Imperial College London

ProfessorAdolfoBronstein

Faculty of MedicineDepartment of Brain Sciences

Clinical Professor Head of Neuro-otology Unit
 
 
 
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Contact

 

+44 (0)20 3313 5525a.bronstein

 
 
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Assistant

 

Miss Lorna Stevenson +44 (0)20 3313 5525

 
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Location

 

10 L15bLab BlockCharing Cross Campus

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Summary

 

Publications

Publication Type
Year
to

403 results found

Anastasopoulos D, Ziavra N, Bronstein AM, 2019, Large gaze shift generation whilst standing up - the role of the vestibular system., J Neurophysiol

The functional significance of vestibular information for the generation of gaze shifts is controversial and less well established than the vestibular contribution to gaze stability. Here, we asked seven bilaterally avestibular patients to execute voluntary, whole-body pivot turns to visual targets up to 180° whilst standing. In these conditions not only the demands imposed on gaze transfer mechanisms are more challenging but also neck-proprioceptive input represents an inadequate source of head-in-space motion information. Patients' body segments motion was slower and jerky. In the absence of visual feedback, gaze advanced in small steps, closely resembling normal multiple-step gaze shift patterns but, as a consequence of the slow head motion, target acquisition was delayed. In approximately 25% of trials, however, patients moved faster but the velocity of prematurely emerging slow-phase compensatory eye movements remained lower than head-in-space velocity due to vestibulo-ocular failure. During these trials, therefore, gaze advanced towards the target without interruption but taking again longer than when normal controls use single-step gaze transfers. That is, even when patients attempted faster gaze shifts, exposing themselves to gaze instability they acquired distant targets significantly later than controls. Thus, whilst upright, loss of vestibular information not only disrupts gaze stability but also gaze transfers. The slow and ataxic head and trunk movements introduce significant foveation delays. These deficits explain patients' symptoms during upright activities and show, for the first time, the clinical significance of losing the so called "anti-compensatory" (gaze shifting) function of the vestibulo-ocular reflex.

Journal article

Arshad Q, Ortega MC, Goga U, Lobo R, Siddiqui S, Mediratta S, Bednarczuk NF, Kaski D, Bronstein AMet al., 2019, Interhemispheric control of sensory cue integration and self-motion perception, Neuroscience, Vol: 408, Pages: 378-387, ISSN: 0306-4522

Spatial orientation necessitates the integration of visual and vestibular sensory cues, in-turn facilitating self-motion perception. However, the neural mechanisms underpinning sensory integration remain unknown. Recently we have illustrated that spatial orientation and vestibular thresholds are influenced by interhemispheric asymmetries associated with the posterior parietal cortices (PPC) that predominantly house the vestibulo-cortical network. Given that sensory integration is a prerequisite to both spatial orientation and motion perception, we hypothesized that sensory integration is similarly subject to interhemispheric influences. Accordingly, we explored the relationship between vestibulo-cortical dominance – assessed using a biomarker, the degree of vestibular-nystagmus suppression following transcranial direct current stimulation over the PPC – with visual dependence measures obtained during performance of a sensory integration task (the rod-and-disk task). We observed that the degree of visual dependence was correlated with vestibulo-cortical dominance. Specifically, individuals with greater right hemispheric vestibulo-cortical dominance had reduced visual dependence. We proceeded to assess the significance of such dominance on behavior by correlating measures of visual dependence with self-motion perception in healthy subjects. We observed that right-handed individuals experienced illusionary self-motion (vection) quicker than left-handers and that the degree of vestibular cortical dominance was correlated with the time taken to experience vection, only during conditions that induced interhemispheric conflict. To conclude, we demonstrate that interhemispheric asymmetries associated with vestibulo-cortical processing in the PPC functionally and mechanistically link sensory integration and self-motion perception, facilitating spatial orientation. Our findings highlight the importance of dynamic interhemispheric competition upon control of vestib

Journal article

Khan AN, Bronstein A, Bain P, Pavese N, Nandi Det al., 2019, Pedunculopontine and Subthalamic Nucleus Stimulation Effect on Saccades in Parkinson Disease, WORLD NEUROSURGERY, Vol: 126, Pages: E219-E231, ISSN: 1878-8750

Journal article

Bronstein AM, A conceptual model of the visual control of posture., Prog Brain Res, Vol: 248, Pages: 285-302

