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Objective: The clinical manifestation of amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration, whereas frontotemporal dementia (FTD) patients show alterations of behavior and cognition. Both share repeat expansions in C9orf72 as the most prevalent genetic cause. Before disease-defining symptoms onset, structural and functional changes at cortical level may emerge in C9orf72 carriers. Here, we characterized oculomotor parameters and their association to neuropsychological domains in apparently asymptomatic individuals with mutations in ALS/FTD genes., Patients and Methods: Forty-eight carriers of ALS genes, without any clinical symptoms underwent video-oculographic examination, including 22 subjects with C9orf72 mutation, 17 with SOD1, and 9 with other ALS associated gene mutations (n = 3 KIF5A; n = 3 FUS/FUS + TBK1; n = 1 NEK1; n = 1 SETX; n = 1 TDP43). A total of 17 subjects underwent a follow-up measurement. Data were compared to 54 age- and gender-matched healthy controls. Additionally, mutation carriers performed a neuropsychological assessment., Results: In comparison to controls, the presymptomatic subjects performed significantly worse in executive oculomotor tasks such as the ability to perform correct anti-saccades. A gene mutation subgroup analysis showed that dysfunctions in C9orf72 carriers were much more pronounced than in SOD1 carriers. The anti-saccade error rate of ALS mutation carriers was associated with cognitive deficits: this correlation was increased in subjects with C9orf72 mutation, whereas SOD1 carriers showed no associations., Conclusion: In C9orf72 carriers, executive eye movement dysfunctions, especially the increased anti-saccade error rate, were associated with cognitive impairment and unrelated to time. These oculomotor impairments are in support of developmental deficits in these mutations, especially in prefrontal areas., (© 2021. The Author(s).)

Objective: Reliable assessment of cognitive functions is a challenging task in amyotrophic lateral sclerosis (ALS) patients unable to speak and write. We therefore present an eye-tracking based neuropsychological screening tool based on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), a standard screening tool for cognitive deficits in ALS., Methods: In total, 46 ALS patients and 50 healthy controls matched for age, gender and education were tested with an oculomotor based and a standard paper-and-pencil version of the ECAS., Results: Significant correlation between both versions was observed for ALS patients and healthy controls in the ECAS total score and in all of its ALS-specific domains (all r > 0.3; all p < 0.05). The eye-tracking version of the ECAS reliably distinguished between ALS patients and healthy controls in the ECAS total score (p < 0.05). Also, cognitively impaired and non-impaired patients could be reliably distinguished with a specificity of 95%., Conclusion: This study provides first evidence that the eye-tracking based ECAS version is a promising approach for assessing cognitive deficits in ALS patients who are unable to speak or write.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with pathological involvement of upper and lower motoneurons, subsequently leading to progressive loss of motor and speech abilities. In addition, cognitive functions are impaired in a subset of patients. To evaluate these potential deficits in severely physically impaired ALS patients, eye-tracking is a promising means to conduct cognitive tests. The present article focuses on how eye movements, an indirect means of communication for physically disabled patients, can be utilized to allow for detailed neuropsychological assessment. The requirements, in terms of oculomotor parameters that have to be met for sufficient eye-tracking in ALS patients are presented. The properties of stimuli, including type of neuropsychological tests and style of presentation, best suited to successfully assess cognitive functioning, are also described. Furthermore, recommendations regarding procedural requirements are provided. Overall, this methodology provides a reliable, easy to administer and fast approach for assessing cognitive deficits in patients who are unable to speak or write such as patients with severe ALS. The only confounding factor might be deficits in voluntary eye movement control in a subset of ALS patients.

Background: The neuropathological process underlying amyotrophic lateral sclerosis (ALS) can be traced as a four-stage progression scheme of sequential corticofugal axonal spread. The examination of eye movement control gains deep insights into brain network pathology and provides the opportunity to detect both disturbance of the brainstem oculomotor circuitry as well as executive deficits of oculomotor function associated with higher brain networks., Objective: To study systematically oculomotor characteristics in ALS and its underlying network pathology in order to determine whether eye movement deterioration can be categorized within a staging system of oculomotor decline that corresponds to the neuropathological model., Methods: Sixty-eight ALS patients and 31 controls underwent video-oculographic, clinical and neuropsychological assessments., Results: Oculomotor examinations revealed increased anti- and delayed saccades' errors, gaze-palsy and a cerebellary type of smooth pursuit disturbance. The oculomotor disturbances occurred in a sequential manner: Stage 1, only executive control of eye movements was affected. Stage 2 indicates disturbed executive control plus 'genuine' oculomotor dysfunctions such as gaze-paly. We found high correlations (p<0.001) between the oculomotor stages and both, the clinical presentation as assessed by the ALS Functional Rating Scale (ALSFRS) score, and cognitive scores from the Edinburgh Cognitive and Behavioral ALS Screen (ECAS)., Conclusions: Dysfunction of eye movement control in ALS can be characterized by a two-staged sequential pattern comprising executive deficits in Stage 1 and additional impaired infratentorial oculomotor control pathways in Stage 2. This pattern parallels the neuropathological staging of ALS and may serve as a technical marker of the neuropathological spreading.

