42 research outputs found

    Development of an Eye Movement Based Predictive Model for Discrimination of Parkinson\u27s Disease from Other Parkinsonisms and Controls

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    Purpose: Due to the neurological aspects of Parkinson’s Disease (PD) and the sensitivity of eye movements to neurological issues, eye tracking has the potential to be an objective biomarker with higher accuracy in diagnosis than current clinical standards. Currently when PD is diagnosed clinically, there is an accuracy of 74% when diagnosed by a general practitioner and 82% when diagnosed by a movement disorder specialist. This study was designed to: 1. Assess eye movements as a potential biomarker for Parkinson’s Disease. 2. Determine if eye movements can distinguish between Parkinson’s Disease and commonly confounded movement disorders with parkinsonian symptoms. 3. Determine if the eye movements of Rapid Eye Movement Behavior Disorder (RBD) patients who will likely convert to PD are distinguishable from healthy controls and if RBD patients have eye movements with similar features to PD. Methods: The eye movements of 160 subjects (43 healthy controls, 63 PD, 31 REM Behavior Disorder, and 22 Other Parkinsonisms) were recorded at 500 Hz and analyzed. Each subject performed five eye tracking tasks that included reflexive saccades, inhibition of reflexive saccades, predictive saccades, and reading. Based on an analysis of selected eye movement measurement parameters, a multivariable logistic regression model was developed that compared: PD vs. Control, PD vs. “Other”, PD vs RBD, and Control vs RBD. The resulting predictive model was then assessed for accuracy, sensitivity, and specificity. Results: After screening, the most statistically significant predictors that were included in the final multivariate model were: Site, Sex, Age, Age squared, UPDRS Score, mean absolute fixation velocity (Horizontal Step Task), saccadic duration, average saccadic velocity, and mean fixation velocity (Predictive Task). The model predicted with an accuracy of: 92% for Controls, 88% for PD, 86% for RBD, and 68% for Other Parkinsonisms. The model was best at distinguishing between PD and Other Parkinsomisms with an accuracy of 89% and RBD and Controls with an accuracy of 88%. Conclusion: This research found that specific combinations of eye tracking parameters from simple tasks can be used to distinguish between PD and commonly confounded movement disorders with parkinsonism symptoms. The model’s ability to distinguish between groups indicates that in a confirmatory study we should have relatively high accuracy in discriminating between groups. This model is able to accurately distinguish Controls from RBDs, however due to an insufficient number of follow-up visits to date, the current study is unable to confirm if the RBDs tested will convert to PD. With such high error rates in diagnosing PD clinically, this model is a potentially beneficial and could serve as an easy screening tool to add to the suite of diagnostic tests and improve clinician’s ability to diagnose accurately

    Eye Movement Metrics in the Differentiation of Parkinsonian Syndromes.

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    Oční pohyby v diferenciaci parkinsonských syndromů MUDr. Cecilia Bonnet Shrnutí dizertační práce pro obhajobu PhD., Univerzita Karlova, Praha 2017 V této práci jsme zkoumali konjugované a dyskonjugované oční pohyby (EM) u Parkinsonovy nemoci (PD) a dalších parkinsonských syndromů s cílem charakterizovat a diferencovat některé aspekty jejich okulomotoriky pomocí infračervené videookulografie (VOG). Nejprve jsme zveřejnili přehledový článek popisující klinické vyšetření očních pohybů a interpretaci hlavních nálezů. Poté jsme zkoumali sakadické a sledovací oční pohyby v horizontálním a vertikálním směru ve velké skupině zdravých subjektů s cílem získat vlastní normy a pomoci okulografickým laboratořím při sestavování vlastních norem. Dospěli jsme k závěru, že věk, ale nikoliv pohlaví nebo vzdělání ovlivňuje metriky EM. Zvyšuje se latence sakád a chybovost antisakád, zatímco rychlost a zisk se s věkem snižují. Ve třetím projektu jsme se zaměřili na časté zrakové obtíže pacientů s PD, zejména rozmazané vidění na blízko a zrakové nepohodlí při čtení. Objektivně jsme poprvé zkoumali vergenční oční pohyby (VEM) u pacientů s PD s použitím VOG. Pacienti vykazují zvýšenou latenci VEM a divergence je pomalá a hypometrická. Intraoperační mikroelektrodový záznam jednotkové neuronální aktivity v bazálních gangliích u...Eye Movement Metrics in the Differentiation of Parkinsonian Syndromes Cecilia Bonnet, MD Summary of thesis submitted for the degree of Ph.D., Charles University, Prague 2017 In this thesis we investigated conjugate and dis-conjugate eye movements (EM) in Parkinson's disease (PD) and other parkinsonian syndromes aiming to characterize and differentiate some aspects of their oculomotricity using infrared video-oculography. First of all we published a practical review for medical students and clinicians describing clinical examination of eye movements, and interpretation of principal findings. Then we examined principal saccadic eye movements and smooth pursuit in the horizontal and vertical directions with video-oculography in a large group of healthy subjects, aiming to help new oculomotor laboratories in the constitution of their own norms. We conclude that age influence EM metrics but not gender or education level. The latency of saccades and the error rate of antisaccaes increases, while the velocity and gain diminishes with age. Saccades should be investigated in the horizontal and vertical plane because they are influenced by the direction of the target, resulting in a right/left and up/down asymmetry. In a third project we focused on a frequent complain of PD patients, namely blurred near vision and...Department of Neurology First Faculty of Medicine and General University Hospital in PragueNeurologická klinika 1. LF UK a VFN v PrazeFirst Faculty of Medicine1. lékařská fakult

