eye-tracking-control-to-assess-cognitive-functions-patients-with

Eye-Tracking Control to Assess Cognitive Functions in Patients with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with pathological involvement of upper and lower motoneurons, subsequently leading to ...

Ulm University

Abstract In addition to the skeleto-motor deficits, patients with Parkinson's disease (PD) frequently present with oculomotor dysfunctions such as impaired smooth pursuit and saccadic abnormalities. There is increasing evidence for an impaired cortical function to be responsible for oculomotor deficits that are associated with lack of inhibitory control; however, these pathomechanisms still remain poorly understood. By means of "task-free" resting-state functional magnetic resonance imaging (rs-fMRI), functional connectivity changes in PD within the default mode network (DMN) have been reported. The aim of this study was to investigate whether altered functional connectivity within the DMN was correlated with oculomotor parameter changes in PD. Twelve PD patients and 13 matched healthy controls underwent rs-fMRI at 1.5 T and videooculography (VOG) using Eye-Link-System. Rs-fMRI seed-based region-to-region connectivity analysis was performed, including medial prefrontal cortex (mPFC), medial temporal lobe (MTL), posterior cingulate cortex (PCC), and hippocampal formation (HF); while VOG examination comprised ocular reactive saccades, smooth pursuit, and executive tests. Rs-fMRI analysis demonstrated a decreased region-to-region functional connectivity between mPFC and PCC as well as increased connectivity between bilateral HF in PD compared with controls. In VOG, patients and controls differed in terms of executive tests outcome, smooth pursuit eye movement, and visually guided reactive saccades but not in peak eye velocity. A significant relationship was observed between saccadic accuracy and functional connectivity strengths between MTL and PCC. These results suggest that PD-associated changes of DMN connectivity are correlated with PD-associated saccadic hypometria, in particular in the vertical direction.

Functional connectivity within the default mode network is associated with saccadic accuracy in Parkinson's disease: a resting-state FMRI and videooculographic study.

R&eacute;sum&eacute; en addition aux d&eacute;ficits skeleto-moteur, patients atteints de la maladie de Parkinson (PD) souvent pr&eacute;sente avec dysfonctionnement oculomoteur r&eacute;duite tels que poursuite lisse et anomalies par saccades. Il est plus en plus &eacute;vident pour une fonction corticale alt&eacute;r&eacute;e d&#39;&ecirc;tre responsable des d&eacute;ficits oculomoteurs qui sont associ&eacute;s &agrave; l&#39;absence de contr&ocirc;le inhibiteur ; Toutefois, ces pathom&eacute;canismes restent encore mal compris. Au moyen de la &quot;t&acirc;che libres&quot; de repos-&Eacute;tat fonctionnelle imagerie par r&eacute;sonance magn&eacute;tique (rs-IRMf), changements de connectivit&eacute; fonctionnelle dans PD dans le r&eacute;seau en mode par d&eacute;faut (DMN) ont &eacute;t&eacute; signal&eacute;s. Cette &eacute;tude visait &agrave; &eacute;tudier si alt&eacute;r&eacute; la connectivit&eacute; fonctionnelle au sein de la DMN est en corr&eacute;lation avec les changements de param&egrave;tre oculomoteur chez les douze PD PD. et 13 t&eacute;moins en sant&eacute; appari&eacute;s ont subi une rs-IRMf &agrave; 1,5 T et videooculography (VOG) &agrave; l&#39;aide de syst&egrave;me-lien-Eye. RS-IRMf connectivit&eacute; de r&eacute;gion &agrave; r&eacute;gion ax&eacute;e sur les semences analyse a &eacute;t&eacute; effectu&eacute;e, y compris le cortex pr&eacute;frontal m&eacute;dial (MFPC), lobe temporal m&eacute;dial (MTL), cortex cingulaire post&eacute;rieur (PCC) et formation de l&#39;hippocampe (HF) ; alors que l&#39;examen VOG compos&eacute; oculaires saccades r&eacute;actives, poursuite lisse et tests de l&#39;ex&eacute;cutifs. RS-IRMf analyse a d&eacute;montr&eacute; une diminution connectivit&eacute; fonctionnelle de r&eacute;gion &agrave; entre MFPC et PCC ainsi qu&#39;une connectivit&eacute; accrue entre HF bilat&eacute;rale dans PD compar&eacute;e aux t&eacute;moins. Dans VOG, patients et t&eacute;moins diff&egrave;rent en termes de r&eacute;sultat de tests ex&eacute;cutif, mouvement des yeux sans heurt de poursuite et visuellement guid&eacute;es saccades r&eacute;actives mais pas en vitesse de pointe oeil. Une relation significative a &eacute;t&eacute; observ&eacute;e entre la pr&eacute;cision par saccades et atouts de la connectivit&eacute; fonctionnelle entre MTL et PCC. Ces r&eacute;sultats sugg&egrave;rent que le PD associ&eacute;es aux changements de connectivit&eacute; DMN sont corr&eacute;l&eacute;s avec PD-associated hypometria par saccades, en particulier dans le sens vertical.

