Assessment of vestibulo-ocular reflex and its adaptation during stop-and-go car rides in motion sickness susceptible passengers.

Motion sickness is a physiological condition that negatively impacts a person's comfort and will be an emerging condition in autonomous vehicles without proper countermeasures. The vestibular system plays a key role in the origin of motion sickness. Understanding the susceptibility and (mal) adaptive mechanisms of the highly integrated vestibular system is a prerequisite for the development of countermeasures. We hypothesize a differential association between motion sickness and vestibular function in healthy individuals with and without susceptibility for motion sickness. We quantified vestibular function by measuring the high-frequency vestibulo-ocular reflex (VOR) using video head impulse testing (vHIT) in 17 healthy volunteers before and after a 11 min motion sickness-inducing naturalistic stop-and-go car ride on a test track (Dekra Test Oval, Klettwitz, Germany). The cohort was classified as motion sickness susceptible (n = 11) and non-susceptible (n = 6). Six (out of 11) susceptible participants developed nausea symptoms, while a total of nine participants were free of these symptoms. The VOR gain (1) did not differ significantly between participant groups with (n = 8) and without motion sickness symptoms (n = 9), (2) did not differ significantly in the factor time before and after the car ride, and showed no interaction between symptom groups and time, as indicated by a repeated measures ANOVA (F(1,15) = 2.19, p = 0.16. Bayesian inference confirmed that there was "anecdotal evidence" for equality of gain rather than difference across groups and time (BF10 < 0.77). Our results suggest that individual differences in VOR measures or adaptation to motion sickness provocative stimuli during naturalistic stop-and-go driving cannot predict motion sickness susceptibility or the likelihood of developing motion sickness.

Altered Gaze Control During Emotional Face Exploration in Patients With Amyotrophic Lateral Sclerosis.

OBJECTIVES: Up to 50% of patients with amyotrophic lateral sclerosis (ALS) present with cognitive problems and behavioral dysfunctions including recognition of human faces presenting different emotions. We investigated whether impaired processing of emotional faces is associated with abnormal scan paths during visual exploration. METHODS: Cognitively unimpaired patients with ALS (n = 45) and matched healthy controls (n = 37) underwent neuropsychological assessment and video-based eye tracking. Eye movements were recorded while participants visually explored faces expressing different emotions (neutral, disgusted, happy, fearful, and sad) and houses mimicking faces. RESULTS: Compared with controls, patients with ALS fixated significantly longer to regions which are not relevant for emotional information when faces expressed fear (p = 0.007) and disgust (p = 0.006), whereas the eyes received less attention in faces expressing disgust (p = 0.041). Fixation duration in any area of interest was not significantly associated with the cognitive state or clinical symptoms of disease severity. DISCUSSION: In cognitively unimpaired patients with ALS, altered gaze patterns while visually exploring faces expressing different emotions might derive from impaired top-down attentional control with possible involvement of subliminal frontotemporal areas. This may account for indistinctness in emotion recognition reported in previous studies because nonsalient features retrieve more attention compared with salient areas. Current findings may indicate distinct emotion processing dysfunction of ALS pathology, which may be different from, for example, executive dysfunction.

Brain age and Alzheimer's-like atrophy are domain-specific predictors of cognitive impairment in Parkinson's disease.

Recently, it was shown that patients with Parkinson's disease (PD) who exhibit an "Alzheimer's disease (AD)-like" pattern of brain atrophy are at greater risk for future cognitive decline. This study aimed to investigate whether this association is domain-specific and whether atrophy associated with brain aging also relates to cognitive impairment in PD. SPARE-AD, an MRI index capturing AD-like atrophy, and atrophy-based estimates of brain age were computed from longitudinal structural imaging data of 178 PD patients and 84 healthy subjects from the LANDSCAPE cohort. All patients underwent an extensive neuropsychological test battery. Patients diagnosed with mild cognitive impairment or dementia were found to have higher SPARE-AD scores as compared to patients with normal cognition and healthy controls. All patient groups showed increased brain age. SPARE-AD predicted impairment in memory, language and executive functions, whereas advanced brain age was associated with deficits in attention and working memory. Data suggest that SPARE-AD and brain age are differentially related to domain-specific cognitive decline in PD. The underlying pathomechanisms remain to be determined.