In order to isolate the visual contribution to the control of postural balance, experiments in which subjects are exposed to large-field visual motion (optokinetic) stimuli are reviewed. In these situations, at motion onset, the visual stimulus signals subject self-motion but inertial (vestibulo-proprioceptive) cues do not. Visually evoked postural responses (VEPR) thus induced can be quickly suppressed by cognitive status or simple repetition of the stimulus, if the inertial self-motion cues available to the subject are reliable. In the conceptual model presented here, the process of assessing the reliability, and degree of matching, of visual and inertial signals is carried out by a General comparator; in turn able to access the Gain control mechanism of the visuo-postural system. Complexity and congruency in the visual stimulus itself are assessed by a Visual comparator, e.g., the presence of motion parallax in the visual stimulus can reverse the sway response direction. VEPR can also be re-oriented according to the position of the eyes in the head and the head on the trunk. This indicates that ocular and cervical proprioceptors must also access the gain control mechanism so that visual stimuli can recruit and silence different postural muscles appropriately. The overall gain of the visuo-postural system is also influenced by less easily defined idiosyncratic factors, such as visual dependence and psychological traits; interestingly both these factors have been found to be associated with poor long term outcome in vestibular disorders. The experimental results and model presented illustrate that the visuo-postural system is a wonderful example of interaction between physics (e.g., stimuli geometry, body dynamics), neuroscience and the border zone between neurology and psycho-somatic medicine.

Journal article

Castro P, Kaski D, Al-Fazly H, Ak D, Oktay L, Bronstein A, Arshad Qet al., 2019, Body sway during postural perturbations is mediated by the degree of vestibulo-cortical dominance, Brain Stimulation, ISSN: 1935-861X

Journal article

Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, Humphrey J, Jaunmuktane Z, Sivakumar P, Polke J, Ilyas M, Tribollet E, Tomaselli PJ, Devigili G, Callegari I, Versino M, Salpietro V, Efthymiou S, Kaski D, Wood NW, Andrade NS, Buglo E, Rebelo A, Rossor AM, Bronstein A, Fratta P, Marques WJ, Züchner S, Reilly MM, Houlden Het al., 2019, Author Correction: Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia., Nat Genet, Vol: 51, Pages: 920-920

In the version of this article initially published, the name of author Wai Yan Yau was misspelled. The error has been corrected in the HTML and PDF versions of the article.

Journal article

Harcourt JP, Lambert A, Wong PY, Patel M, Agarwal K, Golding JF, Bronstein AMet al., 2019, Long-term follow-up of intratympanic methylprednisolone versus gentamicin in patients with unilateral Menière's disease, Otology and Neurotology, Vol: 40, Pages: 491-496, ISSN: 1531-7129

OBJECTIVES: To determine whether long term (>48 months) symptomatic vertigo control is sustained in patients with Menière's disease from a previous comparative trial of intratympanic methylprednisolone versus gentamicin, and if the two treatments remain nonsignificantly different at long-term follow-up. STUDY DESIGN: Mail survey recording vertigo frequency in the previous one and six months, further intratympanic treatment received, and validated symptom questionnaires. SETTING: Outpatient hospital clinic setting. PATIENTS: Adult patients with definite unilateral refractory Menière's disease, who previously received intratympanic treatment in a comparative trial. INTERVENTION: A survey of trial participants who received intratympanic gentamicin (40 mg/mL) or methylprednisolone (62.5 mg/mL). OUTCOME MEASURES: Primary: number of vertigo attacks in the 6 months prior to receiving this survey compared with the 6 months before the first trial injection. Secondary number of vertigo attacks over the previous 1 month; validated symptom questionnaire scores of tinnitus, dizziness, vertigo, aural fullness, and functional disability. RESULTS: Forty six of the 60 original trial patients (77%) completed the survey, 24 from the gentamicin and 22 from the methylprednisolone group. Average follow-up was 70.8 months (standard deviation 17.0) from the first treatment injection. Vertigo attacks in the 6 months prior to receiving the current survey reduced by 95% compared to baseline in both drug groups (intention-to-treat analysis, both p < 0.001). No significant difference between drugs was found for the primary and secondary outcomes. Eight participants (methylprednisolone = 5 and gentamicin = 3) required further injections for relapse after completing the original trial. CONCLUSION: Intratympanic methylprednisolone treatment provides effective long-lasting relief of vertigo, without the known inner-ear toxicity associated with gentamicin. There are no significan

Journal article

Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, Humphrey J, Jaunmuktane Z, Sivakumar P, Polke J, Ilyas M, Tribollet E, Tomaselli PJ, Devigili G, Callegari I, Versino M, Salpietro V, Efthymiou S, Kaski D, Wood NW, Andrade NS, Buglo E, Rebelo A, Rossor AM, Bronstein A, Fratta P, Marques WJ, Züchner S, Reilly MM, Houlden Het al., 2019, Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia., Nature Genetics, Vol: 51, Pages: 649-658, ISSN: 1061-4036

Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG)11 allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia.

