Impact of distinct cognitive domains on gait variability in individuals with mild cognitive impairment and dementia.

BACKGROUND: Gait variability is a common feature in neurodegenerative diseases and has been linked to cognitive impairment. Despite this link, the influence of specific cognitive domains, such as memory, visual spatial skills, executive function, and verbal function on gait variability is not well-understood. OBJECTIVE: To investigate the predictive value of these specific cognitive domains on gait variability in people with mild cognitive impairment (MCI) and dementia during preferred and dual task walking. METHOD: One hundred and two participants with either MCI or dementia underwent a comprehensive cognitive assessment and completed preferred and dual-task walking trials on a pressure-sensing walkway. Gait variability was assessed using the PKMAS software. Lower extremity function was evaluated with a self-reported validated scale. RESULTS: Our findings indicate that only visual spatial abilities had a moderate predictive value on gait variability [F (1, 78) = 17.30, p < 0.01, r = 0.43], both in preferred pace walking (70% direct effect) and dual-task walking (90% direct effect) (p's < 0.05). Additionally, lower extremity functional skills had a significant indirect effect (30%) on gait variability in preferred walking contexts. CONCLUSION: For individuals diagnosed with MCI or dementia, increased gait variability may be driven by deficits in visual spatial processing. An increased understanding of the role of visual spatial processing in gait variability can aid in the assessment and management of individuals with MCI or dementia, potentially leading to targeted interventions to improve mobility and safety.

Multimodal immersive trail making-virtual reality paradigm to study cognitive-motor interactions.

BACKGROUND: Neuropsychological tests of executive function have limited real-world predictive and functional relevance. An emerging solution for this limitation is to adapt the tests for implementation in virtual reality (VR). We thus developed two VR-based versions of the classic Color-Trails Test (CTT), a well-validated pencil-and-paper executive function test assessing sustained (Trails A) and divided (Trails B) attention-one for a large-scale VR system (DOME-CTT) and the other for a portable head-mount display VR system (HMD-CTT). We then evaluated construct validity, test-retest reliability, and age-related discriminant validity of the VR-based versions and explored effects on motor function. METHODS: Healthy adults (n = 147) in three age groups (young: n = 50; middle-aged: n = 80; older: n = 17) participated. All participants were administered the original CTT, some completing the DOME-CTT (14 young, 29 middle-aged) and the rest completing the HMD-CTT. Primary outcomes were Trails A and B completion times (tA, tB). Spatiotemporal characteristics of upper-limb reaching movements during VR test performance were reconstructed from motion capture data. Statistics included correlations and repeated measures analysis of variance. RESULTS: Construct validity was substantiated by moderate correlations between the'gold standard' pencil-and-paper CTT and the VR adaptations (DOME-CTT: tA 0.58, tB 0.71; HMD-CTT: tA 0.62, tB 0.69). VR versions showed relatively high test-retest reliability (intraclass correlation; VR: tA 0.60-0.75, tB 0.59-0.89; original: tA 0.75-0.85, tB 0.77-0.80) and discriminant validity (area under the curve; VR: tA 0.70-0.92, tB 0.71-0.92; original: tA 0.73-0.95, tB 0.77-0.95). VR completion times were longer than for the original pencil-and-paper test; completion times were longer with advanced age. Compared with Trails A, Trails B target-to-target VR hand trajectories were characterized by delayed, more erratic acceleration and deceleration, consistent with the greater executive function demands of divided vs. sustained attention; acceleration onset later for older participants. CONCLUSIONS: The present study demonstrates the feasibility and validity of converting a neuropsychological test from two-dimensional pencil-and-paper to three-dimensional VR-based format while preserving core neuropsychological task features. Findings on the spatiotemporal morphology of motor planning/execution during the cognitive tasks may lead to multimodal analysis methods that enrich the ecological validity of VR-based neuropsychological testing, representing a novel paradigm for studying cognitive-motor interactions.

The association between MRI brain volumes and computerized cognitive scores of people with multiple sclerosis.