Eye movement biomarkers allow for the definition of phenotypes in Gaucher Disease.

BACKGROUND: Neurological forms of Gaucher disease, the inherited disorder of ß-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. Systemic manifestations of disease are effectively treated with enzyme replacement therapy, however, molecules which cross the blood-brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of 'type 3' Gaucher disease. METHODS: We undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video-oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups. RESULTS: We confirmed the saccadic abnormality in patients with type 3 Gaucher disease and identified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared a GBA1 variant. CONCLUSIONS: This striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.

Longitudinal brain atrophy distribution in advanced Parkinson's disease: What makes the difference in "cognitive status" converters?

We investigated the brain atrophy distribution pattern and rate of regional atrophy change in Parkinson's disease (PD) in association with the cognitive status to identify the morphological characteristics of conversion to mild cognitive impairment (MCI) and dementia (PDD). T1-weighted longitudinal 3T MRI data (up to four follow-up assessments) from neuropsychologically well-characterized advanced PD patients (n = 172, 8.9 years disease duration) and healthy elderly controls (n = 85) enrolled in the LANDSCAPE study were longitudinally analyzed using a linear mixed effect model and atlas-based volumetry and cortical thickness measures. At baseline, PD patients presented with cerebral atrophy and cortical thinning including striatum, temporoparietal regions, and primary/premotor cortex. The atrophy was already observed in "cognitively normal" PD patients (PD-N) and was considerably more pronounced in cognitively impaired PD patients. Linear mixed effect modeling revealed almost similar rates of atrophy change in PD and controls. The group comparison at baseline between those PD-N whose cognitive performance remained stable (n = 42) and those PD-N patients who converted to MCI/PDD ("converter" cPD-N, n = 26) indicated suggested cortical thinning in the anterior cingulate cortex in cPD-N patients which was correlated with cognitive performance. Our results suggest that cortical brain atrophy has been already expanded in advanced PD patients without overt cognitive deficits while atrophy progression in late disease did not differ from "normal" aging regardless of the cognitive status. It appears that cortical atrophy begins early and progresses already in the initial disease stages emphasizing the need for therapeutic interventions already at disease onset.

Longitudinal diffusion tensor magnetic resonance imaging analysis at the cohort level reveals disturbed cortical and callosal microstructure with spared corticospinal tract in the TDP-43 G298S ALS mouse model.

BACKGROUND: In vivo diffusion tensor imaging (DTI) of the mouse brain was used to identify TDP-43 associated alterations in a mouse model for amyotrophic lateral sclerosis (ALS). METHODS: Ten mice with TDP-43 G298S overexpression under control of the Thy1.2 promoter and 10 wild type (wt) underwent longitudinal DTI scans at 11.7 T, including one baseline and one follow-up scan with an interval of about 5 months. Whole brain-based spatial statistics (WBSS) of DTI-based parameter maps was used to identify longitudinal alterations of TDP-43 G298S mice compared to wt at the cohort level. Results were supplemented by tractwise fractional anisotropy statistics (TFAS) and histological evaluation of motor cortex for signs of neuronal loss. RESULTS: Alterations at the cohort level in TDP-43 G298S mice were observed cross-sectionally and longitudinally in motor areas M1/M2 and in transcallosal fibers but not in the corticospinal tract. Neuronal loss in layer V of motor cortex was detected in TDP-43 G298S at the later (but not at the earlier) timepoint compared to wt. CONCLUSION: DTI mapping of TDP-43 G298S mice demonstrated progression in motor areas M1/M2. WBSS and TFAS are useful techniques to localize TDP-43 G298S associated alterations over time in this ALS mouse model, as a biological marker.

Morphological MRI investigations of the hypothalamus in 232 individuals with Parkinson's disease.