    A Longtitudinal Analysis of Cognitive and Eye Movement Deficits in Alzheimer's Disease.

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    The main purpose of this thesis was to investigate longitudinally, cognitive and eye movement deficits in Alzheimer's disease. A key aspect of the work was to examine the potential utility of saccadic eye movements in the diagnosis of Alzheimer's disease. Study I investigated saccadic error rates and error correction in Alzheimer's disease, other dementias and healthy elderly control participants using reflexive and voluntary saccade paradigms, to identify salient findings for further analysis. Study II explored the fixation offset effect in Alzheimer's disease, other dementias and healthy elderly control participants, to study the attention (fixation) disengagement deficit previously reported in Alzheimer's disease. Study III examined the effects of normal aging and disease, comparing Alzheimer's disease patients and other dementia types with healthy young adult control participants, healthy elderly control participants and Parkinson's disease patients. Study IV assessed the potential effects of acetylcholinesterase inhibitors on baseline data to eliminate medication effects. Study V investigated repeated measures data for salient observations from Studies I and II in Alzheimer's disease patients and healthy elderly control participants over an 18 month period. Study VI evaluated salient saccadic eye movement and neuropsychological assessment variables, with a view to generating regression models that could predict dementia. Alzheimer's disease patients were found to commit inhibition errors that increased in proportion according to the demands of the voluntary saccade task. Error-correction analysis, revealed that a high proportion of errors remain uncorrected in the antisaccade task, a finding apparently specific to dementia. The results were found to be consistent with the notion that the voluntary saccade tasks require selective attention, the facilitation of which is dependent on task goals being sufficiently activated in working memory. The magnitude of fixation offset effect was greater for Alzheimer's disease patients than controls and Parkinson's disease patients at baseline, but the longitudinal analysis showed that this magnitude decreased over subsequent test sessions. The large initial magnitude of fixation offset effect is believed to have been caused by over compensation of volitional compensation strategies at baseline, when the Alzheimer's disease patients had mild dementia. Regression models using antisaccade variables and neuropsychological assessment scores as predictors both performed well. It is feasible that models could be developed that would enable a reduced set of neuropsychological assessments to be used and three predictors from one antisaccade task. The results confirm that the antisaccade task is a useful model paradigm for the study of oculomotor dysfunction in dementia

    Clinical and neurophysiological assessment of DBS frequency

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    Deep brain stimulation is a surgical treatment for patients with advanced Parkin son’s disease whose symptoms have become challenging to control with available drug therapy. It involves implanting electrodes bilaterally into the subthalamic nu clei and then connecting them to a stimulator placed under the skin in the thoracic area. Several stimulation parameters can be adjusted to produce the best clinical effect, namely: frequency, pulse width, and voltage. After several years of DBS, many patients develop postural instability, gait, and speech disorders. Those prob lems have been attributed to disease progression. Nevertheless, recent studies have shown that they might improve using a lower frequency of stimulation than the one commonly used. We have decided to conduct this thesis to try to understand better the role of the DBS frequency. We looked at the effect of 80Hz vs. 130Hz. We have per formed four studies exploring different domains. Fifteen patients were randomized in a cross-over trial to receive 3 weeks of stimulation at 80 Hz and 130 Hz. Study 1 was dedicated to assessing the motor outcome, which showed that: a) overall clinical scores were unchanged and stable throughout the trial, b) proximal and complex movements were slightly improved at 80Hz, but more distal movements were improved at 130 Hz. Study 2 analyzed the cognitive aspects and showed an improvement of 80 Hz on phonetic fluency but not on semantic fluency. Study 3: looked at the neurophysiological aspects: various paradigms assessed cortical ex citability by transcranial magnetic stimulation (TMS): short intracortical inhibition ended up being more physiological at 130Hz. Study 4 was performed to compare saccades and antisaccades’ performances at 80 and 130Hz, respectively. 21 patients and 16 matched healthy controls (HC) were enrolled: saccades were facilitated at 80Hz instead of 130Hz; however, more errors were seen

