The use of event-related potentials in the investigation of cognitive performance in people with Multiple Sclerosis: Systematic review.

A biomarker of cognition in Multiple Sclerosis (MS) that is independent from the response of people with MS (PwMS) to test questions would provide a more holistic assessment of cognitive decline. One suggested method involves event-related potentials (ERPs). This systematic review tried to answer five questions about the use of ERPs in distinguishing PwMS from controls: which stimulus modality, which experimental paradigm, which electrodes, and which ERP components are most discriminatory, and whether amplitude or latency is a better measure. Our results show larger pooled effect sizes for visual stimuli than auditory stimuli, and larger pooled effect sizes for latency measurements than amplitude measurements. We observed great heterogeneity in methods and suggest that future research would benefit from more uniformity in methods and that results should be reported for the individual subtypes of PwMS. With more standardised methods, ERPs have the potential to be developed into a clinical tool in MS.

Evaluating Effects of Resting-State Electroencephalography Data Pre-Processing on a Machine Learning Task for Parkinson's Disease.

Resting-state electroencephalography pre-processing methods in machine learning studies into Parkinson's disease classification vary widely. Here three separate data sets were pre-processed to four different stages to investigate the effects on evaluation metrics, using power features from six regions-of-interest, Random Forest Classifiers for feature selection, and Support Vector Machines for classification. This showed muscle artefact inflated evaluation metrics, and alpha and theta band features produced the best results when fully pre-processing data.

Evaluating methods of oversampling and averaging resting-state electroencephalography data in classifying Parkinson's disease.

Collecting resting-state electroencephalography (RSEEG) data is time-consuming and data sets are therefore often small. Because many machine learning (ML) algorithms work better with ample data, researchers looking to use RSEEG and ML to develop diagnostic models have used oversampling methods that may seem to contradict averaging methods used in conventional electroencephalography (EEG) research to improve the signal-to-noise ratio. Using eyes open (EO) and eyes closed (EC) recordings from 3 different research groups, we investigated the effect of different averaging and oversampling methods on classification metrics when classifying people with Parkinson's disease (PD) and controls. Both EC and EO recordings were used due to differences found between these methods. Our results indicated that grouping 58 electrodes into regions-of-interest (ROI) based on anatomical location is preferable to using single electrodes. Furthermore, although recording EO data led to slightly better classification, the number of data points for each participant was reduced and recordings for three participants entirely lost during pre-processing due to a higher level of artefacts than in the EC data.Clinical relevance- RSEEG is a potential biomarker for the diagnosis and prognostication of PD, but for RSEEG to have clinical relevance, it is necessary to establish which averaging and oversampling of data most reliably segregates the classes for people with PD and controls. We found that using of ROIs and EC data performed the best, as EO data was often contaminated with artefacts.

The Impact of Depression, Anxiety and Personality Disorders on the Outcome of Patients with Functional Limb Weakness - Individual Patient Data Meta-Analysis.

OBJECTIVE: Psychiatric comorbidities such as depression, anxiety, and personality disorders are common in patients with functional limb weakness/paresis (FND-par). The impact of these conditions on the prognosis of FND-par has not been systematically reviewed. The aim of this study was to identify a potential prognostic effect of comorbid depression, anxiety, and/or personality disorder on prognosis in patients with FND-par. METHODS: A systematic review was performed to identify studies that reported measures of baseline depression, anxiety, and/or personality disorder, and physical disability. An individual patient data meta-analysis was subsequently performed. RESULTS: Eight studies comprising 348 individuals were included (7 prospective cohorts; 1 case-control study). There was heterogeneity in sample size, follow-up duration, and treatment modality. Depression and anxiety were present in 51.4% and 53.0% of FND-par patients, respectively. In individuals whose FND-par improved, there was no significant difference between those with versus without depression (52.6% vs 47.4%, p = 0.69) or those with versus without anxiety (50.3% vs 49.7%, p = 0.38). Meta-analysis showed no clear impact of baseline depression or anxiety per se [pooled OR for depression 0.85 (95%CI 0.50-1.45; p = 0.40) and anxiety 0.84 (95%CI 0.51-1.38; p = 0.91)]; and of depression or anxiety severity [pooled OR for depression 1.23 (95%CI 0.63-2.39; p = 0.91) and anxiety 1.40 (95%CI 0.70-2.78; p = 0.58)] on FND-par outcome. Insufficient data were available to assess the impact of personality disorders. CONCLUSION: We found no evidence that depression or anxiety influenced outcome in FND-par. Large-scale, prospective studies in FND-par, and other FND subtypes, are needed to fully contextualize the impact of concurrent mental health concerns on outcomes.

