applied strategy of wayfinding and quality of life. Spatial memory and navigation were tested directly using a virtual Morris Water Maze Task. The hippocampal volume of these two groups was evaluated by voxel-based morphometry. In the patients, the questionnaire showed a higher spatial anxiety and the Morris Water Maze Task a delayed spatial learning performance. MRI revealed a significant decrease in the gray matter mid-hippocampal volume (Left: p = 0.006, Z = 4.58, Right: p < 0.001, Z = 3.63) and posterior parahippocampal volume (Right: p = 0.005, Z = 4.65, Left: p < 0.001, Z = 3.87) compared to those of healthy controls. In addition, a decrease in hippocampal formation volume correlated with a more dominant route-finding strategy. Our current findings demonstrate that even partial bilateral vestibular loss leads to anatomical and functional changes in the hippocampal formation and objective and subjective behavioral deficits.

The effect of supine body position on human heading perception.

The use of virtual environments in functional imaging experiments is a promising method to investigate and understand the neural basis of human navigation and self-motion perception. However, the supine position in the fMRI scanner is unnatural for everyday motion. In particular, the head-horizontal self-motion plane is parallel rather than perpendicular to gravity. Earlier studies have shown that perception of heading from visual self-motion stimuli, such as optic flow, can be modified due to visuo-vestibular interactions. With this study, we aimed to identify the effects of the supine body position on visual heading estimation, which is a basic component of human navigation. Visual and vestibular heading judgments were measured separately in 11 healthy subjects in upright and supine body positions. We measured two planes of self-motion, the transverse and the coronal plane, and found that, although vestibular heading perception was strongly modified in a supine position, visual performance, in particular for the preferred head-horizontal (i.e., transverse) plane, did not change. This provides behavioral evidence in humans that direction estimation from self-motion consistent optic flow is not modified by supine body orientation, demonstrating that visual heading estimation is one component of human navigation that is not influenced by the supine body position required for functional brain imaging experiments.

Aural localization of silent objects by active human biosonar: neural representations of virtual echo-acoustic space.

Some blind humans have developed the remarkable ability to detect and localize objects through the auditory analysis of self-generated tongue clicks. These echolocation experts show a corresponding increase in 'visual' cortex activity when listening to echo-acoustic sounds. Echolocation in real-life settings involves multiple reflections as well as active sound production, neither of which has been systematically addressed. We developed a virtualization technique that allows participants to actively perform such biosonar tasks in virtual echo-acoustic space during magnetic resonance imaging (MRI). Tongue clicks, emitted in the MRI scanner, are picked up by a microphone, convolved in real time with the binaural impulse responses of a virtual space, and presented via headphones as virtual echoes. In this manner, we investigated the brain activity during active echo-acoustic localization tasks. Our data show that, in blind echolocation experts, activations in the calcarine cortex are dramatically enhanced when a single reflector is introduced into otherwise anechoic virtual space. A pattern-classification analysis revealed that, in the blind, calcarine cortex activation patterns could discriminate left-side from right-side reflectors. This was found in both blind experts, but the effect was significant for only one of them. In sighted controls, 'visual' cortex activations were insignificant, but activation patterns in the planum temporale were sufficient to discriminate left-side from right-side reflectors. Our data suggest that blind and echolocation-trained, sighted subjects may recruit different neural substrates for the same active-echolocation task.

An fMRI investigation of expectation violation in magic tricks.

Magic tricks violate the expected causal relationships that form an implicit belief system about what is possible in the world around us. Observing a magic effect seemingly invalidates our implicit assumptions about what action causes which outcome. We aimed at identifying the neural correlates of such expectation violations by contrasting 24 video clips of magic tricks with 24 control clips in which the expected action-outcome relationship is upheld. Using fMRI, we measured the brain activity of 25 normal volunteers while they watched the clips in the scanner. Additionally, we measured the professional magician who had performed the magic tricks under the assumption that, in contrast to naïve observers, the magician himself would not perceive his own magic tricks as an expectation violation. As the main effect of magic - control clips in the normal sample, we found higher activity for magic in the head of the caudate nucleus (CN) bilaterally, the left inferior frontal gyrus and the left anterior insula. As expected, the magician's brain activity substantially differed from these results, with mainly parietal areas (supramarginal gyrus bilaterally) activated, supporting our hypothesis that he did not experience any expectation violation. These findings are in accordance with previous research that has implicated the head of the CN in processing changes in the contingency between action and outcome, even in the absence of reward or feedback.