Connectivit&eacute; fonctionnelle au sein du r&eacute;seau du mode par d&eacute;faut est associ&eacute;e &agrave; une exactitude par saccades dans la maladie de Parkinson : une &eacute;tude de l&#39;IRMf et videooculographic &eacute;tat de repos.

Small vessel cerebrovascular disease (SVCD) is one of the most frequent vessel disorders in the aged brain. Among the spectrum of neurological disturbances related to SVCD, oculomotor dysfunction is a not well understood symptom- in particular, it remains unclear whether vascular lesion load in specific brain regions affects oculomotor function independent of cognitive decline in SVCD patients or whether the effect of higher brain function deficits prevails. In this study, we examined a cohort of 25 SVCD patients and 19 healthy controls using video-oculographic eye movement recording in a laboratory environment, computer-based MRI assessment of white matter lesion load (WMLL), assessment of extrapyramidal motor deficits, and psychometric testing. In comparison to controls, the mean WMLL of patients was significantly larger than in controls. With respect to eye movement control, patients performed significantly worse than controls in almost all aspects of oculomotion. Likewise, patients showed a significantly worse performance in all but one of the neuropsychological tests. Oculomotor deficits in SVCD correlated with the patients' cognitive dysfunctioning while there was only weak evidence for a direct effect of WMLL on eye movement control. In conclusion, oculomotor impairment in SVCD seems to be mainly contingent upon cognitive deterioration in SVCD while WMLL might have only a minor specific effect upon oculomotor pathways.

Do eye movement impairments in patients with small vessel cerebrovascular disease depend on lesion load or on cognitive deficits? A video-oculographic and MRI study.

In amyotrophic lateral sclerosis (ALS), cognition is affected. Cortical atrophy in frontal and temporal areas has been associated with the cognitive profile of patients. Additionally, reduced metabolic turnover and regional cerebral blood flow in frontal areas indicative of reduced neural activity have been reported for ALS. We hypothesize that functional connectivity in non-task associated functional default mode network (DMN) is associated with cognitive profile and white matter integrity. This study focused on specific cognitive tasks known to be impaired in ALS such as verbal fluency and attention, and the relationship with functional connectivity in the DMN and white matter integrity. Nine patients and 11 controls were measured with an extensive neuropsychological battery. Resting-state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data were acquired. Results showed that ALS patients performed significantly worse in attention and verbal fluency task. Patients showed increased functional connectivity in parahippocampal and parietal areas of the non-task associated DMN compared to controls. The more pronounced the cognitive deficits, the stronger the increase in functional connectivity in those areas. White matter integrity was reduced in frontal areas in the patients. In conclusion, increased connectivity in the DMN in parahippocampal and parietal areas might represent recruitment of accessory brain regions to compensate for dysfunctional frontal networks.

Additional resources and the default mode network: Evidence of increased connectivity and decreased white matter integrity in amyotrophic lateral sclerosis.

The evolution of the fovea centralis, the most central part of the retina and the area of the highest visual accuracy, requires humans to shift their gaze rapidly (saccades) to bring some object of interest within the visual field onto the fovea. In addition, humans are equipped with the ability to rotate the eye ball continuously in a highly predicting manner (smooth pursuit) to hold a moving target steadily upon the retina. The functional deficits in neurodegenerative movement disorders (e.g., Parkinsonian syndromes) involve the basal ganglia that are critical in all aspects of movement control. Moreover, neocortical structures, the cerebellum, and the midbrain may become affected by the pathological process. A broad spectrum of eye movement alterations may result, comprising smooth pursuit disturbance (e.g., interrupting saccades), saccadic dysfunction (e.g., hypometric saccades), and abnormal attempted fixation (e.g., pathological nystagmus and square wave jerks). On clinical grounds, videooculography is a sensitive noninvasive in vivo technique to classify oculomotion function alterations. Eye movements are a valuable window into the integrity of central nervous system structures and their changes in defined neurodegenerative conditions, that is, the oculomotor nuclei in the brainstem together with their directly activating supranuclear centers and the basal ganglia as well as cortical areas of higher cognitive control of attention.