BACKGROUND: Computerized cognitive assessment facilitates the incorporation of multi-domain cognitive monitoring into routine clinical care. The predictive validity of computerized cognitive assessment among people with multiple sclerosis (PwMS) has scarcely been investigated. OBJECTIVE: To explore the associations between brain volumes and cognitive scores from a computerized cognitive assessment battery (CAB, NeuroTrax) among PwMS. METHODS: PwMS were evaluated with the CAB and underwent brain MRI within 40 days. Cognitive assessment yielded age- and education-adjusted scores in 9 cognitive domains: memory, executive function, attention, information processing speed, visual spatial, verbal function, motor skills, problem solving, and working memory. The global cognitive score (GCS) is the average of all domain scores. MRI brain and lesion volumes were assessed with icobrain ms, a fully automated tissue and lesion segmentation and quantification software. RESULTS: 91 PwMS were included [Age: 52.1 ± 11.7 years, 64 (70%) female, EDSS: 3.4 ± 2.0, 79 (87%) with a relapsing remitting course]. Significant correlations were found between the GCS and whole brain, white matter, grey matter, thalamic, lateral ventricles, hippocampal and lesion volumes (Correlation coefficients: 0.46, 0.40, 0.25, 0.42, -0.36, 0.21, -0.3, respectively). Regression analysis revealed that lateral ventricles and thalamic volumes were the most consistent predictors of all cognitive domain scores. CONCLUSION: Computerized cognitive scores were significantly associated with quantified MRI. These findings support the predictive validity of multi-domain computerized cognitive assessment for people with multiple sclerosis.

The impact of subjective cognitive fatigue and depression on cognitive function in patients with multiple sclerosis.

BACKGROUND: The association between subjective cognitive fatigue and objective cognitive dysfunction in patients with multiple sclerosis (PwMS) has been studied, with conflicting results. OBJECTIVE: To explore the impact of fatigue on cognitive function, while controlling for the influence of depression, disability, comorbidities, and psychotropic medications. METHODS: PwMS completed a computerized cognitive testing battery with age- and education-adjusted cognitive domain scores. Disability (Expanded Disability Status Scale (EDSS)), cognitive fatigue, and depression were concurrently evaluated. RESULTS: In all, 699 PwMS were included. Both cognitive fatigue and depression were significantly and negatively correlated with the same cognitive domains: information processing speed, executive function, attention, motor function, and memory (-0.15 ⩽ r ⩽ -0.14 for cognitive fatigue; -0.24 ⩽ r ⩽ -0.19 for depression). Multivariate analysis revealed significant but small independent correlations only between depression and neuropsychological test results, while cognitive fatigue had no independent correlation with objective cognitive function except for a trend toward impaired motor function in highly fatigued PwMS. Depression and cognitive fatigue accounted for no more than 6% of the variance in objective cognitive domain scores. CONCLUSION: Cognitive fatigue is not independently related to objective cognitive impairment. Depression may influence cognitive function of PwMS primarily when it is severe. Cognitive impairment in PwMS should not be ascribed to fatigue or mild depression.

Fasting plasma glucose in young adults free of diabetes is associated with cognitive function in midlife.

Background: Evidence for an association of fasting plasma glucose (FPG) with cognitive function in adults free of diabetes is scarce and based on middle-aged and older adults. We examined the association of FPG, measured at age 30, and of change in FPG from age 30 to 43, with cognitive function at age 50. Methods: 505 nondiabetic participants of the population-based Jerusalem Lipid Research Clinic (LRC) cohort study had baseline FPG, 2-h post-oral challenge plasma glucose (OGTT) and insulin determined at ages 28-32, and FPG and OGTT again at ages 41-46. Subsequently at ages 48-52, global cognitive function and its five specific component domains were assessed with a NeuroTrax computerized test battery, using multiple linear regression and multivariable logistic models. Results: Hyperglycemia (FPG ≥ 5.6 mmol/l vs. <5.6 mmol/l) at baseline was associated with poorer global cognitive function in midlife (predominantly in the visual spatial and attention domains), independent of socio-demographic characteristics, life style variables, body mass index (BMI), and inflammatory and biochemical variables (standardized Beta = -0.121, P = 0.002, plinear trend(FPG continuous) =0.016). Similarly, increased odds for low-ranked (lowest fifth) global cognition was evident (ORper mmol/l FPG=2.31, 95% CI = 1.30-4.13, P = 0.005). Baseline OGTT, insulin resistance (HOMA-IR) and change in FPG and OGTT over 13 years were not associated with cognition. Conclusion: A higher FPG in young adults was associated with lower cognitive performance in midlife. Although we cannot dismiss the possibility of reverse causation, hyperglycemia at a young age may be a modifiable risk factor for low-ranked cognitive function in midlife.

Invasive Prenatal Diagnostic Testing Recommendations are Influenced by Maternal Age, Statistical Misconception and Perceived Liability.