Background: The basal ganglia (BG) are thought to play an important role in the control of eye movements. Accordingly, the broad variety of subtle oculomotor alterations that has been described in Parkinson's disease (PD) are generally attributed to the dysfunction of the BG dopaminergic system. However, the present study suggest that dopamine substitution is much less effective in improving oculomotor performance than it is in restoring skeletomotor abilities., Methods: We investigated reactive, visually guided saccades (RS), smooth pursuit eye movements (SPEM), and rapidly left-right alternating voluntary gaze shifts (AVGS) by video-oculography in 34 PD patients receiving oral dopaminergic medication (PD-DA), 14 patients with deep brain stimulation of the nucleus subthalamicus (DBS-STN), and 23 control subjects (CTL);In addition, we performed a thorough review of recent literature according therapeuthic effects on oculomotor performance in PD by switching deep brain stimulation off and on in the PD-DBS patients, we achieved swift changes between their therapeutic states without the delays of dopamine withdrawal. In addition, participants underwent neuropsychological testing., Results: Patients exhibited the well known deficits such as increased saccade latency, reduced SPEM gain, and reduced frequency and amplitude of AVGS. Across patients none of the investigated oculomotor parameters correlated with UPDRS III whereas there was a negative correlation between SPEM gain and susceptibility to interference (Stroop score). Of the observed deficiencies, DBS-STN slightly improved AVGS frequency but neither AVGS amplitude nor SPEM or RS performance., Conclusions: We conclude that the impairment of SPEM in PD results from a cortical, conceivably non-dopaminergic dysfunction, whereas patients' difficulty to rapidly execute AVGS might be related to their BG dysfunction.

Oculomotor abnormalities can be observed in all Parkinsonian syndromes (PS). Nevertheless, due to the considerable overlap of oculomotor pathology in Parkinsonism, oculomotor changes are not generally considered to contribute substantially to the differential diagnosis of PS. Here we review the characteristics of oculomotor disturbances in the major PS, we provide a survey of the current concepts of the underlying neural physiology of oculomotor control and a summary of the major recording techniques for eye movements. The main focus of this review is to outline the subtle differences between apparently similar oculomotor alterations in Parkinson's disease (PD) and atypical neurodegenerative PS that can contribute to the early differential diagnosis of these entities., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Vertical gaze palsy is a highly relevant clinical sign in parkinsonian syndromes. As the eponymous sign of progressive supranuclear palsy (PSP), it is one of the core features in the diagnosis of this disease. Recent studies have suggested a further differentiation of PSP in Richardson's syndrome (RS) and PSP-parkinsonism (PSPP). The aim of this study was to search for oculomotor abnormalities in the PSP-P subset of a sample of PSP patients and to compare these findings with those of (i) RS patients, (ii) patients with idiopathic Parkinson's disease (IPD), and (iii) a control group. Twelve cases of RS, 5 cases of PSP-P, and 27 cases of IPD were examined by use of video-oculography (VOG) and compared to 23 healthy normal controls. Both groups of PSP patients (RS, PSP-P) had significantly slower saccades than either IPD patients or controls, whereas no differences in saccadic eye peak velocity were found between the two PSP groups or in the comparison of IPD with controls. RS and PSP-P were also similar to each other with regard to smooth pursuit eye movements (SPEM), with both groups having significantly lower gain than controls (except for downward pursuit); however, SPEM gain exhibited no consistent difference between PSP and IPD. A correlation between eye movement data and clinical data (Hoehn & Yahr scale or disease duration) could not be observed. As PSP-P patients were still in an early stage of the disease when a differentiation from IPD is difficult on clinical grounds, the clear-cut separation between PSP-P and IPD obtained by measuring saccade velocity suggests that VOG could contribute to the early differentiation between these patient groups.

