Whole-Brain Calcium Imaging during Physiological Vestibular Stimulation in Larval Zebrafish.
ABSTRACT: The vestibular apparatus provides animals with postural and movement-related information that is essential to adequately execute numerous sensorimotor tasks. In order to activate this sensory system in a physiological manner, one needs to macroscopically rotate or translate the animal's head, which in turn renders simultaneous neural recordings highly challenging. Here we report on a novel miniaturized, light-sheet microscope that can be dynamically co-rotated with a head-restrained zebrafish larva, enabling controlled vestibular stimulation. The mechanical rigidity of the microscope allows one to perform whole-brain functional imaging with state-of-the-art resolution and signal-to-noise ratio while imposing up to 25° in angular position and 6,000°/s2 in rotational acceleration. We illustrate the potential of this novel setup by producing the first whole-brain response maps to sinusoidal and stepwise vestibular stimulation. The responsive population spans multiple brain areas and displays bilateral symmetry, and its organization is highly stereotypic across individuals. Using Fourier and regression analysis, we identified three major functional clusters that exhibit well-defined phasic and tonic response patterns to vestibular stimulation. Our rotatable light-sheet microscope provides a unique tool for systematically studying vestibular processing in the vertebrate brain and extends the potential of virtual-reality systems to explore complex multisensory and motor integration during simulated 3D navigation.
Project description:Vertigo in and around magnetic resonance imaging (MRI) machines has been noted for years [1, 2]. Several mechanisms have been suggested to explain these sensations [3, 4], yet without direct, objective measures, the cause is unknown. We found that all of our healthy human subjects developed a robust nystagmus while simply lying in the static magnetic field of an MRI machine. Patients lacking labyrinthine function did not. We use the pattern of eye movements as a measure of vestibular stimulation to show that the stimulation is static (continuous, proportional to static magnetic field strength, requiring neither head movement nor dynamic change in magnetic field strength) and directional (sensitive to magnetic field polarity and head orientation). Our calculations and geometric model suggest that magnetic vestibular stimulation (MVS) derives from a Lorentz force resulting from interaction between the magnetic field and naturally occurring ionic currents in the labyrinthine endolymph fluid. This force pushes on the semicircular canal cupula, leading to nystagmus. We emphasize that the unique, dual role of endolymph in the delivery of both ionic current and fluid pressure, coupled with the cupula's function as a pressure sensor, makes magnetic-field-induced nystagmus and vertigo possible. Such effects could confound functional MRI studies of brain behavior, including resting-state brain activity.
Project description:The integration of neck proprioceptive and vestibular inputs underlies the generation of accurate postural and motor control. Recent studies have shown that central mechanisms underlying the integration of these sensory inputs differ across species. Notably, in rhesus monkey (Macaca mulata), an Old World monkey, neurons in the vestibular nuclei are insensitive to passive stimulation of neck proprioceptors. In contrast, in squirrel monkey, a New World monkey, stimulation produces robust modulation. This has led to the suggestion that there are differences in how sensory information is integrated during self-motion in Old versus New World monkeys. To test this hypothesis, we recorded from neurons in the vestibular nuclei of another species in the Macaca genus [i.e., M. fascicularis (cynomolgus monkey)]. Recordings were made from vestibular-only (VO) and position-vestibular-pause (PVP) neurons. The majority (53%) of neurons in both groups were sensitive to neck proprioceptive and vestibular stimulation during passive body-under-head and whole-body rotation, respectively. Furthermore, responses during passive rotations of the head-on-body were well predicted by the linear summation of vestibular and neck responses (which were typically antagonistic). During active head movement, the responses of VO and PVP neurons were further attenuated (relative to a model based on linear summation) for the duration of the active head movement or gaze shift, respectively. Taken together, our findings show that the brain's strategy for the central processing of sensory information can vary even within a single genus. We suggest that similar divergence may be observed in other areas in which multimodal integration occurs.