Alterations of eye movement control in neurodegenerative movement disorders.

Intrinsic functional connectivity magnetic resonance imaging (iFCMRI) provides an encouraging approach for mapping large-scale intrinsic connectivity networks (ICNs) in the "resting" brain. Structural connections as measured by diffusion tensor imaging (DTI) are a major constraint on the identified ICNs. This study aimed at the combined investigation of ten well-defined ICNs in healthy elderly subjects at single subject level as well as at the group level, together with the underlying structural connectivity. IFCMRI and DTI data were acquired in twelve subjects (68 ± 7 years) at a 3T scanner and were studied using the tensor imaging and fiber tracking software package. The seed-based iFCMRI analysis approach was comprehensively performed with DTI analysis, following standardized procedures including an 8-step processing of iFCMRI data. Our findings demonstrated robust ICNs at the single subject level and conclusive brain maps at the group level in the healthy elderly sample, supported by the complementary fiber tractography. The findings demonstrated here provide a methodological framework for future comparisons of pathological (e.g., neurodegenerative) conditions with healthy controls on the basis of multiparametric functional connectivity mapping.

Intrinsic functional connectivity networks in healthy elderly subjects: a multiparametric approach with structural connectivity analysis.

Diffusion tensor imaging (DTI) for assessing ALS-associated white matter alterations has still not reached the level of a neuroimaging biomarker. Since large-scale multicentre DTI studies in ALS may be hampered by differences in scanning protocols, an approach for pooling of DTI data acquired with different protocols was investigated. Three hundred and nine datasets from 170 ALS patients and 139 controls were collected ex post facto from a monocentric database reflecting different scanning protocols. A 3D correction algorithm was introduced for a combined analysis of DTI metrics despite different acquisition protocols, with the focus on the CST as the tract correlate of ALS neuropathological stage 1. A homogenous set of data was obtained by application of 3D correction matrices. Results showed that a fractional anisotropy (FA) threshold of 0.41 could be defined to discriminate ALS patients from controls (sensitivity/specificity, 74%/72%). For the remaining test sample, sensitivity/specificity values of 68%/74% were obtained. In conclusion, the objective was to merge data recorded with different DTI protocols with 3D correction matrices for analyses at group level. These post processing tools might facilitate analysis of large study samples in a multicentre setting for DTI analysis at group level to aid in establishing DTI as a non-invasive biomarker for ALS.

Ex post facto assessment of diffusion tensor imaging metrics from different MRI protocols: preparing for multicentre studies in ALS.

Cognitive decline is a burdensome extra-motor symptom associated with Parkinson's disease (PD). This study aimed at investigating intrinsic functional connectivity (iFC) of the brain in cognitively unimpaired (PD-CU) and impaired PD patients (PD-CI) compared with age-matched healthy controls. "Resting-state" functional magnetic resonance imaging was acquired in 53 subjects, that is, 14 PD-CU patients, 17 PD-CI patients, and 22 control subjects. Cognition and cognitive status for patient classification were assessed using detailed neuropsychological testing. In PD-CU patients versus controls, we demonstrated significantly increased iFC (hyperconnectivity) presenting as network expansions in cortical, limbic, and basal ganglia-thalamic areas. Significantly, decreased iFC in PD-CI patients compared with control subjects was observed, predominantly between major nodes of the default mode network. In conclusion, the increased iFC might be the initial manifestation of altered brain function preceding cognitive deficits. Hyperconnectivity could be an adaptive (compensatory) mechanism by recruiting additional resources to maintain normal cognitive performance. As PD-related pathology progresses, functional disruptions within the default mode networks seem to be considerably associated with cognitive decline.

To rise and to fall: functional connectivity in cognitively normal and cognitively impaired patients with Parkinson's disease.