Stabilising horizontal body orientation in space without sight on a rotating platform by holding to a stationary structure and circular 'treadmill' stepping in the opposite direction can elicit an illusion of self-turning in space (Bles and Kapteyn in Agressologie 18:325-328, ). Because this illusion is analogous to the well-known illusion of optokinetic circular vection (oCV), we call it 'podokinetic circular vection' (pCV) here. Previous studies using eccentric stepping on a path tangential to the rotation found that pCV was always contraversive relative to platform rotation. In contrast, when our subjects stepped at the centre of rotation about their vertical axis, we observed an inverted, ipsiversive pCV as a reproducible trait in many of our subjects. This ipCV occurred at the same latency as the pCV of subjects reporting the actually expected contraversive direction, but had lower gain. In contrast to pCV, the nystagmus accompanying circular treadmill stepping had the same direction in all individuals (slow phase in the direction of platform motion). The direction of an individual's pCV predicted the characteristics of the CV resulting from combined opto- and podokinetic stimulation (circular treadmill stepping while viewing a pattern rotating together with the platform): in individuals with contraversive pCV, latency shortened and both gain and felt naturalness increased in comparison with pure oCV, whereas the opposite (longer latency, reduced gain and naturalness) occurred in individuals with ipCV. Taken together, the reproducibility of ipCV, the constant direction of nystagmus and the fact that pCV direction predicts the outcome of combined stimulation suggest that ipCV is an individual trait of many subjects during compensatory stepping at the centre of rotation. A hypothetical model is presented of how ipCV possibly could arise. [ABSTRACT FROM AUTHOR]

In addition to many other symptoms, Huntington’s Disease (HD) also causes an impairment of oculomotor functions. In particular, saccadic eye movements become progressively slower and more difficult to initiate; ultimately, patients are forced to recur to large head thrusts as means to initiate gaze shifts. We wondered whether, as a precursor of this condition, head movements would facilitate gaze shifts already in early stages of the disease. We studied horizontal head movements and eye–head coordination in 29 early stage HD patients (Ps) and 24 age matched controls (Cs). Subjects tracked random horizontal steps of visual or auditory targets while their heads were either stabilised (saccade amplitudes ≤40°) or free to move (amplitudes ≤160°). Subjects were to react either immediately (reactive mode), or wait until a go signal was sounded (delayed mode), or by antisaccades. Ps’ head velocity was found to depend on the age of disease onset in a similar way as their saccadic eye velocity does, being clearly reduced in early affected Ps, but increasing to normal levels in lately affected Ps. Yet, saccade and head velocity were only loosely correlated although both exhibited a negative correlation with the severity of Ps’ genetic condition (number of Ps’ CAG repeats). Eye–head coordination turned out to be identical in Ps and Cs except for quantitative differences caused by the lower saccade and head velocities of Ps. Specifically, the timing between head and eyes and the head contribution to gaze shifts were similar in both groups. Moreover, preventing head movements did not affect the saccade latency or accuracy of Ps. Although Ps made more small involuntary head movements in this condition than Cs, these movements were not instrumental in generating saccades since they occurred only late after saccade onset. Thus, the head manoeuvres of severely affected patients must be considered a late adaptive behaviour. Finally, the ability of both Ps and Cs to suppress immediate reactions in the delayed and antisaccade conditions diminished as target distance decreased, with failure rates in Ps being much larger than in Cs. Unlike eye and head velocity, these failure rates were not correlated with age and, by the same token, neither with the variations in head and eye velocity nor with the number of CAG repeats. Hence, the pattern of brain areas prominently affected by HD is likely to vary significantly among individuals. [ABSTRACT FROM AUTHOR]

We investigated the quantitative relationship between saccadic activity (as reflected in frequency of occurrence and amplitude of saccades) and blood oxygenation level dependent (BOLD) changes in the cerebral cortex using functional magnetic resonance imaging (fMRI). Furthermore, we investigated quantitative changes in cortical activity associated with qualitative changes in the saccade task for comparable levels of saccadic activity. All experiments required the simultaneous acquisition of eye movement and fMRI data. For this purpose we used a new high-resolution limbus-tracking technique for recording eye movements in the magnetic resonance tomograph. In the first two experimental series we varied both frequency and amplitude of saccade stimuli (target jumps). In the third series we varied task difficulty; subjects performed either pro-saccades or anti-saccades. The brain volume investigated comprised the frontal and supplementary eye fields, parietal as well as striate cortex, and the motion sensitive area of the parieto-occipital cortex. All these regions showed saccade-related BOLD responses. The responses in these regions were highly correlated with saccade frequency, indicating that repeated processing of saccades is integrated over time in the BOLD response. In contrast, there was no comparable BOLD change with variation of saccade amplitude. This finding speaks for a topological rather than activity-dependent coding of saccade amplitudes in most cortical regions. In the experiments comparing pro- vs anti-saccades we found higher BOLD activation in the "anti" task than in the "pro" task. A comparison of saccade parameters revealed that saccade frequency and cumulative amplitude were comparable between the two tasks, whereas reaction times were longer in the "anti" task than the pro task. The latter finding is taken to indicate a more demanding cortical processing in the "anti" task than the "pro" task, which could explain the observed difference in BOLD activation. We hold that a quantitative analysis of saccade parameters (especially saccade frequency and latency) is important for the interpretation of the BOLD changes observed with visual stimuli in fMRI. [ABSTRACT FROM AUTHOR]