Funding policy and medico-legal climate are part of physicians' reality and might permeate clinical decisions. This study evaluates the influence of maternal age and government funding on obstetrician/gynecologist recommendation for invasive prenatal testing (i.e. amniocentesis) for Down syndrome (DS), and its association with the physician's assessment of the risk of liability for medical malpractice unless they recommend amniocentesis. Israeli physicians (N = 171) completed a questionnaire and provided amniocentesis recommendations for women at 18 weeks gestation with normal preliminary screening results, identical except aged 28 and 37. Amniocentesis recommendations were reversed for the younger ('yes' regardless of testing results: 6.4%; 'no' regardless of testing results: 31.6%) versus older woman ('yes' regardless of testing results: 40.9%; 'no' regardless of testing results: 7.0%; χ2 = 71.55, p < .01). About half of the physicians endorsed different recommendations per scenario; of these, 65.6% recommended amniocentesis regardless of testing results for the 37-year-old woman. Physicians routinely performing amniocentesis and those advocating for amniocentesis for all women ≥ age 35 were approximately twice as likely to vary their recommendations per scenario. Physicians who perceived risk of liability for malpractice as large were nearly one-and-a-half times more likely to vary recommendations. The results indicate physicians' recommendations are influenced by maternal age, though age is already incorporated in prenatal DS risk evaluations. The physician's assessment of the risk that they will be sued unless they recommend amniocentesis may contribute to this spurious influence.

Peering further into the mind's eye: combining visual evoked potential and optical coherence tomography measures enhances insight into the variance in cognitive functioning in multiple sclerosis.

BACKGROUND: Spectral Optical Coherence Tomography (OCT) and Visual Evoked Potentials (VEPs) have both emerged as potentially useful biomarkers of cognitive decline in people with multiple sclerosis (PwMS). Their combined use may provide additional predictive value for identifying disease impact, progression, and remyelination capacity above-and-beyond what is captured using either approach alone. OBJECTIVE: We examined the relationship between OCT/VEP measures and cognitive functioning in 205 PwMS. OCT measures included Retinal Nerve Fiber Layer Volume (RNFLV), Papillo-Macular Bundle Volume (PBMV), and Macular Volume (MV). VEP measures included latency of the P100, and inter-ocular latency. Cognitive performance was evaluated across seven separate domains of performance, and for overall cognition, using the NeuroTrax computerized testing battery. RESULTS: Both OCT and VEP measures were significantly correlated with cognitive performance across several domains. Linear regression models that controlled for the influence of visual acuity revealed (1) that reduced MV was significantly predictive of poorer visual-spatial functioning, and (2) that delayed VEP latency was significantly predictive of performance in global cognitive functioning and visual-spatial functioning, after controlling for multiple comparisons. Among PwMS with normal visual acuity, PwMS with a combination of both relatively low MV and delayed VEP latency tended to have poorer performance in the domains of global, executive, and visual-spatial functioning compared to PwMS with both high MV and normal VEP latency. CONCLUSION: Approaches that combine the use of OCT and VEP measures can enhance insight into underlying factors that contribute to variance in cognitive functioning in PwMS.

Exploring the relationship between manual dexterity and cognition in people with multiple sclerosis: 9-hole peg and multiple cognitive functions.

AIM AND RATIONALE: Problems with manual dexterity and cognition impact the everyday performance of people with multiple sclerosis (PwMS). Accumulated findings point to the relationship between deficits in manual dexterity and auditory domains of cognition with a lack of evidence on visuospatial and verbal aspects of cognitive functioning. Therefore, this study explores the relationship between manual dexterity and cognition in a cohort of PwMS. METHOD: This cross-sectional study collected data from 63 PwMS aged 22 to 55 through a convenient sampling method. Participants were diagnosed with relapsing-remitting multiple sclerosis (RRMS). Cognition was measured using a multi-domain computerized cognitive testing, NeuroTrax, and manual dexterity was measured using a 9-hole peg assessment. Spearman correlation was used to identify the correlation among cognition subtests as well as with manual dexterity. Linear regression analysis was also conducted to identify whether manual dexterity predicts cognitive functioning. RESULTS: A significant negative correlation was found between 9-hole peg scores and global cognitive scores (GCS), r = -0.34, p = 006. The manual dexterity scores were also shown to predict GCS, R2= 0.165, p = 0.001. CONCLUSION: Manual dexterity was found to not only predict cognitive dysfunction but was also associated with multiple cognitive domains. Understanding the relationship between manual dexterity and cognition and the inferred progression of deficits can assist clinicians to provide interventions at earlier stages of disease progression to potentially increase daily functioning and quality of life (QoL).