Clinician perspectives on rapid transition to telehealth during COVID-19 in Australia - a qualitative study.

Objective The coronavirus disease 2019 (COVID-19) pandemic precipitated a major shift in the use of telehealth in Australia. The changes highlighted gaps in our knowledge regarding the efficacy of, and clinician attitudes to, the use of telehealth. The current study expands and deepens the available evidence as a result of being collected in unique circumstances that removed one of the major barriers (lack of Medicare rebates) and also one major enablers (willingness) of telehealth uptake. Methods Using a semi-structured interview, we invited clinicians (N = 39) to share their perspectives, attitudes and experiences of using telehealth. Topics covered included perceptions of the strengths and challenges of telehealth, and how experience of using telehealth during the COVID-19 pandemic had influenced clinicians' views and intentions regarding their future practice. Participants included clinicians from five disciplines across public and private practice: paediatrics, neurology, immunology, rural general practice, and orthopaedics. Results We found three key dimensions for consideration when assessing the suitability of telehealth for ongoing practice: the attributes of the patient population, the attributes of the clinical context and environment, and the risks and benefits of a telehealth approach. These findings map to the existing literature and allow us to infer that the experiences of clinicians who previously would have chosen telehealth did not differ significantly from those of our 'pandemic-conscripted' clinicians. Conclusions Our findings map clearly to the existing literature and allow us to infer that the experiences of the clinicians who have chosen telehealth (and are already represented in the literature) did not differ significantly from those trying out telehealth under the unique circumstances of the removal of the Medicare Benefits Scheme barrier and external pressure that over-rides the 'willingness' enabling factor in uptake decisions.

Rapid, non-contact multifocal visual assessment in multiple sclerosis.

OBJECTIVE: Previous work on temporally sparse multifocal methods suggests that the results are correlated with disability and progression in people with multiple sclerosis (PwMS). Here, we assess the diagnostic power of three cortically mediated sparse multifocal pupillographic objective perimetry (mfPOP) methods that quantified response-delay and light-sensitivity at up to 44 regions of both visual fields concurrently. METHODS: One high-spatial-resolution mfPOP method, P129, and two rapid medium-resolution methods, W12 and W20, were tested on 44 PwMS and controls. W12 and W20 took 82 s to test both visual fields concurrently, providing response delay and sensitivity at each field location, while P129 took 7 min. Diagnostic power was assessed using areas under the receiver operating characteristic (AUROC) curves and effect-size (Hedges' g). Linear models examined significance. Concurrent testing of both eyes permitted assessment of between-eye asymmetries. RESULTS: Per-region response delays and asymmetries achieved AUROCs of 86.6% ± 4.72% (mean ± SE) in relapsing-remitting MS, and 96.5% ± 2.30% in progressive MS. Performance increased with increasing disability scores, with even moderate EDSS 2 to 4.5 PwMS producing AUROCs of 82.1 to 89.8%, Hedge's g values up to 2.06, and p = 4.0e - 13. All tests performed well regardless of any history of optic neuritis. W12 and W20 performed as well or better than P129. CONCLUSION: Overall, the 82-s tests (W12 and W20) performed better than P129. The results suggest that mfPOP assesses a correlate of disease severity rather than a history of inflammation, and that it may be useful in the clinical management of PwMS.

Objective perimetry and progression of multiple sclerosis.

Introduction: We re-examined the per-region response amplitudes and delays obtained from multifocal pupillographic objective perimetry (mfPOP) after 10 years in 44 persons living with multiple sclerosis (PwMS), both to examine which parts of the visual field had progressed in terms of response properties and to examine if the baseline data could predict the overall progression of disease. Methods: Expanded Disability Status Scale (EDSS) scores were assessed in 2009 and 2019. Both eyes of each participant were concurrently tested at 44 locations/eye on both occasions. Several measures of clinical progression were examined, using logistic regression to determine the odds of progression. Results: At the second examination the 44 PwMS (31 females) were aged 61.0 ± 12.2 y. Mean EDSS had not changed significantly (3.69 ± 1.23 in 2009, 3.81 ± 2.00 in 2019). mfPOP delay increased progressively from inferior to superior regions of the visual fields while amplitudes demonstrated a temporal to nasal gradient. The mean of the 3 most delayed visual field regions was correlated with progression of MS by 2019 (p = 0.023). Logistic regression indicated a significant association between delay and odds of progression (p = 0.045): an individual with 3 regions at least 1 SD (40 ms) slower than the mean in 2009 had 2.05× (±SE: 1.43× to 2.95×) the odds of progression by 2019. A 1 SD shorter delay was associated with 2.05× lower odds of progression. Amplitude changes were not predictive of progression. Significance: mfPOP may provide a rapid, convenient method of monitoring and predicting MS progression.