Introduction. For progressive supranuclear palsy (PSP), oculomotor function is one of the core features on which the diagnosis is based upon according to the diagnostic criteria by the Movement Disorder Society (MDS) supported PSP-Study-Group from 2017 ("O criterion"). The aim of this study was to analyze the value of specific oculomotor parameters. Material/Method. An analysis of the videooculographic examinations of smooth pursuit eye movements and visually guided reactive saccades in 100 PSP patients and 49 matched control subjects was performed. Group differences as well as correlations were tested at a two-sided level α=0.05. Cut-off values for the development of new subgroups were defined by the fifth or 95th percentile of specific parameters of the control group. ROC-analyses were used to determine sensitivity and specificity. Results. Each of the investigated oculomotor parameters (for smooth pursuit eye movements gain, for saccades latency, gain, peak eye velocity, asymmetry of velocities up- and downwards, rate of saccadic intrusions (SI)) was significantly altered in PSP compared with the control population (p<0.0001 each). The threshold for vertical saccade velocity was approximately 240°/s for both components so that about 70% of the patients could be captured. A cut-off value of 9.60°/s was determined for SI, and approximately 56% of the patients achieved higher values. By combining both parameters, almost 80% of the patients could be classified. With regard to the specifically calculated asymmetry of the vertical saccade velocities, 34% of the patients were abnormal at a threshold of 0.42 (overview in Fig. 1). The majority of patients (63.5%) performed faster downward than upward saccades. The vertical saccade velocity and SI had a high specificity of more than 95%, while sensitivity was maximally 60% for the velocity components and 54.2% for the SI. At similar specificity, the asymmetry reached a sensitivity of 27.1%. Discussion. The results for vertical saccade velocity and SI, respectively, emphasized their relevance as part of the MDS-PSP diagnostic criteria, whereas the significance of the asymmetry of the vertical velocities was limited. With respect to directional tendency, the findings are still heterogeneous. In future evaluations, unbiased quantifications of clinical parameters offer a good possibility to further develop the quality of the diagnostic procedures used for PSP. ▪ Fig. 1. [ABSTRACT FROM AUTHOR]

Impaired energy expenditure parallels ongoing motor neuron degeneration in patients with amyotrophic lateral sclerosis (ALS). Translational animals provide evidence that energy metabolism is associated with impaired hypothalamic function. We aimed at analyzing the hypothalamic volumes in ALS patients compared with controls. Hypothalamic volume of 281 ALS patients and 116 healthy matched controls were manually delineated based on high-resolution anatomic T1-weighted MRI images using a dedicated segmentation technique.The volume of the hypothalamus, was normalized to the intracranial volume and adjusted with age.The total hypothalmic volume was significantly decreased in ALS patients compared with controls ( p < 0.0001 ); morespecifically the posterior part of the hypothalamus was more severely atrophied compared with the anterior part. The volume loss didnotcorrelate significantly with clinical and metabolic parameters which suggests an early affection of hypothalamic function possibly preceding motor symptom onset in ALS. Volumetric alterations of the hypothalamus could be an early feature of ALS. [ABSTRACT FROM AUTHOR]