Cognitive impairment in people with multiple sclerosis: Perception vs. performance - factors that drive perception of impairment differ for patients and clinicians.

BACKGROUND: Neurologists' perceptions of the presence of cognitive impairment (CI) in people with multiple sclerosis (PwMS) may not always align with findings of objective cognitive assessment. The accuracy of self-reported CI in PwMS can also be highly variable across individuals, and may not align with objective measurement of cognitive disturbances. Research suggests that additional factors impact perceived cognitive ability, such as depression and fatigue. Objective cognitive screening regardless of patient or neurologist perception has been recommended but still is often limited in routine care. Moreover, comprehensive neuropsychological assessment is even less routinely done. OBJECTIVE: To explore how neurologists' perceptions of PwMS' CI compare to the perception of the patient by determining whether PwMS and their clinicians are accurate in detecting the presence and degree of CI as defined by a multi-domain validated computerized test battery in PwMS, as well as investigate what factors influence perception of CI in each group. METHODS: PwMS completed a computerized multi-domain cognitive testing battery, and self-reported measures of disease impact (MSIS-29), fatigue (MFIS), and depression (BDI-II). Disability was assessed by the clinician using the Expanded Disability Status Scale (EDSS). Clinicians and patients also provided an estimation of cognitive deficits along a Likert scale. RESULTS: In this cohort of PwMS (N=202, age range: 20 to 88, gender: 71% female), their level of accuracy in detecting attention deficits (k = -.028, p = .010) was low but statistically significant. In contrast, clinicians' accuracy in detecting global CI (k = -.037, p < .001) and a number of specific domain deficits was moderate. Fatigue (p < .001) and cognitive performance (p = .012) significantly predicted patient perceived cognitive deficits. Clinician perceived cognitive performance was significantly predicted by multiple factors: cognitive scores (p < .001), physical disability (p = .011), age (p = .021), and depression (p = .038). CONCLUSION: The need to objectively screen for CI in PwMS, regardless of perception, can be aided by a better understanding of the agreement and discrepancies between the patient and clinician regarding perceived cognitive disturbances and the presence of CI defined by a multi-dimensional objective screening battery.

Multiple sclerosis and quality of life: The role of cognitive impairment on quality of life in people with multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS), a chronic disease of the central nervous system (CNS), affects functional ability and quality of life (QoL). Depression, fatigue, and disability status are among the many factors that have been shown to impact QoL in people with MS, but the extent to which MS-related cognitive impairment is related to QoL is understudied in the literature. OBJECTIVE: The purpose of this study was to determine relevant predictors of QoL from a wide list of symptoms including physical disability, and a multi-dimensional computerized cognitive assessment battery (CAB), depression, fatigue, and demographic variables (including employment status). In addition, the unique predictive power of cognitive impairment on QoL was explored in relation to other common factors of disease impact. METHODS: 171 people with MS (PwMS) were evaluated with a computerized assessment battery (CAB), EDSS examination, and validated Patient Reported Outcome (PRO) measures (Multiple Sclerosis Impact Scale, MSIS-29; Beck Depression Inventory - Second Edition BDI-2; and the Modified Fatigue Impact Scale, MFIS). RESULTS: 171 PwMS were included [Age: 46.02 years ± 9.85, 124 (72.5%) female]. Depression and fatigue scores were highly correlated with MSIS-29. EDSS, unemployment, memory, executive functioning, and motor skills were moderately correlated with MSIS-29. Predictors of QoL were EDSS, depression, fatigue, executive functioning, and attention. Attention and executive functioning were predictive of QoL even after controlling for demographic variables, fatigue, depression, and physical disability status. CONCLUSION: Findings indicate the need for comprehensive and quantified evaluation of all factors associated with disease burden, which will ultimately serve to improve the QoL in PwMS through more targeted and patient-centered care.

Cognitive impairment, fatigue and depression in multiple sclerosis: Is there a difference between benign and non-benign MS?

