Novel ways to modulate the vestibular system: Magnetic vestibular stimulation, deep brain stimulation and transcranial magnetic stimulation / transcranial direct current stimulation.

BACKGROUND: Advances in neurotechnologies are revolutionizing our understanding of complex neural circuits and enabling new treatments for disorders of the human brain. In the vestibular system, electromagnetic stimuli can now modulate vestibular reflexes and sensations of self-motion by artificially stimulating the labyrinth, cerebellum, cerebral cortex, and their connections. OBJECTIVE: In this narrative review, we describe evolving neuromodulatory techniques including magnetic vestibular stimulation (MVS), deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), and transcranial direct-current stimulation (tDCS) and discuss current and potential future application in the field of neuro-otology. RESULTS: MVS triggers both vestibular nystagmic (persistent) and perceptual (lasting ∼1 min) responses that may serve as a model to study central adaptational mechanisms and pathomechanisms of hemispatial neglect. By systematically mapping DBS electrodes, targeted stimulation of central vestibular pathways allowed modulating eye movements, vestibular heading perception, spatial attention and graviception, resulting in reduced anti-saccade error rates and hypometria, improved heading discrimination, shifts in verticality perception and transiently decreased spatial attention. For TMS/tDCS treatment trials have demonstrated amelioration of vestibular symptoms in various neuro-otological conditions, including chronic vestibular insufficiency, Mal-de-Debarquement and cerebellar ataxia. CONCLUSION: Neuromodulation has a bright future as a potential treatment of vestibular dysfunction. MVS, DBS and TMS may provide new and sophisticated, customizable, and specific treatment options of vestibular symptoms in humans. While promising treatment responses have been reported for TMS/tDCS, treatment trials for vestibular disorders using MVS or DBS have yet to be defined and performed.

[Cerebral and spinal cavernomas]. / Zerebrale und spinale Kavernome.

CLINICAL/METHODICAL ISSUE: Cavernous malformations or cavernomas belong to the angiodysplasias. They may be sporadic or familial and cause symptoms (epilepsy) despite the absence of a left-to-right shunt. In addition to intracranial locations, spinal cavernomas are also found. STANDARD RADIOLOGICAL METHODS: Magnetic resonance imaging (MRI) and computed tomography (CT) are used for diagnosis PERFORMANCE: MRI, except for acutely or subacutely hemorrhaged cavernomas, is superior to CT for lesion detection. ACHIEVEMENTS: CT is reserved for acute diagnosis. MRI, especially susceptibility-sensitive gradient echo sequences, can also detect cavernomas without (sub-)acute hemorrhage or calcifications. PRACTICAL RECOMMENDATIONS: MRI is also useful for differentiating the familial form vs. sporadic form. Digital subtraction angiography (DSA) is used for differential diagnosis in rare cases, as cavernomas show no correlate here.

Pattern analysis of peripheral-vestibular deficits with machine learning using hierarchical clustering.

Background Disorders affecting the vestibular organs (semicircular canals, utriculus, sacculus), may result in distinct patterns of peripheral-vestibular loss that may facilitate the diagnostic assessment. When neuropathological tests of these sensors are available, it is possible to classify responses as being due to different deficit types. Objective To provide a topical review and to summarize recent advances in pattern-recognition of unilateral and bilateral vestibular disease by use of hierarchical cluster analysis (HCA) as published by the authors. Hypothesis We propose that certain patterns of peripheral-vestibular loss are associated with specific underlying disorders and that HCA is a suitable approach to identify such patterns. Discussion In the studies reviewed, disease-specific patterns could be recognized in different patient cohorts, with anterior-canal sparing being a hallmark feature in aminoglycoside-related bilateral vestibulopathy, Menière's disease and vestibular Schwannoma. The reasons for such anterior-canal sparing remain subject to debate, but potential explanations include reduced toxic exposure, faster recovery and lower vulnerability of the anterior canals. The pattern observed in acute superior-branch vestibular neuropathy, i.e., involvement of the horizontal and anterior canal and the utricle, matches neural inner-ear physiology. The broadly varying extent of damage to the different vestibular sensors even within given disorders underlines the necessity for detailed vestibular-testing. Conclusion HCA significantly facilitates pattern-identification in unilateral and bilateral vestibulopathies and underlines the extensive range of vestibular end-organ damage in the different study populations and subgroups. The large number of existing clustering algorithms with distinct strengths and weaknesses emphasizes the need for careful selection of the most suitable algorithm.