Project description:A major focus in neurobiology is how the brain adapts its motor behavior to changes in its internal and external environments [1, 2]. Much is known about adaptively optimizing the amplitude and direction of eye and limb movements, for example, but little is known about another essential form of learning, "set-point" adaptation. Set-point adaptation balances tonic activity so that reciprocally acting, agonist and antagonist muscles have a stable platform from which to launch accurate movements. Here, we use the vestibulo-ocular reflex-a simple behavior that stabilizes the position of the eye while the head is moving-to investigate how tonic activity is adapted toward a new set point to prevent eye drift when the head is still [3, 4]. Set-point adaptation was elicited with magneto-hydrodynamic vestibular stimulation (MVS) by placing normal humans in a 7T MRI for 90 min. MVS is ideal for prolonged labyrinthine activation because it mimics constant head acceleration and induces a sustained nystagmus similar to natural vestibular lesions [5, 6]. The MVS-induced nystagmus diminished slowly but incompletely over multiple timescales. We propose a new adaptation hypothesis, using a cascade of imperfect mathematical integrators, that reproduces the response to MVS (and more natural chair rotations), including the gradual decrease in nystagmus as the set point changes over progressively longer time courses. MVS set-point adaptation is a biological model with applications to basic neurophysiological research into all types of movements , functional brain imaging , and treatment of vestibular and higher-level attentional disorders by introducing new biases to counteract pathological ones .
Project description:Vestibular neuritis (VN) is characterised by acute vertigo due to a sudden loss of unilateral vestibular function. A considerable proportion of VN patients proceed to develop chronic symptoms of dizziness, including visually induced dizziness, specifically during head turns. Here we investigated whether the development of such poor clinical outcomes following VN, is associated with abnormal visuo-vestibular cortical processing. Accordingly, we applied functional magnetic resonance imaging to assess brain responses of chronic VN patients and compared these to controls during both congruent (co-directional) and incongruent (opposite directions) visuo-vestibular stimulation (i.e. emulating situations that provoke symptoms in patients). We observed a focal significant difference in BOLD signal in the primary visual cortex V1 between patients and controls in the congruent condition (small volume corrected level of p?<?.05 FWE). Importantly, this reduced BOLD signal in V1 was negatively correlated with functional status measured with validated clinical questionnaires. Our findings suggest that central compensation and in turn clinical outcomes in VN are partly mediated by adaptive mechanisms associated with the early visual cortex.
Project description:Humans often experience dizziness and vertigo around strong static magnetic fields such as those present in an MRI scanner. Recent evidence supports the idea that this effect is the result of inner ear vestibular stimulation and that the mechanism is a magnetohydrodynamic force (Lorentz force) that is generated by the interactions between normal ionic currents in the inner ear endolymph and the strong static magnetic field of MRI machines. While in the MRI, the Lorentz force displaces the cupula of the lateral and anterior semicircular canals, as if the head was rotating with a constant acceleration. If a human subject's eye movements are recorded when they are in darkness in an MRI machine (i.e., without fixation), there is a persistent nystagmus that diminishes but does not completely disappear over time. When the person exits the magnetic field, there is a transient aftereffect (nystagmus beating in the opposite direction) that reflects adaptation that occurred in the MRI. This magnetic vestibular stimulation (MVS) is a useful technique for exploring set-point adaptation, the process by which the brain adapts to a change in its environment, which in this case is vestibular imbalance. Here, we review the mechanism of MVS, how MVS produces a unique stimulus to the labyrinth that allows us to explore set-point adaptation, and how this technique might apply to the understanding and treatment of vestibular and other neurological disorders.
Project description:Galvanic vestibular stimulation (GVS) can be applied to induce the feeling of directional virtual head motion by stimulating the vestibular organs electrically. Conventional studies used a two-pole GVS, in which electrodes are placed behind each ear, or a three-pole GVS, in which an additional electrode is placed on the forehead. These stimulation methods can be used to induce virtual head roll and pitch motions when a subject is looking upright. Here, we proved our hypothesis that there are current paths between the forehead and mastoids in the head and show that our invented GVS system using four electrodes succeeded in inducing directional virtual head motion around three perpendicular axes containing yaw rotation by applying different current patterns. Our novel method produced subjective virtual head yaw motions and evoked yaw rotational body sway in participants. These results support the existence of three isolated current paths located between the mastoids, and between the left and right mastoids and the forehead. Our findings show that by using these current paths, the generation of an additional virtual head yaw motion is possible.
Project description:Vestibular sensation contributes to cervical-head stabilization and fall prevention. To what extent fear of falling influences the associated vestibular feedback processes is currently undetermined. We used galanic vestibular stimulation (GVS) to induce vestibular reflexes while participants stood at ground level and on a narrow walkway at 3.85 m height to induce fear of falling. Fear was confirmed by questionnaires and elevated skin conductance. Full-body kinematics was measured to differentiate the whole-body centre of mass response (CoM) into component parts (cervical, axial trunk, appendicular short latency, and medium latency). We studied the effect of fear of falling on each component to discern their underlying mechanisms. Statistical parametric mapping analysis provided sensitive discrimination of early GVS and height effects. Kinematic analysis revealed responses at 1 mA stimulation previously believed marginal through EMG and force plate analysis. The GVS response comprised a rapid, anode-directed cervical-head acceleration, a short-latency cathode-directed acceleration (cathodal buckling) of lower extremities and pelvis, an anode-directed upper thorax acceleration, and subsequently a medium-latency anode-directed acceleration of all body parts. At height, head and upper thorax early acceleration were unaltered, however, short-latency lower extremity acceleration was increased. The effect of height on balance was a decreased duration and increased rate of change in the CoM acceleration pattern. These results demonstrate that fear modifies vestibular control of balance, whereas cervical-head stabilization is governed by different mechanisms unaffected by fear of falling. The mechanical pattern of cathodal buckling and its modulation by fear of falling both support the hypothesis that short-latency responses contribute to regulate balance.