Journal article

Kim HA, Bisdorff A, Bronstein AM, Lempert T, Rossi-Izquierdo M, Staab JP, Strupp M, Kim J-Set al., 2019, Hemodynamic orthostatic dizziness/vertigo: diagnostic criteria, Journal of Vestibular Research, Pages: 1-12, ISSN: 0957-4271

This paper presents the diagnostic criteria for hemodynamic orthostatic dizziness/vertigo to be included in the International Classification of Vestibular Disorders (ICVD). The aim of defining diagnostic criteria of hemodynamic orthostatic dizziness/vertigo is to help the clinicians to understand the terminology related to orthostatic dizziness/vertigo and to distinguish orthostatic dizziness/vertigo due to global brain hypoperfusion from that caused by other etiologies. Diagnosis of hemodynamic orthostatic dizziness/vertigo requires: A) one or more episodes of dizziness/vertigo or unsteadiness triggered by arising or present during upright position, which subsides by sitting or lying down; B) orthostatic hypotension, postural tachycardia syndrome or syncope documented on standing or during head-up tilt test; and C) not better accounted for by another disease or disorder. Probable hemodynamic orthostatic dizziness/vertigo is defined as follows: A) at least 5 episodes of dizziness/vertigo or unsteadiness triggered by arising or present during upright position, which subsides by sitting or lying down; B) at least one of the following accompanying symptoms: generalized weakness/tiredness, difficulty of thinking/concentration, blurred vision, and tachycardia/palpitations; and C) not better accounted for by another disease or disorder. These diagnostic criteria have been derived by expert consensus from an extensive review of 90 years of research on hemodynamic orthostatic dizziness/vertigo, postural hypotension or tachycardia, and autonomic dizziness. Measurements of orthostatic blood pressure and heart rate are important for the screening and documentation of orthostatic hypotension or postural tachycardia syndrome to establish the diagnosis of hemodynamic orthostatic dizziness/vertigo.

Journal article

Minakaran N, Soorma T, Bronstein AM, Plant GTet al., 2019, Charles Bonnet syndrome and periodic alternating nystagmus Moving visual hallucinations, Neurology, Vol: 92, Pages: E1072-E1075, ISSN: 1526-632X

ObjectiveTo describe and discuss potential mechanisms for modulation of visual hallucinations by nystagmus.MethodsWe present 2 patients with coexistent Charles Bonnet syndrome and periodic alternating nystagmus in the context of acquired visual loss.ResultsThe combination has given rise to a rare phenomenon: visual hallucinations that move in a manner governed by the nystagmus, specifically by the direction and velocity of the slow phase. The perceived modulation of movement is selective for a surface in one case and a landscape in the other but not present for hallucinated individual objects and people separate from the hallucinated background visual scene.ConclusionsThe collision of Charles Bonnet syndrome and periodic alternating nystagmus in these 2 patients has demonstrated that some visual hallucinations can be modulated by, or collaterally with, ocular movements. We propose 2 potential mechanisms based on ocular proprioceptive input from extraocular muscles projecting to either extrastriate processing of visual scene, or to higher-order visual cortical areas involved in analysis of motion signals across the whole visual field.

Journal article

Bednarczuk NF, Bonsu A, Ortega MC, Fluri A-S, Chan J, Rust H, de Melo F, Sharif M, Seemungal BM, Golding JF, Kaski D, Bronstein AM, Arshad Qet al., 2019, Abnormal visuo-vestibular interactions in vestibular migraine: a cross sectional study, Brain, Vol: 142, Pages: 606-616, ISSN: 1460-2156

Vestibular migraine is among the commonest causes of episodic vertigo. Chronically, patients with vestibular migraine develop abnormal responsiveness to both vestibular and visual stimuli characterized by heightened self-motion sensitivity and visually-induced dizziness. Yet, the neural mechanisms mediating such symptoms remain unknown. We postulate that such symptoms are attributable to impaired visuo-vestibular cortical interactions, which in turn disrupts normal vestibular function. To assess this, we investigated whether prolonged, full-field visual motion exposure, which has been previously shown to modulate visual cortical excitability in both healthy individuals and avestibular patients, could disrupt vestibular ocular reflex and vestibular-perceptual thresholds of self-motion during rotations. Our findings reveal that vestibular migraine patients exhibited abnormally elevated reflexive and perceptual vestibular thresholds at baseline. Following visual motion exposure, both reflex and perceptual thresholds were significantly further increased in vestibular migraine patients relative to healthy controls, migraineurs without vestibular symptoms and patients with episodic vertigo due to a peripheral inner-ear disorder. Our results provide support for the notion of altered visuo-vestibular cortical interactions in vestibular migraine, as evidenced by vestibular threshold elevation following visual motion exposure.