BACKGROUND: The pathophysiology of the hypothalamic involvement in Parkinson's disease (PD) is not well understood. The objective of this study was the quantification of hypothalamic volumes in vivo in PD. METHODS: High-resolution T1 -weighted magnetic resonance imaging (MRI) data from 232 individuals with PD and 130 healthy non-PD individuals were used for quantification of the hypothalamic volumes. RESULTS: The hypothalamus in PD was not atrophied, as indicated by volumetric analyses in the prospectively collected subcohort (30 PD, V = 921 ± 78 mm3 vs 30 non-PD, V = 917 ± 67 mm3 ; P = 0.850) and validated in a large cohort (202 PD, V = 925 ± 88 mm3 vs 100 non-PD, V = 932 ± 114 mm3 ; P = 0.602). CONCLUSIONS: Hypothalamic involvement in PD as shown by a large body of histopathological evidence does not appear to be detectable by MRI-based volumetric quantification. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

The same cortico-efferent tract involvement in progressive bulbar palsy and in 'classical' ALS: A tract of interest-based MRI study.

BACKGROUND: There is an ongoing debate about the concept of restricted phenotypes of amyotrophic lateral sclerosis (ALS), including progressive bulbar palsy (PBP). OBJECTIVE: The study was designed to investigate specific white matter alterations in diffusion tensor imaging (DTI) data from PBP patients using a hypothesis-guided tract-of-interest-based approach (compared with 'classical' ALS patients and controls) to identify in vivo microstructural changes according to the neuropathologically defined ALS-related corticoefferent tract pathology. METHODS: DTI-based white matter mapping was performed both by an unbiased voxel-wise statistical comparison and by a hypothesis-guided tract-wise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 23 PBP and 23 ALS patients vs 23 matched controls. RESULTS: The analysis of white matter integrity demonstrated regional FA reductions along the CST and also in frontal and prefrontal brain areas both in PBP patients and ALS patients with additional regional FA reduction in the pons of the PBP group. In the tract-specific analysis according to the neuropathological ALS-staging pattern, PBP and ALS patients showed identical significant alterations of ALS-related tract systems when compared with controls. CONCLUSIONS: The DTI study including the tract-of-interest-based analysis showed the same microstructural corticoefferent involvement patterns in PBP patients as in ALS, which supports the hypothesis that PBP is a phenotypical variant of ALS.

Structural brain signature of cognitive decline in Parkinson's disease: DTI-based evidence from the LANDSCAPE study.

BACKGROUND: The nonmotor symptom spectrum of Parkinson's disease (PD) includes progressive cognitive decline mainly in late stages of the disease. The aim of this study was to map the patterns of altered structural connectivity of patients with PD with different cognitive profiles ranging from cognitively unimpaired to PD-associated dementia. METHODS: Diffusion tensor imaging and neuropsychological data from the observational multicentre LANDSCAPE study were analyzed. A total of 134 patients with PD with normal cognitive function (56 PD-N), mild cognitive impairment (67 PD-MCI), and dementia (11 PD-D) as well as 72 healthy controls were subjected to whole-brain-based fractional anisotropy mapping and covariance analysis with cognitive performance measures. RESULTS: Structural data indicated subtle changes in the corpus callosum and thalamic radiation in PD-N, whereas severe white matter impairment was observed in both PD-MCI and PD-D patients including anterior and inferior fronto-occipital, uncinate, insular cortices, superior longitudinal fasciculi, corona radiata, and the body of the corpus callosum. These regional alterations were demonstrated for PD-MCI and were more pronounced in PD-D. The pattern of involved regions was significantly correlated with the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score. CONCLUSIONS: The findings in PD-N suggest impaired cross-hemispherical white matter connectivity that can apparently be compensated for. More pronounced involvement of the corpus callosum as demonstrated for PD-MCI together with affection of fronto-parieto-temporal structural connectivity seems to lead to gradual disruption of cognition-related cortico-cortical networks and to be associated with the onset of overt cognitive deficits. The increase of regional white matter damage appears to be associated with the development of PD-associated dementia.

10Kin1day: A Bottom-Up Neuroimaging Initiative.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.

Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis.

OBJECTIVE: To determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS). METHODS: This single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer's disease, 19 with Parkinson's disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology. RESULTS: Serum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (rs=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time. CONCLUSIONS: Serum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS.

Analysis of CACNA1A CAG repeat lengths in patients with familial ALS.