Influence of panoramic cues during prolonged roll-tilt adaptation on the percept of vertical.

The percept of vertical, which mainly relies on vestibular and visual cues, is known to be affected after sustained whole-body roll tilt, mostly at roll positions adjacent to the position of adaptation. Here we ask whether the viewing of panoramic visual cues during the adaptation further influences the percept of the visual vertical. Participants were rotated in the frontal plane to a 90° clockwise tilt position, which was maintained for 4-minutes. During this period, the subject was either kept in darkness, or viewed panoramic pictures that were either veridical (aligned with gravity) or oriented along the body longitudinal axis. Errors of the subsequent subjective visual vertical (SVV), measured at various tilt angles, showed that the adaptation effect of panoramic cues is local, i.e. for a narrow range of tilts in the direction of the adaptation angle. This distortion was found irrespective of the orientation of the panoramic cues. We conclude that sustained exposure to panoramic and vestibular cues does not adapt the subsequent percept of vertical to the direction of the panoramic cue. Rather, our results suggest that sustained panoramic cues affect the SVV by an indirect effect on head orientation, with a 90° periodicity, that interacts with a vestibular cue to determine the percept of vertical.

Effects of prolonged roll-tilt on the subjective visual and haptic vertical in healthy human subjects.

BACKGROUND: While verticality perception is normally accurate when upright, a systematic bias ("post-tilt bias") is seen after prolonged roll-tilt. The source of the bias could either be central (shifting "null" position) or related to changes in torsional eye-position. OBJECTIVE: To study the mechanisms of the post-tilt bias in vision-dependent and vision-independent paradigms and to characterize the impact of optokinetic stimulation. METHODS: The subjective visual-vertical (SVV) and subjective haptic-vertical (SHV) were measured after static roll-tilt (±90deg ear-down ("adaptation") position; duration = 5 min; n = 9 subjects). To assess the effect of visual stimuli, a control condition (darkness) was compared with an optokinetic stimulus (clockwise/counter-clockwise rotation, 60deg/sec) during adaptation. RESULTS: A significant post-tilt bias was more frequent for the SVV than the SHV (72% vs. 54%, p = 0.007) with shifts pointing towards or away from the adaptation position with similar frequency. Exponential-decay time-constants were comparable for both paradigms and directions of shifts. The optokinetic stimulus had no effect on the bias for either paradigm. CONCLUSIONS: Emerging in both vision-dependent and vision-independent paradigms, the results support the hypothesis that the post-tilt bias results from a shift in the internal estimate of direction of gravity, while optokinetic nystagmus seems not to be a major contributor.

Precision of perceived direction of gravity in partial bilateral vestibulopathy correlates with residual utricular function.

OBJECTIVE: Gait imbalance in patients with bilateral-vestibular-deficiency (BVD) was linked to increased variability in perceived direction of gravity while upright. We hypothesized this to be true also when roll-tilted. Moreover, as utricular input is essential for spatial orientation, we predicted the variability of perceived vertical to correlate inversely with utricular function. METHODS: Subjective visual vertical (SVV) and haptic vertical (SHV) were measured in various roll-orientations (0°/±45°/±90°) and postural adjustments along earth-vertical/earth-horizontal were collected in patients with partial BVD (n = 10) and healthy controls (n = 11). Patients with bilaterally-absent bone-conducted ocular vestibular-evoked myogenic-potentials (oVEMPs) were compared to those with (partially) preserved oVEMPs. RESULTS: For the SVV (p < 0.001) and SHV (p = 0.004) variability was larger in patients than controls. Compared to those with (partially) preserved oVEMPs, patients with bilaterally-absent oVEMPs had higher SVV (p = 0.024) and SHV (p = 0.006) variability. Self-positioning along earth-horizontal was more variable in BVD-patients compared to controls (p < 0.001). Again, variability was higher in those with bilaterally-absent oVEMPs (p = 0.032). SVV/SHV-variability was correlated (R2 = 0.61, slope = 1.06 [95%-CI = 0.80-1.54]) in BVD-patients. CONCLUSION: With variability correlating amongst the different paradigms and with oVEMP-responses, this emphasizes the role of bilaterally intact utricular input for precise perception of gravity. SIGNIFICANCE: In BVD-patients with bilaterally-absent oVEMPs intensified vestibular rehabilitation should be considered.