Journal article

Castro P, Kaskia D, Schieppati M, Furman M, Arshad Q, Bronstein Aet al., 2019, Subjective stability perception is related to postural anxiety in older subjects, GAIT & POSTURE, Vol: 68, Pages: 538-544, ISSN: 0966-6362

Journal article

Bronstein AM, Dieterich M, 2019, Long-term clinical outcome in vestibular neuritis., Curr Opin Neurol, Vol: 32, Pages: 174-180

PURPOSE OF REVIEW: To review recent work on clinical and imaging aspects of vestibular neuritis (or acute vestibular syndrome), in particular with a view to identifying factors predicting long-term clinical outcome. RECENT FINDINGS: Evidence for a role of inflammation in the vestibular nerve, and the presence of Gadolinium enhancement acutely in vestibular neuritis, is accruing. Visual dependence, anxiety and somatization traits predict the development of chronic dizziness after acute vestibular neuritis. Adaptation to asymmetric rotation is impaired in vestibular neuritis and this may indicate insufficient central compensation in chronic dizzy patients. Corticosteroids appear ineffective at improving long-term clinical outcome. Functional imaging changes during the central compensation period lead to structural brain changes; both processes correlate with clinical recovery. SUMMARY: Vestibular neuritis appears to be the result of postviral neuroinflammation of the vestibular nerve. However, long-term prognosis is not dependent on the magnitude of the peripheral residual damage (as measured with caloric and video head-impulse test). Instead, a combination of visuovestibular psychophysical factors (visual dependence), psychological traits and dysfunctional vestibular perception are relevant. Several functional and structural neuroimaging changes develop after vestibular neuritis, which reflect and underlie the aforementioned psychophysiological and psychological features.

Journal article

Kaski D, Rust HM, Ibitoye R, Arshad Q, Allum JHJ, Bronstein AMet al., 2019, Theoretical framework for "unexplained" dizziness in the elderly: The role of small vessel disease., Pages: 225-240

In this paper we postulate that disruption of connectivity in the human brain can lead to dizziness, a symptom normally associated with focal disease of the vestibular system. The specific case that we will examine is the development of "unexplained" dizziness in the elderly-an extremely common clinical problem. Magnetic resonance imaging of the brain in the elderly usually show variable degrees of multifocal micro-angiopathy (small vessel white matter disease, SVD); thus, we review the literature, present a conceptual model and report preliminary quantitative EEG data in support of the hypothesis that such hemispheric SVD leads to central nervous system disconnection that elderly patients report as dizziness. Loss of connectivity by age-related build-up of SVD could lead to dizzy feelings through one or more of the following mechanisms: disconnection of cortical vestibular centers, disconnection between frontal gait centers and the basal ganglia, and disconnection between intended motor action (efference copy) and sensory re-afference. Finally, we propose that SVD-mediated dysregulation of cerebral blood pressure is linked to dizziness during standing and walking in elderly patients with "unexplained" dizziness.

Book chapter

Castro P, Sena Esteves S, Lerchundi F, Buckwell D, Gresty M, Bronstein A, Arshad Qet al., 2018, Viewing target distance influences the vestibulo-ocular reflex gain when assessed using the video head impulse test, Audiology and Neurotology, Vol: 23, Pages: 285-289, ISSN: 1420-3030

Gaze stabilization during head movements is provided by the vestibulo-ocular reflex (VOR). Clinical assessment of this reflex is performed using the video Head Impulse Test (vHIT). To date, the influence of different fixation distances on VOR gain using the vHIT has not been explored. We assessed the effect of target proximity on the horizontal VOR using the vHIT. Firstly, we assessed the VOR gain in 18 healthy subjects with 5 viewing target distances (150, 40, 30, 20, and 10 cm). The gain increased significantly as the viewing target distance decreased. A second experiment on 10 subjects was performed in darkness whilst the subjects were imagining targets at different distances. There were significant inverse relationships between gain and distance for both the real and the imaginary targets. There was a statistically significant difference between light and dark gains for the 20- and 40-cm distances, but not for the 150-cm distance. Theoretical VOR gains for different target distances were calculated and compared with those found in light and darkness. The increase in gain observed for near targets was lower than predicted by geometrical calculations, implying a physiological ceiling effect on the VOR. The VOR gain in the dark, as assessed with the vHIT, demonstrates an enhancement associated with a reduced target distance.