    NEURAL CORRELATES AND PROGRESSION OF SACCADE IMPAIRMENT IN PREMANIFEST AND MANIFEST HUNTINGTON DISEASE

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    Indiana University-Purdue University Indianapolis (IUPUI)Huntington disease (HD) is an autosomal dominant disorder characterized by progressive decline of motor, cognitive, and behavioral function. Saccades (rapid, gaze-shifting eye movements) are affected before a clinical diagnosis of HD is certain (i.e. during the premanifest period of the disease). Fundamental questions remain regarding the neural substrates of abnormal saccades and the course of premanifest disease. This work addressed these questions using magnetic resonance imaging (MRI) and a longitudinal study of premanifest disease progression. Gray matter atrophy is a characteristic of HD that can be reliably detected during the premanifest period, but it is not known how such changes influence saccadic behavior. We evaluated antisaccades (AS) and memory guided saccades (MG) in premanifest and manifest HD, then tested for associations between impaired saccadic measures and gray matter atrophy in brain regions involved in these saccadic tasks. The results suggest that slowed vertical AS responses indicate cortical and subcortical atrophy and may be a noninvasive marker of atrophic changes in the brain. We also investigated the brain changes that underlie AS impairment using an event-related AS design with functional MRI (fMRI). We found that, in premanifest and manifest HD, blood oxygenation level dependent (BOLD) response was abnormally absent in the pre-supplementary motor area and dorsal anterior cingulate cortex following incorrect AS responses. These results are the first to suggest that abnormalities in an error-related response network underlie early disease-related saccadic changes, and they emphasize the important influence of regions outside the striatum and frontal cortex in disease manifestations. Though saccadic abnormalities have been repeatedly observed cross sectionally, they have not yet been studied longitudinally in premanifest HD. We found different patterns of decline; for some measures the rate of decline increased as individuals approached onset, while for others the rate was constant throughout the premanifest period. These results establish the effectiveness of saccadic measures in tracking premanifest disease progression, and argue for their use in clinical trials. Together, these studies establish the utility of saccade measures as a marker of HD neurodegeneration and suggest that they would be a valuable component of batteries evaluating the efficacy of neuroprotective therapies

    Consensus Paper: Neurophysiological Assessments of Ataxias in Daily Practice

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    The purpose of this consensus paper is to review electrophysiological abnormalities and to provide a guideline of neurophysiological assessments in cerebellar ataxias. All authors agree that standard electrophysiological methods should be systematically applied in all cases of ataxia to reveal accompanying peripheral neuropathy, the involvement of the dorsal columns, pyramidal tracts and the brainstem. Electroencephalography should also be considered, although findings are frequently non-specific. Electrophysiology helps define the neuronal systems affected by the disease in an individual patient and to understand the phenotypes of the different types of ataxia on a more general level. As yet, there is no established electrophysiological measure which is sensitive and specific of cerebellar dysfunction in ataxias. The authors agree that cerebellar brain inhibition (CBI), which is based on a paired-pulse transcranial magnetic stimulation (TMS) paradigm assessing cerebellar-cortical connectivity, is likely a useful measure of cerebellar function. Although its role in the investigation and diagnoses of different types of ataxias is unclear, it will be of interest to study its utility in this type of conditions. The authors agree that detailed clinical examination reveals core features of ataxia (i.e., dysarthria, truncal, gait and limb ataxia, oculomotor dysfunction) and is sufficient for formulating a differential diagnosis. Clinical assessment of oculomotor function, especially saccades and the vestibulo-ocular reflex (VOR) which are most easily examined both at the bedside and with quantitative testing techniques, is of particular help for differential diagnosis in many cases. Pure clinical measures, however, are not sensitive enough to reveal minute fluctuations or early treatment response as most relevant for pre-clinical stages of disease which might be amenable to study in future intervention trials. The authors agree that quantitative measures of ataxia are desirable as biomarkers. Methods are discussed that allow quantification of ataxia in laboratory as well as in clinical and real-life settings, for instance at the patients' home. Future studies are needed to demonstrate their usefulness as biomarkers in pharmaceutical or rehabilitation trials

    Multichannel EEG : towards applications in clinical neurology.