The role of machine learning in developing non-magnetic resonance imaging based biomarkers for multiple sclerosis: a systematic review.

BACKGROUND: Multiple sclerosis (MS) is a neurological condition whose symptoms, severity, and progression over time vary enormously among individuals. Ideally, each person living with MS should be provided with an accurate prognosis at the time of diagnosis, precision in initial and subsequent treatment decisions, and improved timeliness in detecting the need to reassess treatment regimens. To manage these three components, discovering an accurate, objective measure of overall disease severity is essential. Machine learning (ML) algorithms can contribute to finding such a clinically useful biomarker of MS through their ability to search and analyze datasets about potential biomarkers at scale. Our aim was to conduct a systematic review to determine how, and in what way, ML has been applied to the study of MS biomarkers on data from sources other than magnetic resonance imaging. METHODS: Systematic searches through eight databases were conducted for literature published in 2014-2020 on MS and specified ML algorithms. RESULTS: Of the 1, 052 returned papers, 66 met the inclusion criteria. All included papers addressed developing classifiers for MS identification or measuring its progression, typically, using hold-out evaluation on subsets of fewer than 200 participants with MS. These classifiers focused on biomarkers of MS, ranging from those derived from omics and phenotypical data (34.5% clinical, 33.3% biological, 23.0% physiological, and 9.2% drug response). Algorithmic choices were dependent on both the amount of data available for supervised ML (91.5%; 49.2% classification and 42.3% regression) and the requirement to be able to justify the resulting decision-making principles in healthcare settings. Therefore, algorithms based on decision trees and support vector machines were commonly used, and the maximum average performance of 89.9% AUC was found in random forests comparing with other ML algorithms. CONCLUSIONS: ML is applicable to determining how candidate biomarkers perform in the assessment of disease severity. However, applying ML research to develop decision aids to help clinicians optimize treatment strategies and analyze treatment responses in individual patients calls for creating appropriate data resources and shared experimental protocols. They should target proceeding from segregated classification of signals or natural language to both holistic analyses across data modalities and clinically-meaningful differentiation of disease.

Response characteristics of objective perimetry in persons living with epilepsy.

PURPOSE: To investigate safety and visual-field changes in people with epilepsy undergoing multifocal Pupillographic Objective Perimetry (mfPOP). METHODS: 15 people with epilepsy and 15 controls underwent mfPOP in the context of routine clinical EEG testing. Safety measures comprised the proportion of participants developing an aura or seizure, a photoparoxysmal response, or increased epileptiform activity on their EEG during mfPOP. Pupil responses were obtained concurrently from 44 regions/field of each eye. Changes in standardised amplitude of constriction and time-to-peak were compared between people with generalised and focal epilepsy, and controls. RESULTS: No participant developed an epileptic aura or clinical seizure during (or after) testing. One participant demonstrated EEG evidence of a focal subclinical seizure which began before mfPOP testing and continued unchanged during testing. Regional field sensitivities were increased in people with generalised epilepsy (+3.80 ± 1.43 dB compared to controls) but were reduced in individuals taking antiepileptic medication (-4.04 ± 1.74 dB). An extra delay of 24.9 ± 10.2 ms was seen in the time-to-peak of the responses in people with focal epilepsy. Based on receiver-operating characteristic analyses, discrimination of people with epilepsy from controls was greatest when using the 4 to 10 most abnormal visual field regions of each eye (%AUC 77.3 ± 9.70). SIGNIFICANCE: In the absence of any safety signal, mfPOP appears harmless in people with epilepsy. The observed abnormalities in per-region sensitives and delays suggest that mfPOP may provide significant new insights into the study of epilepsy.

The Use of Event-Related Potentials and Machine Learning to Improve Diagnostic Testing and Prediction of Disease Progression in Parkinson's Disease.

Current tests of disease status in Parkinson's disease suffer from high variability, limiting their ability to determine disease severity and prognosis. Event-related potentials, in conjunction with machine learning, may provide a more objective assessment. In this study, we will use event-related potentials to develop machine learning models, aiming to provide an objective way to assess disease status and predict disease progression in Parkinson's disease.

Assessing migraine patients with multifocal pupillographic objective perimetry.