Journal article

Edwards A, Guven O, Furman M, Arshad Q, Bronstein Aet al., 2018, Electroencephalographic correlates of continuous postural tasks of increasing difficulty, Neuroscience, Vol: 395, Pages: 35-48, ISSN: 0306-4522

Cortical involvement in postural control is well recognized, however the role of non-visual afferents remains unclear. Parietal cortical areas are strongly implicated in vestibulo-spatial functions, but topographical localization during balance tasks remains limited. Here, we use electroencephalography (EEG) during continuous balance tasks of increasing difficulty at single electrode positions. Twenty-four healthy, right-handed individuals performed four balance tasks of increasing difficulty (bipedal and unipedal) and a seated control condition with eyes closed. Subjective ratings of task difficulty were obtained. EEG was recorded from 32 electrodes; 5 overlying sensory and motor regions of interest (ROIs) were chosen for further investigation: C3, Cz, C4, P3, P4. Spectral power and coherence during balance tasks were analyzed in theta (4–8 Hz) and alpha (8–12 Hz) bands. Alpha power reduced as task difficulty increased and this reduction correlated with subjective difficulty ratings. Alpha coherence increased with task difficulty between C3–Cz–C4 electrode pairs. Differential changes in power were observed in Cz, suggestive of a distinct role at this electrode location, which captures lower limb cortical representation. Hemispheric asymmetry was observed, as reflected by greater reductions in theta and alpha power in right-sided areas. Our results demonstrate the functional importance of bilateral central and parietal cortices in continuous balance control. The hemispheric asymmetry observed implies that the non-dominant hemisphere is involved with online monitoring of postural control. Although the posterior parietal asymmetry found may relate to vestibular, somatosensory or multisensory feedback processing, we argue that the finding relates to active balance control rather than simple sensory-intake or reflex circuit activation.

Journal article

Roberts R, Ahmad H, Patel M, Danai D, Ibitoye R, Sharif M, Leech R, Arshad Q, Bronstein Aet al., 2018, An fMRI study of visuo-vestibular interaction in Vestibular Neuritis, NeuroImage: Clinical, Vol: 20, Pages: 1010-1017, ISSN: 2213-1582

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.

Journal article

Balint B, Antelmi E, Mencacci NE, Batla A, Eriksson SH, Walker MC, Bronstein AM, Bhatia KPet al., 2018, Oculomotor apraxia and disrupted sleep with nocturnal ballistic bouts in ADCY5-related disease, PARKINSONISM & RELATED DISORDERS, Vol: 54, Pages: 103-106, ISSN: 1353-8020

Journal article

Kaski DN, Haider S, Male A, Liu F, Radunovic A, Cordivari C, Bhatia K, Bronstein AMet al., 2018, Adult periodic alternating nystagmus masked by involuntary head movements: a case report, Frontiers in Neurology, Vol: 9, ISSN: 1664-2295

A 20-year-old previously well female presented with a history of abrupt onset recurrent episodic (seconds) “dizziness” characterized by a shimmering of the world in front of her. By day 3 she began to experience a constant sensation of vertigo, oscillopsia, mild headache, and prominent vomiting. She was afebrile, had no neck stiffness, but described photophobia. She had gradually developed an involuntary mild side-to-side continuous head movement by day 3. On day 6 there was a constant “no-no” head movement with variable frequency (circa. 2–4 Hz) and amplitude (circa. 15° peak-to-peak) and initially had a fast phase component to the right, with occasional oblique movements (Video S1 in Supplementary Material). The family reported that the movement disappeared during sleep. On admission to hospital, there was right-beating nystagmus (RBN) in the primary position intensifying on right gaze and also apparent on upgaze (Video S1 in Supplementary Material). The intensity of the nystagmus was enhanced during positional maneuvers, without a change in nystagmus direction. Oculographic recordings were not available acutely. The gait was unsteady, with asymmetric step length, inconsistent foot placement, and variable left foot intorsion, sug-gesting a functional (psychogenic) etiology (Video S2 in Supplementary Material). There was no limb ataxia, and no myoclonus. Ten days after the original assessment the head movements worsened dramatically, rendering interpretation of the eye movements difficult (Figure 1A; Video S3 in Supplementary Material), but the patient continued to complain of oscillopsia, even when the examiner attempted to restrain the head manually (the patient did not consent to the use of a bite bar). The head tremor resolved immediately on day 21 after symptom onset with subtherapeutic 50 mouse units of abobotulinumtoxin A applied to the levator sc

