Auditory attention measured by EEG in neurological populations: systematic review of literature and meta-analysis.

Sensorimotor synchronization strategies have been frequently used for gait rehabilitation in different neurological populations. Despite these positive effects on gait, attentional processes required to dynamically attend to the auditory stimuli needs elaboration. Here, we investigate auditory attention in neurological populations compared to healthy controls quantified by EEG recordings. Literature was systematically searched in databases PubMed and Web of Science. Inclusion criteria were investigation of auditory attention quantified by EEG recordings in neurological populations in cross-sectional studies. In total, 35 studies were included, including participants with Parkinson's disease (PD), stroke, Traumatic Brain Injury (TBI), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS). A meta-analysis was performed on P3 amplitude and latency separately to look at the differences between neurological populations and healthy controls in terms of P3 amplitude and latency. Overall, neurological populations showed impairments in auditory processing in terms of magnitude and delay compared to healthy controls. Consideration of individual auditory processes and thereafter selecting and/or designing the auditory structure during sensorimotor synchronization paradigms in neurological physical rehabilitation is recommended.

Embodied perspective-taking enhances interpersonal synchronization: A body-swap study.

Humans exhibit a strong tendency to synchronize movements with each other, with visual perspective potentially influencing interpersonal synchronization. By manipulating the visual scenes of participants engaged in a joint finger-tapping task, we examined the effects of 1st person and 2nd person visual perspectives on their coordination dynamics. We hypothesized that perceiving the partner's movements from their 1st person perspective would enhance spontaneous interpersonal synchronization, potentially mediated by the embodiment of the partner's hand. We observed significant differences in attractor dynamics across visual perspectives. Specifically, participants in 1st person coupling were unable to maintain de-coupled trajectories as effectively as in 2nd person coupling. Our findings suggest that visual perspective influences coordination dynamics in dyadic interactions, engaging error-correction mechanisms in individual brains as they integrate the partner's hand into their body representation. Our results have the potential to inform the development of applications for motor training and rehabilitation.

Neural entrainment underpins sensorimotor synchronization to dynamic rhythmic stimuli.

Neural entrainment, defined as unidirectional synchronization of neural oscillations to an external rhythmic stimulus, is a topic of major interest in the field of neuroscience. Despite broad scientific consensus on its existence, on its pivotal role in sensory and motor processes, and on its fundamental definition, empirical research struggles in quantifying it with non-invasive electrophysiology. To this date, broadly adopted state-of-the-art methods still fail to capture the dynamic underlying the phenomenon. Here, we present event-related frequency adjustment (ERFA) as a methodological framework to induce and to measure neural entrainment in human participants, optimized for multivariate EEG datasets. By applying dynamic phase and tempo perturbations to isochronous auditory metronomes during a finger-tapping task, we analyzed adaptive changes in instantaneous frequency of entrained oscillatory components during error correction. Spatial filter design allowed us to untangle, from the multivariate EEG signal, perceptual and sensorimotor oscillatory components attuned to the stimulation frequency. Both components dynamically adjusted their frequency in response to perturbations, tracking the stimulus dynamics by slowing down and speeding up the oscillation over time. Source separation revealed that sensorimotor processing enhanced the entrained response, supporting the notion that the active engagement of the motor system plays a critical role in processing rhythmic stimuli. In the case of phase shift, motor engagement was a necessary condition to observe any response, whereas sustained tempo changes induced frequency adjustment even in the perceptual oscillatory component. Although the magnitude of the perturbations was controlled across positive and negative direction, we observed a general bias in the frequency adjustments towards positive changes, which points at the effect of intrinsic dynamics constraining neural entrainment. We conclude that our findings provide compelling evidence for neural entrainment as mechanism underlying overt sensorimotor synchronization, and highlight that our methodology offers a paradigm and a measure for quantifying its oscillatory dynamics by means of non-invasive electrophysiology, rigorously informed by the fundamental definition of entrainment.

Gaetano Perusini: The Forgotten Neuroscientist Behind "Alzheimer's" Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment with social and occupational impacts. This form of dementia is being increasingly studied, and its prevalence is expected to rise in the near future. Gaetano Perusini, a neuroscientist in the Alzheimer's laboratory, has played a major clinical and pathological role in the earlier study of Alzheimer's disease. This article summarizes his role in the discovery of the disease, which should be fairly named Alzheimer-Perusini disease.

Pliny the Elder: Lessons from the Naturalist as an Early Neuroscientist.