BACKGROUND: To establish the effects of stimulating intrinsically-photosensitive retinal ganglion cells (ipRGCs) on migraine severity, and to determine if migraine produces objectively-measured visual field defects. METHODS: A randomized, open labelled, crossover study tested migraineurs and normal controls using multifocal pupillographic objective perimetry (mfPOP) with 44 test-regions/eye. A slow blue protocol (BP) stimulated ipRGCs, and a fast yellow protocol (YP) stimulated luminance channels. Migraine diaries assessed migraine severity. Per-region responses were analyzed according to response amplitude and time-to-peak. RESULTS: Thirty-eight migraineurs (42.0 ± 16.5 years, 23 females) and 24 normal controls (39.2 ± 15.2 years, 14 females) were tested. The proportion of subjects developing a migraine did not differ after either protocol, either during the 1st day (odds ratio 1.0; 95% confidence interval 0.2-4.4, p = 0.48) or during the first 3 days after testing (odds ratio 0.8; 95% confidence interval 0.3-2.1, p = 0.68). Migraine days/week did not increase following testing with either protocol in comparison to the baseline week (1.4 ± 1.6 pre-testing (mean ± SD), 1.3 ± 1.4 post-BP, and 1.3 ± 1.2 post-YP; p = 0.96), neither did other measures of severity. Migraine occurring up to 2 weeks before testing significantly lowered amplitudes, - 0.64 ± 0.14 dB (mean ± SE), while triptan use increased amplitudes by 0.45 ± 0.10 dB, both at p < 0.001. CONCLUSIONS: Stimulating ipRGCs did not affect migraine occurrence or severity. Pupillary response characteristics were influenced by the occurrence of a recent migraine attack and a history of triptan use.

Illusions, hallucinations, and visual snow.

Illusions and hallucinations are commonly encountered in both daily life and clinical practice. In this chapter, we review definitions and possible underlying mechanisms of these phenomena and then review what is known about specific conditions that are associated with them, including ophthalmic causes, migraine, epilepsy, Parkinson's disease, and schizophrenia. We then discuss specific syndromes including the Charles Bonnet syndrome, visual snow syndrome, Alice in Wonderland syndrome, and peduncular hallucinosis. The scientific study of illusions and hallucinations has contributed significantly to our understanding of how eye and brain process vision and contribute to perception. Important concepts are the distinction between topologic and hodologic mechanisms underlying hallucinations and the involvement of attentional networks. This chapter examines the various ways in which pathological illusions and hallucinations might arise in relation to the phenomenology and known pathology of the various conditions associated with them.

Blackout: Understanding transient vision loss.

BACKGROUND: Transient vision loss may indicate underlying disease of the eye, optic nerve, orbit, brain or heart. Detailed history-taking followed by a complete ocular and neurological examination is therefore a crucial part of any consultation. OBJECTIVE: It is important to determine whether a patient with transient vision loss can be reassured or requires urgent referral for further investigation. This review examines monocular and binocular transient vision loss and provides a structured approach to the examination of a patient with transient vision loss. The aim of this article is to provide clinicians with confidence when encountering these patients. DISCUSSION: Transient vision loss can imply serious underlying pathology; therefore, accurate history-taking and astute observation are paramount. This review discusses the differential diagnosis of monocular and binocular transient vision loss and the relevant localising features of each.

Variation in the Anatomy of the Normal Human Optic Chiasm: An MRI Study.

BACKGROUND: Compression of the optic chiasm typically leads to bitemporal hemianopia. This implies that decussating nasal fibers are selectively affected, but the precise mechanism is unclear. Stress on nasal fibers has been investigated using finite element modeling but requires accurate anatomical data to generate a meaningful output. The precise shape of the chiasm is unclear: A recent photomicrographic study suggested that nasal fibers decussate paracentrally and run parallel to each other in the central arm of an "H." This study aimed to determine the population variation in chiasmal shape to inform future models. METHODS: Sequential MRI scans of 68 healthy individuals were selected. 2D images of each chiasm were created and analyzed to determine the angle of elevation of the chiasm, the width of the chiasm, and the offset between the points of intersection of lines drawn down the centers of the optic nerves and contralateral optic tracts. RESULTS: The mean width of the chiasm was 12.0 ± 1.5 mm (SD), and the mean offset was 4.7 ± 1.4 mm generating a mean offset:width ratio of 0.38 ± 0.09. No chiasm had an offset of zero. The mean incident angle of optic nerves was 56 ± 7°, and for optic tracts, it was 51 ± 7°. CONCLUSIONS: The human optic chiasm is "H" shaped, not "X" shaped. The findings are consistent with nasal fibers decussating an average of 2.4 mm lateral to the midline before travelling in parallel across the midline. This information will inform future models of chiasmal compression.