Journal article

Ahmad H, Requena T, Frejo L, Cobo M, Gallego-Martinez A, Martin F, Lopez-Escamez JA, Bronstein AMet al., 2018, Clinical and functional characterization of a missense ELF2 variant in a CANVAS Family, Frontiers in Genetics, Vol: 9, ISSN: 1664-8021

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a rare disorder with an unknown etiology. We present a British family with presumed autosomal dominant CANVAS with incomplete penetrance and variable expressivity. Exome sequencing identified a rare missense variant in the ELF2 gene at chr4:g.140058846 C > T, c.10G > A, p.A4T which segregated in all affected patients. By using transduced BE (2)-M17 cells, we found that the mutated ELF2 (mt-ELF2) gene increased ATXN2 and reduced ELOVL5 gene expression, the causal genes of type 2 and type 38 spinocerebellar ataxias. Both, western blot and confocal microscopy confirmed an increase of ataxin-2 in BE(2)-M17 cells transduced with lentivirus expressing mt-ELF2 (CEE-mt-ELF2), which was not observed in cells transduced with lentivirus expressing wt-ELF2 (CEE-wt-ELF2). Moreover, we observed a significant decrease in the number and size of lipid droplets in the CEE-mt-ELF2-transduced BE (2)-M17 cells, but not in the CEE-wt-ELF2-transduced BE (2)-M17. Furthermore, changes in the expression of ELOVL5 could be related with the reduction of lipid droplets in BE (2)-M17 cells. This work supports that ELF2 gene regulates the expression of ATXN2 and ELOVL5 genes, and defines new molecular links in the pathophysiology of cerebellar ataxias.

Journal article

Patel M, Arshad Q, Seemungal BM, Harcourt JP, Golding JF, Bronstein AMet al., 2018, Steroid injections through the eardrum reduce dizziness in Meniere’s disease, study finds - REPLY TO ADRION ET AL. ON PATEL ET AL., British Medical Journal, Vol: 355, ISSN: 0959-8138

Journal article

Staab JP, Eckhardt-Henn A, Horii A, Jacob R, Strupp M, Brandt T, Bronstein Aet al., 2018, Diagnostic criteria for persistent postural-perceptual dizziness (PPPD): Consensus document of the committee for the Classification of Vestibular Disorders of the Barany Society, Journal of Vestibular Research, Vol: 27, Pages: 191-208, ISSN: 0957-4271

This paper presents diagnostic criteria for persistent postural-perceptual dizziness (PPPD) to be included in the International Classification of Vestibular Disorders (ICVD). The term PPPD is new, but the disorder is not. Its diagnostic criteria were derived by expert consensus from an exhaustive review of 30 years of research on phobic postural vertigo, space-motion discomfort, visual vertigo, and chronic subjective dizziness. PPPD manifests with one or more symptoms of dizziness, unsteadiness, or non-spinning vertigo that are present on most days for three months or more and are exacerbated by upright posture, active or passive movement, and exposure to moving or complex visual stimuli. PPPD may be precipitated by conditions that disrupt balance or cause vertigo, unsteadiness, or dizziness, including peripheral or central vestibular disorders, other medical illnesses, or psychological distress. PPPD may be present alone or co-exist with other conditions. Possible subtypes await future identification and validation. The pathophysiologic processes underlying PPPD are not fully known. Emerging research suggests that it may arise from functional changes in postural control mechanisms, multi-sensory information processing, or cortical integration of spatial orientation and threat assessment. Thus, PPPD is classified as a chronic functional vestibular disorder. It is not a structural or psychiatric condition.