Persistent effects of playing football and associated (subconcussive) head trauma on brain structure and function: a systematic review of the literature.

AIM/OBJECTIVE: There is ongoing controversy about persistent neurological deficits in active and former football (soccer) players. We reviewed the literature for associations between football activities (including heading/head injuries) and decline in brain structure/function. DESIGN: Systematic literature review. DATA SOURCES: MEDLINE, Embase, PsycINFO, CINAHL, Cochrane-CRCT, SportDiscus, Cochrane-DSR=4 (accessed 2 August 2016). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Original studies reporting on football-related persistent effects on brain structure/function. Results from neurocognitive testing, neuroimaging and EEG were compared with controls and/or correlated with heading frequency and/or head injuries. Methodological quality was rated for risk-of-bias, including appropriateness of controls, correction for multiple statistical testing and assessment of heading frequency and head injuries. RESULTS: 30 studies with 1691 players were included. Those 57% (8/14) of case-control studies reporting persistent neurocognitive impairment had higher odds for inappropriate control of type 1 errors (OR=17.35 (95% CI (10.61 to 28.36)) and for inappropriate selection of controls (OR=1.72 (1.22 to 2.43)) than studies observing no impairment. Studies reporting a correlation between heading frequency and neurocognitive deficits (6/17) had lower quality of heading assessment (OR=14.20 (9.01 to 22.39)) than studies reporting no such correlation. In 7 of 13 studies (54%), the number of head injuries correlated with the degree of neurocognitive impairment. Abnormalities on neuroimaging (6/8 studies) were associated with subclinical neurocognitive deficits in 3 of 4 studies. SUMMARY/CONCLUSIONS: Various methodological shortcomings limit the evidence for persistent effects of football play on brain structure/function. Sources of bias include low-quality assessment of heading frequency, inappropriate control for type 1 errors and inappropriate selection of controls. Combining neuroimaging techniques with neurocognitive testing in prospective studies seems most promising to further clarify on the impact of football on the brain.

Does gravity influence the visual line bisection task?

The visual line bisection task (LBT) is sensitive to perceptual biases of visuospatial attention, showing slight leftward (for horizontal lines) and upward (for vertical lines) errors in healthy subjects. It may be solved in an egocentric or allocentric reference frame, and there is no obvious need for graviceptive input. However, for other visual line adjustments, such as the subjective visual vertical, otolith input is integrated. We hypothesized that graviceptive input is incorporated when performing the LBT and predicted reduced accuracy and precision when roll-tilted. Twenty healthy right-handed subjects repetitively bisected Earth-horizontal and body-horizontal lines in darkness. Recordings were obtained before, during, and after roll-tilt (±45°, ±90°) for 5 min each. Additionally, bisections of Earth-vertical and oblique lines were obtained in 17 subjects. When roll-tilted ±90° ear-down, bisections of Earth-horizontal (i.e., body-vertical) lines were shifted toward the direction of the head (P < 0.001). However, after correction for vertical line-bisection errors when upright, shifts disappeared. Bisecting body-horizontal lines while roll-tilted did not cause any shifts. The precision of Earth-horizontal line bisections decreased (P ≤ 0.006) when roll-tilted, while no such changes were observed for body-horizontal lines. Regardless of the trial condition and paradigm, the scanning direction of the bisecting cursor (leftward vs. rightward) significantly (P ≤ 0.021) affected line bisections. Our findings reject our hypothesis and suggest that gravity does not modulate the LBT. Roll-tilt-dependent shifts are instead explained by the headward bias when bisecting lines oriented along a body-vertical axis. Increased variability when roll-tilted likely reflects larger variability when bisecting body-vertical than body-horizontal lines.