Patients with Parkinson's disease (PD) present with eye movement disturbances that accompany the cardinal motor symptoms. Previous studies have consistently found evidence that large-scale functional networks are critically involved in eye movement control. We challenged the hypothesis that altered eye movement control in patients with PD is closely related to alterations of whole-brain functional connectivity in association with the neurodegenerative process. Saccadic and pursuit eye movements by video-oculography and 'resting-state' functional MRI (3 Tesla) were recorded from 53 subjects, i.e. 31 patients with PD and 22 matched healthy controls. Video-oculographically, a broad spectrum of eye movement impairments was demonstrated in PD patients vs. controls, including interrupted smooth pursuit, hypometric saccades, and a high distractibility in anti-saccades. Significant correlations between altered oculomotor parameters and functional connectivity measures were observed, i.e. the worse the oculomotor performance was, the more the regional functional connectivity in cortical, limbic, thalamic, cerebellar, and brainstem areas was decreased. Remarkably, decreased connectivity between major nodes of the default mode network was tightly correlated with the prevalence of saccadic intrusions as a measure for distractability. In conclusion, dysfunctional eye movement control in PD seems to be primarily associated with (cortical) executive deficits, rather than being related to the ponto-cerebellar circuits or the oculomotor brainstem nuclei. Worsened eye movement performance together with the potential pathophysiological substrate of decreased intrinsic functional connectivity in predominantly oculomotor-associated cerebral functional networks may constitute a behavioral marker in PD.

The association between alterations of eye movement control and cerebral intrinsic functional connectivity in Parkinson's disease.

Amyotrophic lateral sclerosis (ALS) primarily affects motor and speech abilities. In addition, cognitive functions are impaired in a subset of patients. There is a need to establish an eye movement-based method of neuropsychological assessment suitable for severely physically impaired patients with ALS. Forty-eight ALS patients and thirty-two healthy controls matched for age, sex and education performed a hand and speech motor-free version of the Raven's coloured progressive matrices (CPM) and the D2-test which had been especially adapted for eye-tracking control. Data were compared to a classical motor-dependent paper-pencil version. The association of parameters of the eye-tracking and the paper-pencil version of the tests and the differences between and within groups were studied. Subjects presented similar results in the eye-tracking and the corresponding paper-pencil versions of the CPM and D2-test: a correlation between performance accuracy for the CPM was observed for ALS patients (p < 0.001) and controls (p < 0.001) and in the D2-test for controls (p = 0.048), whereas this correlation did not reach statistical significance for ALS patients (p = 0.096). ALS patients performed worse in the CPM than controls in the eye-tracking (p = 0.053) and the paper-pencil version (p = 0.042). Most importantly, eye-tracking versions of the CPM (p < 0.001) and the D2-test (p = 0.024) reliably distinguished between more and less cognitively impaired patients. Eye-tracking-based neuropsychological testing is a promising approach for assessing cognitive deficits in patients who are unable to speak or write such as patients with severe ALS.

Eye-tracking controlled cognitive function tests in patients with amyotrophic lateral sclerosis: a controlled proof-of-principle study.

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.

Eye Movement Deficits Are Consistent with a Staging Model of pTDP-43 Pathology in Amyotrophic Lateral Sclerosis.

In Huntington's disease, the relationship of brain structure, brain function and clinical measures remains incompletely understood. We asked how sensory-motor network brain structure and neural activity relate to each other and to motor performance. Thirty-four early stage HD and 32 age- and sex-matched healthy control participants underwent structural magnetic resonance imaging (MRI), diffusion tensor, and intrinsic functional connectivity MRI. Diffusivity patterns were assessed in the cortico-spinal tract and the thalamus-somatosensory cortex tract. For the motor network connectivity analyses the dominant M1 motor cortex region and for the basal ganglia-thalamic network the thalamus were used as seeds. Region to region structural and functional connectivity was examined between thalamus and somatosensory cortex. Fractional anisotropy (FA) was higher in HD than controls in the basal ganglia, and lower in the external and internal capsule, in the thalamus, and in subcortical white matter. Between-group axial and radial diffusivity differences were more prominent than differences in FA, and correlated with motor performance. Within the motor network, the insula was less connected in HD than in controls, with the degree of connection correlating with motor scores. The basal ganglia-thalamic network's connectivity differed in the insula and basal ganglia. Tract specific white matter diffusivity and functional connectivity were not correlated. In HD sensory-motor white matter organization and functional connectivity in a motor network were independently associated with motor performance. The lack of tract-specific association of structure and function suggests that functional adaptation to structural loss differs between participants.

Motor network structure and function are associated with motor performance in Huntington's disease.