Journal article

Arshad Q, Nigmatullina Y, Siddiqui S, Franka M, Mediratta S, Ramachandaran S, Lobo R, Malhotra PA, Roberts RE, Bronstein AMet al., 2017, Influence of biases in numerical magnitude allocation on human prosocial decision making, JOURNAL OF NEUROPHYSIOLOGY, Vol: 118, Pages: 3007-3013, ISSN: 0022-3077

Journal article

Bronstein A, 2017, Clinical neuro-otology of spatial orientation, 23rd World Congress of Neurology (WCN), Publisher: ELSEVIER SCIENCE BV, Pages: 15-15, ISSN: 0022-510X

Conference paper

Arshad Q, Bonsu A, Lobo R, Fluri A, Sheriff R, Bain P, Pavese N, Bronstein Aet al., 2017, Biased numerical cognition impairs economic decision-making in Parkinson’s disease, Annals of Clinical and Translational Neurology, Vol: 4, Pages: 739-748, ISSN: 2328-9503

ObjectivePrevious findings suggest a context-dependent bihemispheric allocation of numerical magnitude. Accordingly, we predicted that lateralized motor symptoms in Parkinson's disease (PD), which reflect hemispheric asymmetries, would induce systematic lateralized biases in numerical cognition and have a subsequent influence on decision-making.MethodsIn 20 PD patients and matched healthy controls we assessed numerical cognition using a number-pair bisection and random number generation task. Decision-making was assessed using both the dictator game and a validated questionnaire.ResultsPD patients with predominant right-sided motor symptoms exhibited pathological biases toward smaller numerical magnitudes and formulated less favorable prosocial choices during a neuroeconomics task (i.e., dictator game). Conversely, patients with left-sided motor symptoms exhibited pathological biases toward larger numerical magnitudes and formulated more generous prosocial choices. Our account of context-dependent hemispheric allocation of numerical magnitude in PD was corroborated by applying our data to a pre-existing computational model and observing significant concordance. Notably, both numerical biasing and impaired decision-making were correlated with motor asymmetry.InterpretationAccordingly, motor asymmetry and functional impairment of cognitive processes in PD can be functionally intertwined. To conclude, our findings demonstrate context-dependent hemispheric allocation and encoding of numerical magnitude in PD and how biases in numerical magnitude allocation in Parkinsonian patients can correspondingly impair economic decision-making.

Journal article

Bednarczuk NF, Ortega MC, Fluri A-S, Bronstein AM, Arshad Qet al., 2017, Inter-hemispheric control of vestibular thresholds, BRAIN STIMULATION, Vol: 10, Pages: 988-991, ISSN: 1935-861X

Journal article

Bronstein AM, Panichi R, Faralli M, Bruni R, Kiriakarely A, Occhigrossi C, Ferraresi Aet al., 2017, Asymmetric vestibular stimulation reveals persistent disruption of motion perception in unilateral vestibular lesions, American Journal of Physiology, Vol: 118, Pages: 2819-2832, ISSN: 0002-9513

Self-motion perception was studied in patients with unilateral vestibular lesions (UVL) due to acute vestibular neuritis at 1 week, 4, 8 and 12 months after the acute episode. We assessed vestibularly-mediated self-motion perception by measuring the error in reproducing the position of a remembered visual target at the end of 4 cycles of asymmetric whole-body rotation. The oscillatory stimulus consists of a slow (0.09Hz) and a fast (0.38Hz) half cycle. A large error was present in UVL patients when the slow half cycle was delivered towards the lesion side, but minimal towards the healthy side. This asymmetry diminished over time, but it remained abnormally large at 12 months. In contrast, vestibulo-ocular reflex responses showed a large direction-dependent error only initially, then they normalized. Normalization also occurred for conventional reflex vestibular measures (caloric tests, subjective visual vertical and head shaking nystagmus) and for perceptual function during symmetric rotation. Vestibular-related handicap, measured with the Dizziness Handicap Inventory (DHI) at 12 months, correlated with self-motion perception asymmetry but not with abnormalities in vestibulo-ocular function. We conclude that 1) a persistent self-motion perceptual bias is revealed by asymmetric rotation in UVLs despite vestibulo-ocular function becoming symmetric over time 2) this dissociation is caused by differential perceptual-reflex adaptation to high and low frequency rotations when these are combined as with our asymmetric stimulus 3) the findings imply differential central compensation for vestibulo-perceptual and vestibulo-ocular reflex functions 4) self-motion perception disruption may mediate long-term vestibular-related handicap in UVL patients.