Pitfalls in the diagnostic evaluation of subacute combined degeneration.

We report a case of a 43-year-old man presenting with a 2-week history of painless ascending sensory disturbances, suspected to be suffering from acute inflammatory polyneuropathy. On clinical examination, deep tendon reflexes were preserved and muscle strength was 5/5 everywhere. Gait was ataxic with positive Romberg test. Lumbar puncture was normal and electroneurography demonstrated demyelination. With spinal cord involvement centred on the posterior tracts on MRI, differential diagnosis focused on cobalamin deficiency. Initial laboratory work up showed nearly normal holotranscobalamin (43 pmol/L, normal>50) suggesting no vitamin B12 deficiency. Surprisingly, further testing including methylmalonic acid (3732 nmol/L, normal<271) and homocysteine (48.5 µmol/L, normal<10) showed an impairment of vitamin B12-dependent metabolism leading to the diagnosis of subacute combined degeneration. Only after repeated history taking did the patient remember having taken tablets containing cobalamin for 3 days before hospitalisation. In case of B12 deficiency, holotranscobalamin can rapidly normalise during supplementation, whereas methylmalonic acid and homocysteine might help to detect B12 deficiency in patients who recently started supplementation.

Cetuximab induced aseptic meningitis.

We report a 67-year-old man with recurrent advanced oropharyngeal squamous cell carcinoma who developed aseptic meningitis, with first symptoms arising approximately 9hours after the first administration of cetuximab, and review the literature to identify key signs and symptoms of this condition. Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor which has been rarely associated with aseptic meningitis. Besides the case description, a MEDLINE search was performed. In five patients identified in the literature and our patient, the leading signs and symptoms included headache, neck stiffness and high fever developing within a few hours of the first cetuximab administration. Cerebrospinal fluid (CSF) analysis revealed severe pleocytosis (range: 528-2300/µl) with dominance of neutrophils (⩾87%). Clinical recovery within 1-2weeks was accompanied by normalization of CSF cell count within 4-7days. Re-challenge with cetuximab at a reduced dose caused recurrent aseptic meningitis in one of three patients. In summary, aseptic meningitis is a rare complication after first cetuximab exposure that the clinician should be aware of. CSF analysis is the key to diagnosis and recovery is usually complete within days to weeks after withdrawal of the drug. Re-challenge may be considered but bears the risk of recurrence.

Boucher-Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature.

The combination of progressive cerebellar degeneration, hypogonadotropic hypogonadism and chorioretinal dystrophy defines the rare Boucher-Neuhäuser syndrome (BNS), which has recently been linked to autosomal-recessive mutations in the PNPLA6 gene in four index patients. Here we present two novel unrelated patients with BNS, where we identified four recessive PNPLA6 mutations (3 of them novel) as the genetic cause, using a targeted high-throughput approach. This finding provides the first replication from independent families that BNS is caused by PNPLA6 and, moreover, highlights PNPLA6 as the major gene leading to BNS. Given the fact that the major gene causing BNS has thus now been identified, we summarize the spectrum of clinical presentations and phenotype evolution of BNS based on a systematic in-depth review of the literature of previously published cases (n = 40). Both the two cases presented here and our review of the literature propose that the clinical presentation of BNS can be variable regarding both the age (ranging from 1 to 40 years) and the clinical symptoms at onset (cerebellar ataxia in 38 %; vision loss in 36 %; delayed puberty in 26 %). A substantial fraction of BNS cases may present with relatively selective atrophy of the superior and dorsal parts of the cerebellar vermis along with atrophy of the cerebellar hemispheres on MRI, while brainstem or cortical changes on MRI seem to be present only in small fractions. Also in the literature, no other major genetic causes of BNS other than PNPLA6 mutations were identified.

Static roll-tilt over 5 minutes locally distorts the internal estimate of direction of gravity.