Factors delaying intravenous thrombolytic therapy in acute ischaemic stroke: a systematic review of the literature.

BACKGROUND/AIMS: This review examined factors that delay thrombolysis and what management strategies are currently employed to minimise this delay, with the aim of suggesting future directions to overcome bottlenecks in treatment delivery. METHODS: A systematic review was performed according to PRISMA guidelines. The search strategy included a combination of synonyms and controlled vocabularies from Medical Subject Headings (MeSH) and EmTree covering brain ischemia, cerebrovascular accident, fibrinolytic therapy and Alteplase. The search was conducted using Medline (OVID), Embase (OVID), PubMed and Cochrane Library databases using truncations and Boolean operators. The literature search excluded review articles, trial protocols, opinion pieces and case reports. Inclusion criteria were: (1) The article directly related to thrombolysis in ischaemic stroke, and (2) The article examined at least one factor contributing to delay in thrombolytic therapy. RESULTS: One hundred and fifty-two studies were included. Pre-hospital factors resulted in the greatest delay to thrombolysis administration. In-hospital factors relating to assessment, imaging and thrombolysis administration also contributed. Long onset-to-needle times were more common in those with atypical, or less severe, symptoms, the elderly, patients from lower socioeconomic backgrounds, and those living alone. Various strategies currently exist to reduce delays. Processes which have achieved the greatest improvements in time to thrombolysis are those which integrate out-of-hospital and in-hospital processes, such as the Helsinki model. CONCLUSION: Further integrated processes are required to maximise patient benefit from thrombolysis. Expansion of community education to incorporate less common symptoms and provision of alert pagers for patients may provide further reduction in thrombolysis times.

Which features of postural sway are effective in distinguishing Parkinson's disease from controls? A systematic review.

BACKGROUND: Postural sway may be useful as an objective measure of Parkinson's disease (PD). Existing studies have analyzed many different features of sway using different experimental paradigms. We aimed to determine what features have been used to measure sway and then to assess which feature(s) best differentiate PD patients from controls. We also aimed to determine whether any refinements might improve discriminative power and so assist in standardizing experimental conditions and analysis of data. METHODS: In this systematic review of the literature, effect size (ES) was calculated for every feature reported by each article and then collapsed across articles where appropriate. The influence of clinical medication status, visual state, and sampling rate on ES was also assessed. RESULTS: Four hundred and forty-three papers were retrieved. 25 contained enough information for further analysis. The most commonly used features were not the most effective (e.g., PathLength, used 14 times, had ES of 0.47, while TotalEnergy, used only once, had ES of 1.78). Increased sampling rate was associated with increased ES (PathLength ES increased to 1.12 at 100 Hz from 0.40 at 10 Hz). Measurement during "OFF" clinical status was associated with increased ES (PathLength ES was 0.83 OFF compared to 0.21 ON). CONCLUSIONS: This review identified promising features for analysis of postural sway in PD, recommending a sampling rate of 100 Hz and studying patients when OFF to maximize ES. ES complements statistical significance as it is clinically relevant and is easily compared across experiments. We suggest that machine learning is a promising tool for the future analysis of postural sway in PD.

Postural sway correlates with cognition and quality of life in Parkinson's disease.

BACKGROUND: The severity of Parkinson's disease (PD) is difficult to assess objectively owing to the lack of a robust biological marker of underlying disease status, with consequent implications for diagnosis, treatment and prognosis. The current standard tool is the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), but this is hampered by variability between observers and within subjects. Postural sway has been shown to correlate with complex brain functioning in other conditions. This study aimed to investigate the relationship between postural sway, MDS-UPDRS and other non-motor measures of disease severity in patients with PD. METHOD: 25 patients with PD and 18 age-matched controls participated in the study. All participants underwent assessment of postural sway using a force plate, with eyes open and closed. In addition, participants underwent tests of cognition and quality of life: Montreal Cognitive Assessment (MoCA), Neuropsychiatry Unit Cognitive Assessment (NUCOG) and, for the patients, the Parkinson's Disease Questionnaire (PDQ-39-1), and assessment of clinical status using the motor component of the MDS-UPDRS. RESULTS: Patients swayed significantly more than controls. This was most obvious in the eyes-closed condition. Sway path length showed strong correlations with PDQ-39-1, MoCA and the verbal fluency component of the NUCOG, and, to a lesser degree, with the UPDRS-III in patients with PD. CONCLUSION: These results suggest that motor and non-motor symptoms of PD are associated in patients, and, in particular, that postural sway shows potential as a possible measure of underlying disease status in PD, either alone or in combination with other measures.