Potential alterations of intrinsic functional connectivity in idiopathic restless legs syndrome (RLS) are to be assumed since RLS is considered a network disorder. Whole-brain-based investigation of intrinsic functional connectivity networks including the sensorimotor systems in patients with RLS was compared with matched healthy controls.

Patterns of increased intrinsic functional connectivity in patients with restless legs syndrome are associated with attentional control of sensory inputs.

The syndrome of pathological laughing and crying (PLC) is characterized by episodes of involuntary outbursts of emotional expression. Although this phenomenon has been referred to for over a century, a clear-cut clinical definition is still lacking, and underlying pathophysiological mechanisms are not well understood. In particular, it remains ill-defined which kind of stimuli-contextually appropriate or inappropriate-elicit episodes of PLC, and if the phenomenon is a result of a lack of inhibition from the frontal cortex ("top-down-theory") or due to an altered processing of sensory inputs at the brainstem level ("bottom-up-theory"). To address these questions, we studied ten amyotrophic lateral sclerosis (ALS) patients with PLC and ten controls matched for age, sex and education. Subjects were simultaneously exposed to either emotionally congruent or incongruent visual and auditory stimuli and were asked to rate pictures according to their emotional quality. Changes in physiological parameters (heart rate, galvanic skin response, activity of facial muscles) were recorded, and a standardized self-assessment lability score (CNS-LS) was determined. Patients were influenced in their rating behaviour in a negative direction by mood-incongruent music. Compared to controls, they were influenced by negative stimuli, i.e. they rated neutral pictures more negatively when listening to sad music. Patients rated significantly higher on the CNS-LS. In patients, changes of electromyographic activity of mimic muscles during different emotion-eliciting conditions were explained by frontal cortex dysfunction. We conclude that PLC is associated with altered emotional suggestibility and that it is preferentially elicited by mood-incongruent stimuli. In addition, physiological reactions as well as behavioural changes suggest that this phenomenon is primarily an expression of reduced inhibitory activity of the frontal cortex, since frontal dysfunction could explain changes in physiological parameters in the patient group. We consider these findings being important for the clinical interpretation of emotional reactions of ALS patients.

Article	Year
Functional connectivity within the default mode network is associated with saccadic accuracy in Parkinson's disease: a resting-state FMRI and videooculographic study. Brain connectivity\| PubMed ID: 23627641	2013
Do eye movement impairments in patients with small vessel cerebrovascular disease depend on lesion load or on cognitive deficits? A video-oculographic and MRI study. Journal of neurology\| PubMed ID: 24535136	2014
Additional resources and the default mode network: Evidence of increased connectivity and decreased white matter integrity in amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis & frontotemporal degeneration\| PubMed ID: 24862983	2014
Alterations of eye movement control in neurodegenerative movement disorders. Journal of ophthalmology\| PubMed ID: 24955249	2014
Intrinsic functional connectivity networks in healthy elderly subjects: a multiparametric approach with structural connectivity analysis. BioMed research international\| PubMed ID: 24971361	2014
Ex post facto assessment of diffusion tensor imaging metrics from different MRI protocols: preparing for multicentre studies in ALS. Amyotrophic lateral sclerosis & frontotemporal degeneration\| PubMed ID: 25574564	2015
To rise and to fall: functional connectivity in cognitively normal and cognitively impaired patients with Parkinson's disease. Neurobiology of aging\| PubMed ID: 25623332	2015
The association between alterations of eye movement control and cerebral intrinsic functional connectivity in Parkinson's disease. Brain imaging and behavior\| PubMed ID: 25749936	2016
Eye-tracking controlled cognitive function tests in patients with amyotrophic lateral sclerosis: a controlled proof-of-principle study. Journal of neurology\| PubMed ID: 26041615	2015
Eye Movement Deficits Are Consistent with a Staging Model of pTDP-43 Pathology in Amyotrophic Lateral Sclerosis. PloS one\| PubMed ID: 26559944	2015
Motor network structure and function are associated with motor performance in Huntington's disease. Journal of neurology\| PubMed ID: 26762394	2016
Patterns of increased intrinsic functional connectivity in patients with restless legs syndrome are associated with attentional control of sensory inputs. Neuroscience letters\| PubMed ID: 26921454	2016
Pathological laughing and crying in amyotrophic lateral sclerosis is related to frontal cortex function. Journal of neurology\| PubMed ID: 27314961	2016

Martin Gorges

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