Journal article

Ahmad H, Roberts E, Patel M, Lobo R, Seemungal B, Arshad Q, Bronstein Aet al., 2017, Downregulation of early visual cortex excitability mediates oscillopsia, Neurology, Vol: 89, Pages: 1179-1185, ISSN: 0028-3878

Objective; Identifying the neurophysiological mechanisms that mediate adaptation to oscillopsia in patients with bilateral-vestibular failure (BVF); an observational study. Methods; We directly probe the hypothesis that adaptive changes which mediate oscillopsia suppression implicate the early visual-cortex (V1/V2). Accordingly, we investigated (V1/V2) excitability using transcranial magnetic stimulation (TMS) in 12 avestibular patients and 12 healthy controls. Specifically, we assessed TMS-induced phosphene thresholds at baseline and cortical excitability changes whilst performing a visual-motion adaptation paradigm during the following conditions: (i) BASELINE measures (i.e. static), (ii) during visual-motion (i.e. MOTION PRE ADAPTATION) and, (iii) during visual-motion following 5 minutes of unidirectional visual-motion adaptation (i.e. MOTION ADAPTED). Results: Patients had significantly higher baseline phosphene-thresholds, reflecting an underlying adaptive mechanism. Individual thresholds were correlated with oscillopsia symptom load. During the visual-motion adaptation condition, no differences in excitability at BASELINE were observed but, during both MOTION PRE ADAPTATION and MOTION ADAPTED conditions, we observed significantly attenuated cortical excitability in patients. Again this attenuation in excitability was stronger in less symptomatic patients.Conclusion; Our findings provide neurophysiological evidence that cortically-mediated adaptive mechanisms in V1/V2 play a critical role in suppressing oscillopsia in patients with bilateral vestibular failure.

Journal article

Geraghty AWA, Essery R, Kirby S, Stuart B, Turner D, Little P, Bronstein A, Andersson G, Carlbring P, Yardley Let al., 2017, Internet-based Vestibular Rehabilitation for older adults with chronic dizziness: a randomized controlled trial in primary care, Annals of Family Medicine, Vol: 15, Pages: 209-216, ISSN: 1544-1709

PURPOSE Vestibular rehabilitation is an effective intervention for dizziness due to vestibular dysfunction, but is seldom provided. We aimed to determine the effectiveness of an Internet-based vestibular rehabilitation program for older adults experiencing dizziness in primary care.METHODS We undertook a single-center, single-blind randomized controlled trial comparing an Internet-based vestibular rehabilitation intervention (Balance Retraining, freely available from https://balance.lifeguidehealth.org) with usual primary care in patients from 54 primary care practices in southern England. Patients aged 50 years and older with current dizziness exacerbated by head movements were enrolled. Those in the intervention group accessed an automated Internet-based program that taught vestibular rehabilitation exercises and suggested cognitive behavioral management strategies. Dizziness was measured by the Vertigo Symptom Scale–Short Form (VSS-SF) at baseline, 3 months, and 6 months. The primary outcome was VSS-SF score at 6 months.RESULTS A total of 296 patients were randomized in the trial; 66% were female, and the median age was 67 years. The VSS-SF was completed by 250 patients (84%) at 3 months and 230 patients (78%) at 6 months. Compared with the usual care group, the Internet-based vestibular rehabilitation group had less dizziness on the VSS-SF at 3 months (difference, 2.75 points; 95% CI, 1.39–4.12; P <.001) and at 6 months (difference, 2.26 points; 95% CI, 0.39–4.12; P = .02, respectively). Dizziness-related disability was also lower in the Internet-based vestibular rehabilitation group at 3 months (difference, 6.15 points; 95% CI, 2.81–9.49; P <.001) and 6 months (difference, 5.58 points; 95% CI, 1.19–10.0; P = .01).CONCLUSIONS Internet-based vestibular rehabilitation reduces dizziness and dizziness-related disability in older primary care patients without requiring clinical support. This intervention has potential for wide appl

Journal article

Kaski D, Bronstein AM, 2017, Ocular tremor in Parkinson’s disease: discussion, debate, and controversy, Frontiers in Neurology, Vol: 8, ISSN: 1664-2295

The identification of ocular tremor in a small cohort of patients with Parkinson’s disease (PD) had lay somewhat dormant until the recent report of a pervasive ocular tremor as a universal finding in a large PD cohort that was, however, generally absent from a cohort of age-matched healthy subjects. The reported tremor had frequency characteristics similar to those of PD limb tremor, but the amplitude and frequency of the tremor did not correlate with clinical tremor ratings. Much controversy ensued as to the origin of such a tremor, and specifically as to whether a pervasive ocular tremor was a fundamental feature of PD, or rather a compensatory eye oscillation secondary to a transmitted head tremor, and thus a measure of a normal vestibulo-ocular reflex. In this mini review, we summarize some of the evidence for and against the case for a pervasive ocular tremor in PD and suggest future experiments that may help resolve these conflicting opinions.

Journal article

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