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    Electroencephalogram (EEG) measures the electric activity produced by the brain with electrodes placed on the scalp. It is used for monitoring or as diagnostic tool for neurological disorders. In practice a maximum of 21 electrodes are generally used for a clinical EEG recording. However, EEG systems with 128 and 256 electrodes are also available and used for fundamental research. In this thesis we investigate whether the extra information obtained with 128-channel recordings is clinically relevant. We have focused on evoked potentials (EPs). EP is the electric activity of the brain caused by a stimulus (e.g. a flashlight). We showed that a measure often used for evoked potentials, the peak amplitude, can be estimated more accurately by using 128 channels recordings than by conventional recordings. Therefore this technique might be more sensitive to pathological changes. In addition, we developed a new technique to estimate EP symmetry (similarity of EPs generated in left and right hemisphere). This technique might be useful for diagnosis of neurological disorders with brain damage in one hemisphere. Both methods have been applied to a group of patients with parkinsonism; neurological symptoms typical for Parkinson’s disease. No differences could be observed in amplitude or symmetry between patients with different parkinsonian disorders. Therefore, (so far) these methods cannot be used as diagnostic tool for neurological disorders. Future research will show whether small adaptations to the stimulation method or analysis technique will result in an improvement of the diagnostic value and whether these methods are useful for other neurological disorders.

    Frontostriatal contributions to reward processing

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    Dopaminergic projections to striatum and prefrontal cortex are thought to signal rewards, thereby energising movement, facilitating learning, and motivating effort. Extensive evidence links reward to attention and to dopamine. However a direct characterisation of how dopamine influences reward sensitivity in humans is lacking. This thesis examines the effects of dopamine and reward on eye movements. First, I introduced incentive manipulations into an “oculomotor capture” task, in which involuntary saccades are generated towards salient distractors. Whereas rewards increased both speed and accuracy, penalties slowed responses while increasing accuracy. A previously unreported effect is described, in which missed rewards capture attention. Subsequently, I developed a new paradigm that manipulates incentives trial-to-trial, during a speeded saccadic distraction task. In healthy volunteers, reward reduced distractibility and increased vigour (in terms of reaction time and velocity), and pupillary dilatation reflected reward expectation. This new task was then employed in a pharmacological study, in which I found that the dopaminergic D2-selective agonist cabergoline increased reward sensitivity in healthy volunteers. Parkinson's disease (PD) results in dopamine deficiency. PD patients performing my task had reduced reward sensitivity in saccade velocity and distractibility, as well as pupil dilatation. Patients were compared on versus off their dopaminergic medication, and although oculomotor vigour did not improve, medication normalised their blunted autonomic responses. Finally, 20 patients with medial prefrontal damage following subarachnoid haemorrhage performed the oculomotor task. Using lesion mapping, I found specific medial orbitofrontal regions in which damage correlated with reduced reward sensitivity. The results demonstrate that the extent to which reward invigorates behaviour is influenced by dopamine. Importantly, reward improves both speed and accuracy, contravening the theoretically predicted trade-off. To resolve this paradox, I develop an extension of optimal control theory that includes a costly precision signal. This model helps conceptualise reward's power to improve both speed and accuracy

    Functional Organization of the Human Brain: How We See, Feel, and Decide.

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    The human brain is responsible for constructing how we perceive, think, and act in the world around us. The organization of these functions is intricately distributed throughout the brain. Here, I discuss how functional magnetic resonance imaging (fMRI) was employed to understand three broad questions: how do we see, feel, and decide? First, high-resolution fMRI was used to measure the polar angle representation of saccadic eye movements in the superior colliculus. We found that eye movements along the superior-inferior visual field are mapped across the medial-lateral anatomy of a subcortical midbrain structure, the superior colliculus (SC). This result is consistent with the topography in monkey SC. Second, we measured the empathic responses of the brain as people watched a hand get painfully stabbed with a needle. We found that if the hand was labeled as belonging to the same religion as the observer, the empathic neural response was heightened, creating a strong ingroup bias that could not be readily manipulated. Third, we measured brain activity in individuals as they made free decisions (i.e., choosing randomly which of two buttons to press) and found the activity within fronto-thalamic networks to be significantly decreased compared to being instructed (forced) to press a particular button. I also summarize findings from several other projects ranging from addiction therapies to decoding visual imagination to how corporations are represented as people. Together, these approaches illustrate how functional neuroimaging can be used to understand the organization of the human brain
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