The subjective visual vertical (SVV) indicates perceived direction of gravity. Even in healthy human subjects, roll angle-dependent misestimations, roll overcompensation (A-effect, head-roll > 60° and <135°) and undercompensation (E-effect, head-roll < 60°), occur. Previously, we demonstrated that, after prolonged roll-tilt, SVV estimates when upright are biased toward the preceding roll position, which indicates that perceived vertical (PV) is shifted by the prior tilt (Tarnutzer AA, Bertolini G, Bockisch CJ, Straumann D, Marti S. PLoS One 8: e78079, 2013). Hypothetically, PV in any roll position could be biased toward the previous roll position. We asked whether such a "global" bias occurs or whether the bias is "local". The SVV of healthy human subjects (N = 9) was measured in nine roll positions (-120° to +120°, steps = 30°) after 5 min of roll-tilt in one of two adaptation positions (±90°) and compared with control trials without adaptation. After adapting, adjustments were shifted significantly (P < 0.05) toward the previous adaptation position for nearby roll-tilted positions (±30°, ±60°) and upright only. We computationally simulated errors based on the sum of a monotonically increasing function (producing roll undercompensation) and a mixture of Gaussian functions (representing roll overcompensation centered around PV). In combination, the pattern of A- and E-effects could be generated. By shifting the function representing local overcompensation toward the adaptation position, the experimental postadaptation data could be fitted successfully. We conclude that prolonged roll-tilt locally distorts PV rather than globally shifting it. Short-term adaptation of roll overcompensation may explain these shifts and could reflect the brain's strategy to optimize SVV estimates around recent roll positions. Thus postural stability can be improved by visually-mediated compensatory responses at any sustained body-roll orientation.

Continuous theta-burst stimulation of the right superior temporal gyrus impairs self-motion perception.

Sensory input from the semicircular canals (SCC) and otolith organs is centrally combined with signals from other sensory modalities to continuously update the internal estimate of self-motion. Constant velocity vertical on-axis rotation leads to decay of the nystagmus response from the horizontal SCC and of perceived angular velocity (PAV), and when the rotation stops, a similar oppositely directed post-rotatory response occurs. Case reports and electrical stimulation studies suggest an involvement of the temporo-peri-Sylvian vestibular cortex in generating the PAV. Here, we transiently inhibited the right superior temporal gyrus (STG) by use of continuous theta-burst stimulation (cTBS) and predicted an accelerated decay of PAV compared to controls (n = 5 control session first, n = 1 cTBS session first). Constant velocity (100°/s) vertical on-axis rotations were applied over 75 s before (1 block) and after (3 blocks) cTBS over the right STG in six subjects. Breaks between the rotations (75 s) were initiated by abrupt stops. By use of a rotating potentiometer, subjects indicated the PAV during and after the chair rotations. Simultaneously eye positions were recorded using a scleral search coil. One subject was excluded for per-rotary analysis. Early after cTBS, the post-rotary PAV decay time constant (DTC) was significantly (9.4 ± 5.7 vs. 13.6 ± 5.9 s; p = 0.049) reduced (no directionality to this effect observed). Overall, post-rotary PAV showed a trend toward shortened DTC compared to the control trials (p = 0.086) in the first 25 min after cTBS, while per-rotary PAV was not significantly changed. Per-rotary and post-rotary aVOR DTC were not significantly changed after cTBS (p > 0.05). These findings support the hypothesis that the right STG is involved in mediating self-motion perception and can be modulated by cTBS.

Visually guided adjustments of body posture in the roll plane.

Body position relative to gravity is continuously updated to prevent falls. Therefore, the brain integrates input from the otoliths, truncal graviceptors, proprioception and vision. Without visual cues estimated direction of gravity mainly depends on otolith input and becomes more variable with increasing roll-tilt. Contrary, the discrimination threshold for object orientation shows little modulation with varying roll orientation of the visual stimulus. Providing earth-stationary visual cues, this retinal input may be sufficient to perform self-adjustment tasks successfully, with resulting variability being independent of whole-body roll orientation. We compared conditions with informative (earth-fixed) and non-informative (body-fixed) visual cues. If the brain uses exclusively retinal input (if earth-stationary) to solve the task, trial-to-trial variability will be independent from the subject's roll orientation. Alternatively, central integration of both retinal (earth-fixed) and extra-retinal inputs will lead to increasing variability when roll-tilted. Subjects, seated on a motorized chair, were instructed to (1) align themselves parallel to an earth-fixed line oriented earth-vertical or roll-tilted 75° clockwise; (2) move a body-fixed line (aligned with the body-longitudinal axis or roll-tilted 75° counter-clockwise to it) by adjusting their body position until the line was perceived earth-vertical. At 75° right-ear-down position, variability increased significantly (p < 0.05) compared to upright in both paradigms, suggesting that, despite the earth-stationary retinal cues, extra-retinal input is integrated. Self-adjustments in the roll-tilted position were significantly (p < 0.01) more precise for earth-fixed cues than for body-fixed cues, underlining the importance of earth-stable visual cues when estimates of gravity become more variable with increasing whole-body roll.