Pliny the Elder was a prolific Roman author, naturalist, and military leader. Yet, his impact on modern-day neuroscience, psychiatry, and neurology has been little explored. Here, we aimed to trace the origins of our current understanding of the brain in ancient Rome through Pliny and his work, Natural History. As his magnum opus, this 37-book tome catalogs the facts and observations of natural life collected by Pliny, reflecting the knowledge of his time. Following the cephalocentric school of thought, Pliny places the brain as an agent for consciousness and details its diseases. Further, we explore Pliny's methods, which allow him to build a thorough collection of clinical descriptions and remedies. This body of work serves as an important lesson for future neuroscientists on the power of observation, the role of the humanities, and the necessity of understanding the origin of modern scientific thinking.

Mutual beta power modulation in dyadic entrainment.

Across a broad spectrum of interactions, humans exhibit a prominent tendency to synchronize their movements with one another. Traditionally, this phenomenon has been explained from the perspectives of predictive coding or dynamical systems theory. While these theories diverge with respect to whether individuals hold internal models of each other, they both assume a predictive or anticipatory mechanism enabling rhythmic interactions. However, the neural bases underpinning interpersonal synchronization are still a subject under active investigation. Here we provide evidence that the brain relies on a common oscillatory mechanism to pace self-generated rhythmic movements and to track the movements produced by a partner. By performing dual-electroencephalography recordings during a joint finger-tapping task, we identified an oscillatory component in the beta range (∼ 20 Hz), which was significantly modulated by both self-generated and other-generated movement. In conditions where the partners perceived each other, we observed periodic fluctuations of beta power as a function of the reciprocal movement cycles. Crucially, this modulation occurred both in visually and in auditorily coupled conditions, and was accompanied by recurrent periods of dyadic synchronized behavior. Our results show that periodic beta power modulations may be a critical mechanism underlying interpersonal synchronization, possibly enabling mutual predictions between coupled individuals, leading to co-regulation of timing and overt mutual adaptation. Our findings thus provide a potential bridge between influential theories attempting to explain interpersonal coordination, and a concrete connection to its neurophysiological bases.

Temporal trends of multiple sclerosis disease activity: Electronic health records indicators.

BACKGROUND: Long-term data on multiple sclerosis (MS) inflammatory disease activity are limited. We examined electronic health records (EHR) indicators of disease activity in people with MS. METHODS: We analyzed prospectively collected research registry data and linked EHR data in a clinic-based cohort from 2000 to 2016. We used the trend of the yearly incident relapse rate from the registry data as benchmark. We then calculated the temporal trends of potentially relevant EHR measures, including mean count of the MS diagnostic code, mentions of MS-related concepts, MS-related health utilizations and selected prescriptions. RESULTS: 1,555 MS patients had both registry and EHR data. Between 2000 and 2016, the registry data showed a declining trend in the yearly incident relapse rate, parallel to an increasing trend of DMT usage. Among the EHR measures, covariate-adjusted frequency of diagnostic code of MS, procedure codes of MS-related imaging studies and emergency room visits, and electronic prescription for steroids declined over time, mirroring the temporal trend of the benchmark yearly incident relapse rate. CONCLUSION: This study highlights EHR indicators of MS relapse that could enable large-scale examination of long-term disease activities or inform individual patient monitoring in clinical settings where EHR data are available.

Serum NfL levels in the first five years predict 10-year thalamic fraction in patients with MS.

BACKGROUND: Serum neurofilament light chain (sNfL) levels are associated with relapses, MRI lesions, and brain volume in multiple sclerosis (MS). OBJECTIVE: To explore the value of early serum neurofilament light (sNfL) measures in prognosticating 10-year regional brain volumes in MS. METHODS: Patients with MS enrolled in the Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study within five years of disease onset who had annual blood samples from years 1-10 (n = 91) were studied. sNfL was measured with a single molecule array (SIMOA) assay. We quantified global cortical thickness and normalized deep gray matter (DGM) volumes (fractions of the thalamus, caudate, putamen, and globus pallidus) from high-resolution 3 T MRI at 10 years. Correlations between yearly sNfL levels and 10-year MRI outcomes were assessed using linear regression models. RESULTS: sNfL levels from years 1 and 2 were associated with 10-year thalamus fraction. Early sNfL levels were not associated with 10-year putamen, globus pallidus or caudate fractions. At 10 years, cortical thickness was not associated with early sNfL levels, but was weakly correlated with total DGM fraction. CONCLUSIONS: Early sNfL levels correlate with 10-year thalamic volume, supporting its role as a prognostic biomarker in MS.

Modality-specific attractor dynamics in dyadic entrainment.