Intermediate-length ATXN2 CAG repeats are a risk factor for amyotrophic lateral sclerosis (ALS). Here we report on a female patient with heterozygous repeat expansion mutation in the CACNA1A gene presenting with a pure ALS syndrome while her father, who also carries that CACNA1A mutation, suffers from a classical spinocerebellar ataxia type 6. Hypothesizing that CACNA1A CAG repeat expansions could be a monogenic cause for familial ALS (fALS), we analyzed the CAG repeat lengths in CACNA1A in a large cohort of genetically unexplained patients with fALS. Our results indicate that CAG repeat expansion mutations in CACNA1A are not a frequent monogenic cause of fALS but could phenotypically present as ALS in rare instances.

Saccadic intrusions in amyotrophic lateral sclerosis (ALS).

The attempt to quietly fixate at a small visual object is continuously interrupted by a variety of fixational eye movements comprising, among others, a continuum of saccadic intrusions (SI) which range in size from microsaccades with amplitudes ≤0.25° to larger refixation saccades of up to about 2°. The size and frequency of SI varies considerably among individuals and is known to increase in neurodegenerative diseases such as progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). However, studies of ALS disagree whether also the frequency of SI increases. We undertook an analysis of SI in 119 ALS patients and 47 age-matched healthy controls whose eye movements during fixation and tests of executive functions (e.g antisaccades) had been recorded by video-oculography according to standardised procedures. SI were categorised according to their spatio-temporal patterns as stair case, back-and-forth and square wave jerks (a subcategory of back-and-forth). The SI of patients and controls were qualitatively similar (same direction preferences, similar differences between patterns), but were enlarged in ALS. Notably however, no increase of SI frequency could be demonstrated. Yet, there were clear correlations with parameters such as eye blink rate or errors in a delayed saccade task that suggest an impairment of inhibitory mechanisms, in keeping with the notion of a frontal dysfunction in ALS. However, it remains unclear how the impairment of inhibitory mechanisms in ALS could selectively increase the amplitude of intrusions without changing their frequency of occurrence.

Corticoefferent pathology distribution in amyotrophic lateral sclerosis: in vivo evidence from a meta-analysis of diffusion tensor imaging data.

A sequential transaxonal disease spread of amyotrophic lateral sclerosis (ALS)-associated TDP-43 pathology in four stages has been defined by post-mortem data, which have been transferred to in vivo imaging by diffusion tensor imaging (DTI) studies. Here, we aimed to investigate whether DTI meta-data are consistent with this proposed pattern of progression in ALS. A systematic literature search using the search engines PubMed and Scopus yielded a total of 370 publications. Of these, 57 studies with cross-sectional data and 10 longitudinal studies of human whole-brain analyses of fractional anisotropy (FA) were included in the final data analysis. Statistical meta-analyses on coordinates of significant FA alterations were performed on a grand average alteration data set using a fixed-effect model. A widespread pattern of white matter impairment was identified from cross-sectional meta data (n = 2064 ALS patients vs. n = 1688 controls) and supported from longitudinal meta data (n = 266 ALS patients over 8 months). The results from cross-sectional meta-analyses corresponded to the brain regions and tract systems according to the sequential disease spread of ALS. Structural alterations in ALS patients vs. controls followed a power gradient, i.e., the most frequent alterations were observed along the corticospinal tract (CST, related to ALS stage 1), followed by frequent alterations along the corticorubral/-pontine tract (related to ALS stage 2), together with corticostriatal pathways (related to ALS stage 3), and, finally, alterations in the hippocampal regions adjacent to the proximal portion of the perforant path (related to ALS stage 4). The results from the DTI-based neuroimaging meta-analysis strongly support the model of the corticoefferent axonal disease progression in ALS and provides further in vivo evidence for the proposed staging scheme of ALS-associated pathology.

Cortico-efferent tract involvement in primary lateral sclerosis and amyotrophic lateral sclerosis: A two-centre tract of interest-based DTI analysis.