INTRODUCTION: Multiple Sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). The severity of disability in people with MS (PwMS) is generally measured with the Expanded Disability Status Scale (EDSS). A variant of MS known as 'benign MS' (BMS) has been defined as an EDSS score of 3 or lower, combined with a disease duration of 10 years or longer; however, there is disagreement in the field about whether BMS really exists. Given that the EDSS does not capture cognitive issues, communication dysfunction, fatigue, depression, or anxiety properly, its ability to accurately represent disability in all PwMS, including BMS, remains questionable. METHODS: In this study, 141 persons with BMS (PwBMS) were included, consisting of 115 females (82%) and 26 males (18%) with a mean age of 50.8 (±8.68). A computerized test battery (NeuroTrax®) was used to assess cognition, covering seven cognitive domains (memory, executive function, visual-spatial processing, verbal function, attention, information processing, and motor skills). Fatigue was measured using the Fatigue Severity Scale (FSS). The Beck Depression Inventory (BDI) was used to assess symptoms of depression. Cognitive impairment was defined for this study as when someone has a score lower than 85 in at least two subdomains of the cognitive test battery. Rates of impairment were compared to 158 persons with non-benign MS (PwNBMS; with a disease duration of 10 years and longer and an EDSS score higher than 3) and 487 PwMS with a disease duration of fewer than 10 years. RESULTS: Cognitive impairment was found in 38% of PwBMS and in 66% of PwNBMS (p<0.001). In PwBMS, the lowest rate of impairment was found in the verbal function domain (18%) and the highest rate of impairment in the domain of information processing (32%). Fatigue and depression were found in 78% and 55% of all PwBMS, with no difference in these rates between PwBMS and PwNBMS (p = 0.787 and p = 0.316 resp.) CONCLUSION: Cognitive impairment, fatigue and depression are common among people with an EDSS-based definition of benign MS. These aspects should be incorporated into a new and better definition of truly benign MS.

Cognitive testing in Fabry disease: pilot using a brief computerized assessment tool.

BACKGROUND: Recently, cognitive assessments of patients with Fabry disease highlighted neurocognitive impairment using test batteries that are time and labor intensive. OBJECTIVES: To introduce a user-friendly self-administered tool for cognitive testing in patients with Fabry disease. METHODS: We used a computerized system requiring about 1 hour for patient follow-up. All patients with enzymatic and/ or molecular diagnosis of Fabry disease seen in our clinic underwent assessment with the Fabry-specific Mainz Severity Score Index (MSSI) with subscores (neurological, renal, cardiac, and general) and a Mindstreams neurocognitive battery for mild impairment, evaluating memory, executive function, attention, information processing, visual spatial processing, verbal function, and motor skills. A Global Cognitive Score (GCS) was also computed. RESULTS: Ten patients (3 males, 7 females) were tested (mean age 41.5, range 25-56 years). Males were younger, had moderate nephropathy and no cerebrovascular accident (CVA); their Mindstreams GCS was 85.6-107 points. Three females had mild-moderate (8,10,15 points) neurological MSSI subscores (two CVA); all females had Mindstreams GCS of 59-107.7 points. Below-average performance was prevalent, particularly in information processing and motor skills consistent with mild impairment. Average GCS in females (90.3 points) was lowerthan in males (98.2 points). For individual patients, performance was poorest in information processing (n = 4), attention (n = 2), motor skills (n = 2), verbal function (n = 1), and visual spatial processing (n = 1). CONCLUSIONS: MindStreams may simplify cognitive assessment monitoring in Fabry disease.

Selection of deep brain stimulation candidates in private neurology practices: referral may be simpler than a computerized triage system.

OBJECTIVE: The objective of this study is to compare a computerized deep brain stimulation (DBS) screening module (Comparing Private Practice vs. Academic Centers in Selection of DBS Candidates [COMPRESS], NeuroTrax Corp., Bellaire, TX, USA) with traditional triage by a movement disorders specialized neurologist as the gold standard. METHODS: The COMPRESS consists of a combination of the Florida Surgical Questionnaire for Parkinson disease (FLASQ-PD), a cognitive assessment battery provided by MindStreams® (NeuroTrax Corp.), and the Geriatric Depression Scale and the Zung Anxiety Self-Assessment Scale. COMPRESS resulted in the classification of patients into three categories: "optimal candidate,""probable candidate," and "not a good candidate." Similar categorical ratings made by a referring private practice neurologist and by a trained movement disorders specialist were compared with the ratings generated by COMPRESS. RESULTS: A total of 19 subjects with Parkinson's disease were enrolled from five private neurological practices. The clinical impressions of the private practice neurologist vs. those of the movement disorders specialist were in agreement approximately half the time (10/19 cases). The movement disorders specialist and COMPRESS agreed on 15/19 cases. A further comparison between outcomes from the entire COMPRESS module and the FLASQ-PD questionnaire by itself resulted in high agreement (18/19 cases in agreement). CONCLUSIONS: The COMPRESS agreed with an in-person evaluation by a movement disorders neurologist approximately 80% of the time. The computerized COMPRESS did not provide any screening advantage over the short FLASQ-PD paper questionnaire. Larger studies will be needed to assess the utility and cost effectiveness of this computerized triage method for DBS.