Project description:Noisy galvanic vestibular stimulation has been associated with numerous cognitive and behavioural effects, such as enhancement of visual memory in healthy individuals, improvement of visual deficits in stroke patients, as well as possibly improvement of motor function in Parkinson's disease; yet, the mechanism of action is unclear. Since Parkinson's and other neuropsychiatric diseases are characterized by maladaptive dynamics of brain rhythms, we investigated whether noisy galvanic vestibular stimulation was associated with measurable changes in EEG oscillatory rhythms within theta (4-7.5 Hz), low alpha (8-10 Hz), high alpha (10.5-12 Hz), beta (13-30 Hz) and gamma (31-50 Hz) bands. We recorded the EEG while simultaneously delivering noisy bilateral, bipolar stimulation at varying intensities of imperceptible currents - at 10, 26, 42, 58, 74 and 90% of sensory threshold - to ten neurologically healthy subjects. Using standard spectral analysis, we investigated the transient aftereffects of noisy stimulation on rhythms. Subsequently, using robust artifact rejection techniques and the Least Absolute Shrinkage Selection Operator regression and cross-validation, we assessed the combinations of channels and power spectral features within each EEG frequency band that were linearly related with stimulus intensity. We show that noisy galvanic vestibular stimulation predominantly leads to a mild suppression of gamma power in lateral regions immediately after stimulation, followed by delayed increase in beta and gamma power in frontal regions approximately 20-25 s after stimulation ceased. Ongoing changes in the power of each oscillatory band throughout frontal, central/parietal, occipital and bilateral electrodes predicted the intensity of galvanic vestibular stimulation in a stimulus-dependent manner, demonstrating linear effects of stimulation on brain rhythms. We propose that modulation of neural oscillations is a potential mechanism for the previously-described cognitive and motor effects of vestibular stimulation, and noisy galvanic vestibular stimulation may provide an additional non-invasive means for neuromodulation of functional brain networks.
Project description:We tested the hypothesis that the brain uses a variance-based weighting of multisensory cues to estimate head rotation to perceive which way is up. The hypothesis predicts that the known bias in perceived vertical, which occurs when the visual environment is rotated in a vertical-plane, will be reduced by the addition of visual noise. Ten healthy participants sat head-fixed in front of a vertical screen presenting an annulus filled with coloured dots, which could rotate clockwise or counter-clockwise at six angular velocities (1, 2, 4, 6, 8, 16°/s) and with six levels of noise (0, 25, 50, 60, 75, 80%). Participants were required to keep a central bar vertical by rotating a hand-held dial. Continuous adjustments of the bar were required to counteract low-amplitude low-frequency noise that was added to the bar's angular position. During visual rotation, the bias in verticality perception increased over time to reach an asymptotic value. Increases in visual rotation velocity significantly increased this bias, while the addition of visual noise significantly reduced it, but did not affect perception of visual rotation velocity. The biasing phenomena were reproduced by a model that uses a multisensory variance-weighted estimate of head rotation velocity combined with a gravito-inertial acceleration signal (GIA) from the vestibular otoliths. The time-dependent asymptotic behaviour depends on internal feedback loops that act to pull the brain's estimate of gravity direction towards the GIA signal. The model's prediction of our experimental data furthers our understanding of the neural processes underlying human verticality perception.
Project description:In this dataset, we analyzed galvanic-evoked head movements (GEHMs) in the spatial planes of yaw, and roll in normal and unilaterally labyrinthectomized (UL) Wistar rats. The rats were assigned in 4 groups of 10: control, sham, right-UL and left-UL. Bilateral galvanic vestibular stimulation (GVS) was presented by our "ring-shaped electrode" design (see "Short-term galvanic vestibular stimulation promotes functional recovery and neurogenesis in unilaterally labyrinthectomized rats" (M. Shaabani et al., 2016) ). Required data were collected through video recording of GEHMs followed by image processing and statistical analysis.