Background The neurophysiology of eye movement control provides a window into brain pathology in neurodegenerative diseases such as Parkinson’s disease (PD), Multisystem Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) ( Gorges et al., 2016 ). Structural and functional brain architecture can be investigated using Diffusion tensor imaging (DTI), Atlas-based morphometry (ABV) and “resting-state” fMRI. Objective To investigate the association between impaired oculomotor control and both volumetric as well as structural and functional brain connectivity changes in PD, MSA, and PSP patients. Methods A total of 152 patients including 71 PD, 56 PSP, and 25 MSA patients together with 56 matched healthy controls underwent video-oculographic examination (EyeSeeCam®) and whole-brain based DTI, high-resolution3DT1-weighted, and ‘resting-state’ MRI. Results Impaired executive oculomotor control was a prominent feature in PD as measured for the rate of saccadic intrusions ( p < 0.001) which was significantly correlated with cerebral brain atrophy ( p < 0.001, corrected), white matter impairment ( p < 0.01, corrected), and functional connectivity loss along the default mode network’s midline cores ( p < 0.001, corrected), respectively. Vertical gaze palsy is the eponymous feature in PSP and was significantly correlated with midbrain atrophy ( p < 0.01, corrected), midbrain microstructural damage ( p < 0.001, corrected), and regional functional connectivity loss in the midbrain ( p < 0.001, corrected). Pronounced saccadized pursuit ( p < 0.001) was a cardinal feature in MSA which was correlated with pontine atrophy and white matter damage in the middle cerebral peduncle ( p < 0.001). Conclusions Worse oculomotor performance in the disease-specific domain was associated with more severely impaired regional macro- and microstructure and reduced regional functional connectivity in disease-specific brain structures. These findings increase our pathophysiological knowledge of the underlying parkinsonism-associated pathology and pave the way towards a video-oculographic surrogate marker. [ABSTRACT FROM AUTHOR]

Background A common feature of Parkinsonism – including idiopathic Parkinson’s disease (PD), Multisystem Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) – are characteristic alterations of eye movement control ( Gorges et al., 2014 ). Regional microstructural alterations assessed by diffusion tensor imaging (DTI) have been reported in PD ( Agosta et al., 2014 ), MSA ( Prakash et al., 2009 ) and PSP ( Rosskopf et al., 2015 ). Objective To investigate the association between eye movement disturbances and microstructural impairment in patients with PD, MSA and PSP. Methods Video-oculographic recordings (EyeSeeCam®) of smooth pursuit and visually guided reactive saccades as well as whole-brain based fractional anisotropy (FA) maps computed from diffusion tensor imaging (1.5T) data were analyzed for 37 IPS, 31 PSP, 19 MSA and 36 matched healthy control subjects. Results The prevalence of saccadic intrusions as a measure for inhibitory control was significantly increased in PD patients compared with controls ( p < 0.001) and negatively correlated with the fractional anisotropy (FA) in the capsula interna ( p < 0.001, FDR corrected). As a cardinal oculomotor feature in MSA, smooth pursuit was disturbed by characteristic ‘catch-up’ saccades ( p < 0.001) and was significantly correlated with a FA reduction in the middle cerebral peduncle ( p < 0.001, FDR corrected). The hallmark of PSP are pathologically slowed vertical peak eye velocities compared with controls ( p < 0.001); the lower the peak eye velocity the more marked microstructural impairment in midbrain ( p < 0.001, FDR corrected). Conclusions Eye movements alterations are predominantly the result of executive dysfunction in PD and reflect impaired infratentorial oculomotor control pathways in MSA and PSP. The worse the performance of the characteristic oculomotor parameter the more impaired was the associated regional microstructure. [ABSTRACT FROM AUTHOR]

Background Characteristically impaired oculomotor functions are recognized in Parkinsonian syndromes including idiopathic Parkinson disease (PD), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP) ( Pinkhardt and Kassubek, 2011 ). Atrophy of specific brain structures has been reported in Parkinsonian syndromes ( Brenneis et al., 2007; Focke et al., 2011 ). The aim of this study was to investigate possible relationships between oculomotor alterations and volumetric alterations in PD, PSP and MSA. Methods Forty-two PD, 18 MSA, and 32 PSP patients together with 26 healthy controls underwent standardized video-oculographic testing and MRI at a clinical 1.5T scanner. Whole-brain based T1-weighted MRI-images were analyzed using atlas-based volumetry ( Kassubek et al., 2011 ). Data of 5 brain structures (forebrain, brainstem, cerebellum, midbrain, pons) and 5 oculomotor parameters (smooth pursuit gain, peak eye velocity, rate of saccadic intrusions, anti-saccade errors) were used for group comparisons in PD, MSA and PSP with healthy controls. Oculomotor parameters were correlated with regional brain volumes in the patients. Results PD patients compared with control showed a significantly increased rate of saccadic intrusions (p). Conclusions The worse the oculomotor performance the lower the regional brain volume, suggesting a relationship between regional brain atrophy and cerebral oculomotor network disturbances. Deficits in eye movement control in PD appear to be characterized by executive abnormalities, whereas oculomotor dysfunctions in MSA and PSP were associated with impaired pontine and midbrain pathways. [ABSTRACT FROM AUTHOR]