Preliminary Real-World Evidence Supporting the Efficacy of a Remote Neurofeedback System in Improving Mental Health: Retrospective Single-Group Pretest-Posttest Study.

BACKGROUND: Neurofeedback training (NFT) has been shown to be effective in treating several disorders (eg, attention-deficit/hyperactivity disorder [ADHD], anxiety, and depression); however, little is currently known regarding the effectiveness of remote NFT systems. OBJECTIVE: This retrospective study provides real-world data (N=593) to assess the efficacy of app-based remote NFT in improving brain health and cognitive performance. METHODS: Improvement was measured from pre- to postintervention of in-app assessments that included validated symptom questionnaires (the 12-item General Health Questionnaire, the ADHD Rating Scale IV, the Adult ADHD Self-Report Scale, the 7-item Generalized Anxiety Disorder scale, and the 9-item Patient Health Questionnaire), a cognitive test of attention and executive functioning (ie, continuous performance task), and resting electroencephalography (EEG) markers. Clinically significant improvement was evaluated using standard approaches. RESULTS: The greatest improvement was reported for the anxiety questionnaire, for which 69% (68/99) of participants moved from abnormal to healthy score ranges. Overall, adult and child participants who engaged in neurofeedback to improve attention and executive functions demonstrated improved ADHD scores and enhanced performance on a cognitive (ie, response inhibition) task. Adults with ADHD additionally demonstrated elevated delta/alpha and theta/alpha ratios at baseline and a reduction in the delta/alpha ratio indicator following neurofeedback. CONCLUSIONS: Preliminary findings suggest the efficacy of app-based remote neurofeedback in improving mental health, given the reduced symptom severity from pre- to postassessment for general psychological health, ADHD, anxiety, and depression, as well as adjusted resting EEG neural markers for individuals with symptoms of ADHD. Collectively, this supports the utility of the in-app assessment in monitoring behavioral and neural indices of mental health.

Development and validation of virtual reality-based Rey Auditory Verbal Learning Test.

Objective: Translations and adaptations of traditional neuropsychological tests to virtual reality (VR) technology bear the potential to increase their ecological validity since the technology enables simulating everyday life conditions in a controlled manner. The current paper describes our translation of a commonly used neuropsychological test to VR, the Rey Auditory Verbal Learning Test (RAVLT). For this aim, we developed a VR adaptation of the RAVLT (VR-RAVLT) Which is based on a conversation with a secretary in a virtual office using a fully immersive VR system. To validate the VR-RAVLT, we tested its construct validity, its age-related discriminant validity and its test-retest validity in reference to the original gold standard RAVLT (GS-RAVLT). Method: Seventy-eight participants from different age groups performed the GS-RAVLT and the VR-RAVLT tests in a counterbalanced order in addition to other neuropsychological tests. Construct validity was validated using Pearson's correlations coefficients and serial position effects; discriminant validity was validated using receiver operating characteristic area under the curve values and test-retest reliability was validated using intraclass correlation coefficients. Results: Comparing both RAVLTs' format results indicates that the VR-RAVLT has comparable construct, discriminant and test-retest validities. Conclusion: the novel VR-RAVLT and the GS-RAVLT share similar psychometric properties suggesting that the two tests measure the same cognitive construct. This is an indication of the feasibility of adapting the RAVLT to the VR environment. Future developments will employ this approach for clinical diagnosis and treatment.

The relationship between cognitive impairment, cognitive fatigue, and visual evoked potential latency in people with multiple sclerosis.