How stable is perceived direction of gravity over extended periods in darkness?

Previous studies reported linear drift of perceived vertical for brief (≤10 min) observation periods. Here, we repeated estimates of direction of gravity up to 60 min to evaluate whether the drift is sustained, shows saturation or even reverses over time. Fifteen healthy human subjects repetitively adjusted a luminous line along subjective visual vertical (SVV) and horizontal (SVH) over periods of 5 min (constituting one block). We obtained seven blocks within 60 min in each subject for SVV and SVH. In between the first six blocks, subjects remained in darkness for 5 min each, whereas the lights were briefly turned on before block 7. We noted significantly (p < 0.05) increased errors in perceived direction of gravity by block 2 (SVV) and 3 (SVH). These increases disappeared after turning on the lights before block 7. Focusing on blocks 2-6, significant drift started from similar offset positions and pointed to the same direction in a majority of runs in 9/15 (SVV) and 11/15 (SVH) subjects. When pooling data from all blocks, orthogonality of errors was lost in all subjects. Trial-to-trial variability remained stable over the seven runs for SVV and SVH. Only when pooling all runs, precision was significantly (p < 0.05) higher for the SVH. Our findings suggest that perceived direction of gravity continues to fluctuate over extended recording periods with individuals showing unique patterns of direction-specific drift while variability remains stable. As subjects were upright during the entire experiment and as drift persisted over several blocks, sensory adaptation seems unlikely. We therefore favor a central origin of this kind of drift.

Temporal constancy of perceived direction of gravity assessed by visual line adjustments.

Here we investigated how well internal estimates of direction of gravity are preserved over time and if the subjective visual vertical (SVV) and horizontal (SVH) can be used inter-changeably. Fourteen human subjects repetitively aligned a luminous line to SVV, SVH or subjective visual oblique (± 45°) over 5 min in otherwise complete darkness and also in dim light. Both accuracy (i.e., the degree of veracity as reflected by the median adjustment error) and precision (i.e., the degree of reproducability as reflected by the trial-to-trial variability) of adjustments along the principle axes were significantly higher than along the oblique axes. Orthogonality was only preserved in a minority of subjects. Adjustments were significantly different between SVV vs. SVH (7/14 subjects) and between ±45° vs. -45° (12/14) in darkness and in 6/14 and 14/14 subjects, respectively, in dim light. In darkness, significant drifts over 5min were observed in a majority of trials (33/56). Both accuracy and precision were higher if more time was taken to make the adjustment. These results introduce important caveats when interpreting studies related to graviception. The test re-test reliability of SVV and SVH can be influenced by drift of the internal estimate of gravity. Based on spectral density analysis we found a noise pattern consistent with 1/fß noise, indicating that at least part of the trial-to-trial dynamics observed in our experiments is due to the dependence of the serial adjustments over time. Furthermore, using results from the SVV and SVH inter-changeably may be misleading as many subjects do not show orthogonality. The poor fidelity of perceived ± 45° indicates that the brain has limited ability to estimate oblique angles.

Roll-dependent modulation of the subjective visual vertical: contributions of head- and trunk-based signals.