BACKGROUND: After the demonstration of a corticoefferent propagation pattern in amyotrophic lateral sclerosis (ALS) by neuropathological studies, this concept has been used for in vivo staging of individual patients by diffusion tensor imaging (DTI) techniques, both in `classical` ALS and in restricted phenotypes such as primary lateral sclerosis (PLS). OBJECTIVE: The study was designed to investigate that microstructural changes according to the neuropathologically defined ALS alteration pattern in PLS patients could be confirmed to be identical to ´classical´ ALS patients. The novelty in this approach is that the results were independent of the subject samples and the data acquisition parameters (as was validated in two samples from two different centres). That way, reproducibility across (international) centres in addition to harmonisation/standardisation of data analysis has been addressed, for the possible use of MRI-based staging to stratify patients in clinical trials. METHODS: Tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern was applied to DTI data (pooled from two ALS centres) of 88 PLS patients and 88 ALS patients with a 'classical' phenotype in comparison to 88 matched controls in order to identify white matter integrity alterations. RESULTS: In the tract-specific analysis, alterations were identical for PLS and ALS in the tract systems corresponding to the ALS staging pattern, independent of the subject samples and the data acquisition parameters. The individual categorisation into ALS stages did not differ between PLS and ALS patients. CONCLUSIONS: This DTI study in a two-centre setting demonstrated that the neuropathological stages can be mapped in vivo in PLS with high reproducibility and that PLS-associated cerebral propagation, although showing the same corticofugal patterns as ALS, might have a different time course of neuropathology, in analogy to its much slower clinical progression rates.

Screening for Cognitive Function in Complete Immobility Using Brain-Machine Interfaces: A Proof of Principle Study.

Background: In many neurological conditions, there is a combination of decline in physical function and cognitive abilities. For far advanced stages of physical disability where speaking and hand motor abilities are severely impaired, there is a lack of standardized approach to screen for cognitive profile. Methods:N = 40 healthy subjects were included in the study. For proof of principle, N = 6 ALS patients were additionally measured. For cognitive screening, we used the Edinburgh cognitive and behavioral ALS screen (ECAS) in the standard paper-and-pencil version. Additionally, we adapted the ECAS to a brain-machine interface (BMI) control module to screen for cognition in severely advanced patients. Results: There was a high congruency between BMI version and the paper-and-pencil version of the ECAS. Sensitivity and specificity of the ECAS-BMI were mostly high whereas stress and weariness for the patient were low. Discussion/Conclusion: We hereby present evidence that adaptation of a standardized neuropsychological test for BMI control is feasible. BMI driven neuropsychological test provides congruent results compared to standardized tests with a good specificity and sensitivity but low patient load.

Stage-dependent remodeling of projections to motor cortex in ALS mouse model revealed by a new variant retrograde-AAV9.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motoneurons in the primary motor cortex (pMO) and in spinal cord. However, the pathogenic process involves multiple subnetworks in the brain and functional MRI studies demonstrate an increase in functional connectivity in areas connected to pMO despite the ongoing neurodegeneration. The extent and the structural basis of the motor subnetwork remodeling in experimentally tractable models remain unclear. We have developed a new retrograde AAV9 to quantitatively map the projections to pMO in the SOD1(G93A) ALS mouse model. We show an increase in the number of neurons projecting from somatosensory cortex to pMO at presymptomatic stages, followed by an increase in projections from thalamus, auditory cortex and contralateral MO (inputs from 20 other structures remains unchanged) as disease advances. The stage- and structure-dependent remodeling of projection to pMO in ALS may provide insights into the hyperconnectivity observed in ALS patients.

Structural and Functional Brain Mapping Correlates of Impaired Eye Movement Control in Parkinsonian Syndromes: A Systems-Based Concept.

The investigation of the human oculomotor system by eye movement recordings provides an approach to behavior and its alterations in disease. The neurodegenerative process underlying parkinsonian syndromes, including Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multisystem atrophy (MSA) changes structural and functional brain organization, and thus affects eye movement control in a characteristic manner. Video-oculography has been established as a non-invasive recording device for eye movements, and systematic investigations of eye movement control in a clinical framework have emerged as a functional diagnostic tool in neurodegenerative parkinsonism. Disease-specific brain atrophy in parkinsonian syndromes has been reported for decades, these findings were refined by studies utilizing diffusion tensor imaging (DTI) and task-based/task-free functional MRI-both MRI techniques revealed disease-specific patterns of altered structural and functional brain organization. Here, characteristic disturbances of eye movement control in parkinsonian syndromes and their correlations with the structural and functional brain network alterations are reviewed. On this basis, we discuss the growing field of graph-based network analysis of the structural and functional connectome as a promising candidate for explaining abnormal phenotypes of eye movement control at the network level, both in health and in disease.