BACKGROUND: Fatigue in people with multiple sclerosis (PwMS) can impact physical, cognitive, and psychosocial domains of daily life. The experience of fatigue in PwMS is thought to originate from the central nervous system, particularly for the domain of cognitive fatigue. Here, we tested the hypothesis that fatigue scores in PwMS would be significantly associated with an index of neural activity - the latency of the P100 of the visual evoked potential (VEP) - in line with the notion of a centralized origin of fatigue. We predicted that prolonged VEP latency would be associated with greater fatigue, and that this relationship would be the most pronounced within the domain of cognitive fatigue. METHODS: PwMS (n=249) completed the Modified Fatigue Impact Scale (Global, Physical, Cognitive, and Psychosocial scales of the MFIS) and Fatigue Severity Scale. VEP latency was obtained using an alternating checkerboard paradigm. We also examined the influence of depression (Beck Depression Inventory, second edition, BDI-II) and cognitive functioning (NeuroTrax testing battery) on the VEP/fatigue relationship. RESULTS: Surprisingly, we observed that earlier (not later) VEP latency was significantly associated with higher MFIS Cognitive score. The negative relationship between VEP latency and cognitive fatigue was evident in PwMS that had poor cognitive performance as measured by a latent variable that reflected attention, executive function, information processing speed, and motor skills; but a significant relationship was not observed in PwMS that exhibited good performance on this measure. CONCLUSIONS: These findings can be interpreted within a metacognitive framework - greater fatigue may be perceived when neural performance and the level of mental effort expended does not translate to efficient cognitive performance. Cognitive fatigue may be particularly salient in PwMS when neural resources are unable to compensate for cognitive difficulties. The mismatch between the expectation of what ought to occur and what does occur during cognitive performance may be a key feature of the experience of cognitive fatigue for some PwMS.

Longitudinal assessment of the relationship between visual evoked potentials and cognitive performance in multiple sclerosis.

OBJECTIVE: Visual evoked potentials (VEPs) can provide insight into disease activity in people with multiple sclerosis (PwMS). However, few studies have tracked concurrent changes in VEPs and cognitive functioning over time in MS. To address this, we examined the longitudinal relationship between VEP and cognitive performance in PwMS over a two-year period. METHODS: At baseline (T1) and follow-up (T2, 2.14 years after baseline, on average), P100 peak latency and inter-ocular latency (IOL) between eyes were calculated from the VEP elicited for checkerboard pattern-reversal stimuli. Cognitive performance was assessed for seven different domains (NeuroTrax battery). The potential for VEP variables to predict the T1-to-T2 change in cognitive performance was assessed in a series of multiple linear regression models. RESULTS: Baseline IOL and VEP latency were significantly associated with T1-to-T2 change in information processing speed. Post-hoc analyses indicated that PwMS that had both prolonged VEP latency and elevated IOL at baseline tended to exhibit greater information processing speed decline. Increase in VEP latency from T1-to-T2 was also associated with decline in psychomotor function over time. CONCLUSIONS: These findings provide evidence that VEP measures can serve as valuable prognostic indicators of longitudinal cognitive change in PwMS. SIGNIFICANCE: Visual system neurophysiology corresponds with changes in speeded cognitive performance in MS.

Prolonged visual evoked potential latency predicts longitudinal worsening of fatigue in people with multiple sclerosis.

BACKGROUND: Fatigue is a common problem experienced by people with multiple sclerosis (PwMS) and can impact physical, cognitive, and psychosocial aspects of daily living and quality of life. The tracking of meaningful longitudinal change in subjective fatigue that occurs as a result of MS activity may be enhanced by incorporating objective neurophysiological measures into longitudinal assessment. To examine this possibility, we examined the longitudinal relationship between visual evoked potential (VEP) measures and a variety of fatigue measures over an approximately two-year period in PwMS. METHODS: VEP measures were obtained using a checkerboard pattern-reversal paradigm. Fatigue was assessed with the Modified Fatigue Impact Scale (MFIS Global, Physical, Cognitive, and Psychosocial subscales) and the Fatigue Severity Scale (FSS) questionnaires. Multiple linear regression analyses were conducted in which the change in each fatigue scale score from baseline to follow-up (T1-to-T2) served as the outcome variables for separate models. Predictor variables included the peak latency of the P100 component of the VEP (maximum peak among the two eyes) and the inter-ocular latency (IOL) at T1, the T1-to-T2 change score for maximum VEP latency and IOL, and the fatigue score at T1 that corresponded to each outcome measure. RESULTS: Prolonged baseline VEP latency was a significant predictor of the T1-to-T2 increase in MFIS Global score, and increased VEP latency from baseline to follow-up was significantly associated with MFIS Cognitive score over the same time period. Furthermore, VEP latency measures in these two models were better predictors of changes in fatigue than baseline fatigue scores were, based on the magnitude of the standardized beta coefficients. Subsequent post-hoc analyses revealed that the relationship between change in VEP latency and change in MFIS Cognitive score was evident primarily for PwMS that had elevated MFIS Cognitive score at baseline. CONCLUSION: The present study provides novel evidence that prolonged VEP latency is predictive of worsening of global and cognitive fatigue in PwMS. VEP latency measures may therefore provide clinical utility for monitoring changes in fatigue in PwMS, when used in conjunction with other clinical tools.