Precision and accuracy of the subjective visual vertical (SVV) modulate in the roll plane. At large roll angles, systematic SVV errors are biased toward the subject's body-longitudinal axis and SVV precision is decreased. To explain this, SVV models typically implement a bias signal, or a prior, in a head-fixed reference frame and assume the sensory input to be optimally tuned along the head-longitudinal axis. We tested the pattern of SVV adjustments both in terms of accuracy and precision in experiments in which the head and the trunk reference frames were not aligned. Twelve subjects were placed on a turntable with the head rolled about 28 degrees counterclockwise relative to the trunk by lateral tilt of the neck to dissociate the orientation of head- and trunk-fixed sensors relative to gravity. Subjects were brought to various positions (roll of head- or trunk-longitudinal axis relative to gravity: 0 degrees , +/-75 degrees ) and aligned an arrow with perceived vertical. Both accuracy and precision of the SVV were significantly (P < 0.05) better when the head-longitudinal axis was aligned with gravity. Comparing absolute SVV errors for clockwise and counterclockwise roll tilts, statistical analysis yielded no significant differences (P > 0.05) when referenced relative to head upright, but differed significantly (P < 0.001) when referenced relative to trunk upright. These findings indicate that the bias signal, which drives the SVV toward the subject's body-longitudinal axis, operates in a head-fixed reference frame. Further analysis of SVV precision supports the hypothesis that head-based graviceptive signals provide the predominant input for internal estimates of visual vertical.

Gravity dependence of subjective visual vertical variability.

The brain integrates sensory input from the otolith organs, the semicircular canals, and the somatosensory and visual systems to determine self-orientation relative to gravity. Only the otoliths directly sense the gravito-inertial force vector and therefore provide the major input for perceiving static head-roll relative to gravity, as measured by the subjective visual vertical (SVV). Intraindividual SVV variability increases with head roll, which suggests that the effectiveness of the otolith signal is roll-angle dependent. We asked whether SVV variability reflects the spatial distribution of the otolithic sensors and the otolith-derived acceleration estimate. Subjects were placed in different roll orientations (0-360 degrees, 15 degrees steps) and asked to align an arrow with perceived vertical. Variability was minimal in upright, increased with head-roll peaking around 120-135 degrees, and decreased to intermediate values at 180 degrees. Otolith-dependent variability was modeled by taking into consideration the nonuniform distribution of the otolith afferents and their nonlinear firing rate. The otolith-derived estimate was combined with an internal bias shifting the estimated gravity-vector toward the body-longitudinal. Assuming an efficient otolith estimator at all roll angles, peak variability of the model matched our data; however, modeled variability in upside-down and upright positions was very similar, which is at odds with our findings. By decreasing the effectiveness of the otolith estimator with increasing roll, simulated variability matched our experimental findings better. We suggest that modulations of SVV precision in the roll plane are related to the properties of the otolith sensors and to central computational mechanisms that are not optimally tuned for roll-angles distant from upright.

Gaze fixation deficits and their implication in ataxia-telangiectasia.

BACKGROUND AND AIMS: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterised by progressive neurological deficits, including prominent ocular motor dysfunction. Unstable fixation often leads to difficulty reading and blurred vision. Here we characterise the disturbance of visual fixation in A-T. METHODS: Eye movements were recorded from 13 A-T patients (with dual search coils in five patients and video oculography in seven) during attempted fixation. RESULTS: Two abnormalities--nystagmus and saccadic intrusions--were common. Horizontal, vertical and torsional nystagmus was present in straight ahead (spontaneous nystagmus) and eccentric gaze (gaze evoked nystagmus). In eight patients the horizontal nystagmus changed directions--periodic alternating nystagmus (PAN). Two types of saccadic intrusions were seen--micro-saccadic oscillations (SO) and square wave saccadic intrusions (SWSI). SO were small amplitude (0.1-0.9 degrees) and high frequency (14-33 Hz) back to back horizontal saccades. SWSI ranged between 1 degree and 18 degrees (median 3 degrees) with an intersaccadic interval ranging between 50 and 800 ms (median 300 ms). The potential impact of abnormal gaze stabilisation on vision was quantified. DISCUSSION: Degeneration of cerebellar Purkinje neurons disinhibit the caudal fastigial oculomotor region (FOR) and vestibular nuclei (VN). Disinhibition of VN can cause nystagmus, including PAN, while disinhibition of FOR can affect saccade generating mechanisms, leading to SWSI and SO.