Rhythmic joint coordination is ubiquitous in daily-life human activities. In order to coordinate their actions towards shared goals, individuals need to co-regulate their timing and move together at the collective level of behavior. Remarkably, basic forms of coordinated behavior tend to emerge spontaneously as long as two individuals are exposed to each other's rhythmic movements. The present study investigated the dynamics of spontaneous dyadic entrainment, and more specifically how they depend on the sensory modalities mediating informational coupling. By means of a novel interactive paradigm, we showed that dyadic entrainment systematically takes place during a minimalistic rhythmic task despite explicit instructions to ignore the partner. Crucially, the interaction was organized by clear dynamics in a modality-dependent fashion. Our results showed highly consistent coordination patterns in visually-mediated entrainment, whereas we observed more chaotic and more variable profiles in the auditorily-mediated counterpart. The proposed experimental paradigm yields empirical evidence for the overwhelming tendency of dyads to behave as coupled rhythmic units. In the context of our experimental design, it showed that coordination dynamics differ according to availability and nature of perceptual information. Interventions aimed at rehabilitating, teaching or training sensorimotor functions can be ultimately informed and optimized by such fundamental knowledge.

Neural Entrainment Meets Behavior: The Stability Index as a Neural Outcome Measure of Auditory-Motor Coupling.

Understanding rhythmic behavior in the context of coupled auditory and motor systems has been of interest to neurological rehabilitation, in particular, to facilitate walking. Recent work based on behavioral measures revealed an entrainment effect of auditory rhythms on motor rhythms. In this study, we propose a method to compute the neural component of such a process from an electroencephalographic (EEG) signal. A simple auditory-motor synchronization paradigm was used, where 28 healthy participants were instructed to synchronize their finger-tapping with a metronome. The computation of the neural outcome measure was carried out in two blocks. In the first block, we used Generalized Eigendecomposition (GED) to reduce the data dimensionality to the component which maximally entrained to the metronome frequency. The scalp topography pointed at brain activity over contralateral sensorimotor regions. In the second block, we computed instantaneous frequency from the analytic signal of the extracted component. This returned a time-varying measure of frequency fluctuations, whose standard deviation provided our "stability index" as a neural outcome measure of auditory-motor coupling. Finally, the proposed neural measure was validated by conducting a correlation analysis with a set of behavioral outcomes from the synchronization task: resultant vector length, relative phase angle, mean asynchrony, and tempo matching. Significant moderate negative correlations were found with the first three measures, suggesting that the stability index provided a quantifiable neural outcome measure of entrainment, with selectivity towards phase-correction mechanisms. We address further adoption of the proposed approach, especially with populations where sensorimotor abilities are compromised by an underlying pathological condition. The impact of using stability index can potentially be used as an outcome measure to assess rehabilitation protocols, and possibly provide further insight into neuropathological models of auditory-motor coupling.

Obesity is associated with the Optic Neuritis severity in Male patients with Multiple Sclerosis.

BACKGROUND: Obesity is an important modifiable risk factor of MS; a deeper biological understanding of this association is needed. OBJECTIVE: To evaluate the determinants of acute optic neuritis (AON) severity and recovery in multiple sclerosis (MS). METHODS: We included 61 patients with MS with recorded AON severity and recovery according to visual acuity outcomes before, at, and, after the relapse. We measured body mass index (BMI) and the serum concentration of estrogen, leptin, testosterone, sex hormone-binding globulin, and vitamin D. We tested the association between BMI and serum hormones and AON severity and recovery with logistic regressions. RESULTS: In males, moderate/severe AON was associated with higher BMI (31.26 kg/m2 vs 25.73 kg/m2, logistic regression, p= 0.03), higher serum estrogen levels (32.24 nmol/L vs 23.06 nmol/L, logistic regression, p=0.04), and higher serum leptin levels (12.29 ng/mL vs mild AON: 4.1 ng/mL, logistic regression, p=0.06) than mild AON. These observations were not seen in female patients. We did not find an association with BMI or hormone levels and AON recovery. CONCLUSION: BMI, serum leptin, and serum estrogen were associated with AON severity in male patients but not in female patients. No association of these factors and AON recovery was observed.

MRI Lesion State Modulates the Relationship Between Serum Neurofilament Light and Age in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Serum neurofilament light (sNfL) has been studied as a biomarker of disease activity in multiple sclerosis (MS). Several factors, including age, can influence its dynamics, and several studies have shown that sNfL increases with age in controls. Our objective was to explore the relationship of sNfL and age at different MS disease stages, including remission and after a gadolinium-enhancing (Gad+) lesion. METHODS: We included 94 patients with MS with annual sNfL measurements performed with a single-molecule array assay. We used multivariable linear mixed-effects models with random intercept to test the association between age and sNfL during remission and after a Gad+ lesion (ie, within 90 days after the Gad+ lesion). The model was adjusted for medication use and sex. RESULTS: We report a positive association between sNfL level and age during remission (adjusted estimate = 1.18% yearly increase, 95% CI = .34-2.03%, P = .008). In contrast, a negative interaction between age and Gad+ lesion status was observed (adjusted estimate = -1.73%, 95% CI = -2.85 to -.58%, P = .004). CONCLUSION: We propose that younger patients experience a greater elevation in sNfL than older patients in response to Gad+ lesions. Our study provides potential insights into the effects of aging on neuroinflammation in MS.