Frequency-tuned electromagnetic field therapy improves post-stroke motor function: A pilot randomized controlled trial.

Background and purpose: Impaired upper extremity (UE) motor function is a common disability after ischemic stroke. Exposure to extremely low frequency and low intensity electromagnetic fields (ELF-EMF) in a frequency-specific manner (Electromagnetic Network Targeting Field therapy; ENTF therapy) is a non-invasive method available to a wide range of patients that may enhance neuroplasticity, potentially facilitating motor recovery. This study seeks to quantify the benefit of the ENTF therapy on UE motor function in a subacute ischemic stroke population. Methods: In a randomized, sham-controlled, double-blind trial, ischemic stroke patients in the subacute phase with moderately to severely impaired UE function were randomly allocated to active or sham treatment with a novel, non-invasive, brain computer interface-based, extremely low frequency and low intensity ENTF therapy (1-100 Hz, < 1 G). Participants received 40 min of active ENTF or sham treatment 5 days/week for 8 weeks; ~three out of the five treatments were accompanied by 10 min of concurrent physical/occupational therapy. Primary efficacy outcome was improvement on the Fugl-Meyer Assessment - Upper Extremity (FMA-UE) from baseline to end of treatment (8 weeks). Results: In the per protocol set (13 ENTF and 8 sham participants), mean age was 54.7 years (±15.0), 19% were female, baseline FMA-UE score was 23.7 (±11.0), and median time from stroke onset to first stimulation was 11 days (interquartile range (IQR) 8-15). Greater improvement on the FMA-UE from baseline to week 4 was seen with ENTF compared to sham stimulation, 23.2 ± 14.1 vs. 9.6 ± 9.0, p = 0.007; baseline to week 8 improvement was 31.5 ± 10.7 vs. 23.1 ± 14.1. Similar favorable effects at week 8 were observed for other UE and global disability assessments, including the Action Research Arm Test (Pinch, 13.4 ± 5.6 vs. 5.3 ± 6.5, p = 0.008), Box and Blocks Test (affected hand, 22.5 ± 12.4 vs. 8.5 ± 8.6, p < 0.0001), and modified Rankin Scale (-2.5 ± 0.7 vs. -1.3 ± 0.7, p = 0.0005). No treatment-related adverse events were reported. Conclusions: ENTF stimulation in subacute ischemic stroke patients was associated with improved UE motor function and reduced overall disability, and results support its safe use in the indicated population. These results should be confirmed in larger multicenter studies. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04039178, identifier: NCT04039178.

The Efficacy of a Virtual Reality Exposure Therapy Treatment for Fear of Flying: A Retrospective Study.

Background: Fear of flying (FoF) is a phobia with 10-40% prevalence in the industrialized world. FoF is accompanied by severe economic, social, vocational, and emotional consequences. In recent years, virtual reality (VR)-based exposure therapy (VRET) for FoF has been introduced. Positive long-term efficacy of FoF-VRET has been reported by several studies, which, however, were limited by relatively small, non-representative samples and a lack of comparative pre/post functional efficacy outcome measures. Our objective was to evaluate the efficacy of a VRET treatment utilizing a large-scale VR system, experienced by a representative sample of self-referred individuals. Methods: We conducted a retrospective survey. Of 274 individuals who received the treatment (over a period of 3 years), 209 met inclusion/criteria, and 98 agreed to participate. We mainly collected information regarding flight activity before and after treatment relying on evidence such as boarding passes and flight tickets. The primary outcome measures were (1) number of flights per month (FpM) and (2) number of flight hours per month (FHpM). For each participant, these outcomes were computed for the post-treatment period (≥6 months after FoF-VRET) and the corresponding pre-treatment period. Results: FpM (mean ± SD) increased from 0.04 ± 0.06 to 0.16 ± 14 flights (p < 0.0001). FHpM rose from 0.19 ± 0.35 to 0.79 ± 0.87 h per month (p < 0.0001). Conclusion: These results are indicative of FoF-VRET treatment efficacy. Future studies should evaluate long-term maintenance of the treatment effect and thus identify the optimal frequency for delivery of periodic booster treatments.