Neurologic complications of Down syndrome: a systematic review.

Down syndrome (DS) is one of the most well-recognized genetic disorders. Persons with DS are known to have a variety of co-morbid medical problems, affecting nearly all organ systems. Improved healthcare interventions and research have allowed for increased life span of persons with DS, although disorders of the neurologic system remain underexplored. The purpose of this systematic review is to provide clinically pertinent information on the neurological phenotypes of frequently occurring or clinically relevant conditions. A retrospective review of MEDLINE, Scopus, and Pubmed were used to identify sources among seventeen, clinically relevant, search categories. MeSH terms all contained the phrase "Down Syndrome" in conjunction with the topic of interest. 'Frequently-occurring' was defined as prevalent in more than 10% of persons with DS across their lifespan, whereas 'clinically-relevant' was defined as a disease condition where early diagnosis or intervention can augment the disease course. In total, 4896 sources were identified with 159 sources meeting criteria for inclusion. Seventeen clinical conditions were grouped under the following subjects: hypotonia, intellectual and learning disability, cervical instability, autism spectrum disorder, epilepsy, cerebrovascular disease, Alzheimer's disease and neuropsychiatric disease. The results of this review provide a blueprint for the clinical neurologist taking care of persons with DS across the age spectrum and indicate that there are many underrecognized and misdiagnosed co-occurring conditions in DS, highlighting the need for further research.

Down Syndrome Disintegrative Disorder: A Clinical Regression Syndrome of Increasing Importance.

Down syndrome disintegrative disorder (DSDD), a developmental regression in children with Down syndrome (DS), is a clinical entity that is characterized by a loss of previously acquired adaptive, cognitive, and social functioning in persons with DS usually in adolescence to early adulthood. Initially reported in 1946 as "catatonic psychosis," there has been an increasing interest among the DS community, primary care, and subspecialty providers in this clinical area over the past decade. This condition has a subacute onset and can include symptoms of mood lability, decreased participation in activities of daily living, new-onset insomnia, social withdrawal, autistic-like regression, mutism, and catatonia. The acute phase is followed by a chronic phase in which baseline functioning may not return. No strict criteria or definitive testing is currently available to diagnose DSDD, although a comprehensive psychosocial and medical evaluation is warranted for individuals presenting with such symptoms. The etiology of DSDD is unknown, but in several hypotheses for regression in this population, psychological stress, primary psychiatric disease, and autoimmunity are proposed as potential causes of DSDD. Both psychiatric therapy and immunotherapies have been described as DSDD treatments, with both revealing potential benefit in limited cohorts. In this article, we review the current data regarding clinical phenotypes, differential diagnosis, neurodiagnostic workup, and potential therapeutic options for this unique, most disturbing, and infrequently reported disorder.

Temporal association of sNfL and gad-enhancing lesions in multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is an autoimmune demyelinating disorder, which is characterized by relapses and remissions. Serum neurofilament light chain (sNfL) is an emerging biomarker of disease activity but its clinical use is still limited. In this study, we aim to characterize the temporal association between sNfL and new clinical relapses and new gadolinium-enhancing (Gd+) lesions. METHODS: Annual sNfL levels were measured with a single-molecule array (SIMOA) assay in 94 patients with MS enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study. We used a multivariable linear mixed-effects model to test the temporal association of sNfL with clinical relapses and/or new Gd+ lesions. We adjusted this model for age, disease duration, sex, and disease-modifying therapies (DMTs) use. RESULTS: In the 3 months after a Gd+ lesion, we observed an average 35% elevation in sNfL (P < 0.0001) compared to remission samples. We also observed an average 32.3% elevation in sNfL at the time of or prior to a Gd+ lesion (P = 0.002) compared to remission. We observed a significant elevation in sNfL after a clinical relapse only when associated with a Gd+ lesion. INTERPRETATION: Our findings support sNfL as a marker of clinical relapses and Gd+ lesions. sNfL peaks in a 3-month window around Gd+ lesions. sNfL shows promise as a biomarker of neurological inflammation and possibly of simultaneous Gd+ lesions during a clinical relapse.

Targeting IL-6 receptor in the treatment of neuromyelitis optica spectrum: a review of emerging treatment options.

Introduction: Recent research has shown that IL-6 receptor (IL-6 R) inhibitors like tocilizumab and satralizumab are effective in reducing the relapse rate in patients with NMOSD.Areas covered: This review article explores current concepts in NMOSD management and focuses on IL-6 R as a therapeutic target. The authors delve into the biological and immunological role of IL-6 in the pathogenesis of NMOSD. Further, the authors summarize the most recent findings on the use of anti-IL-6 R monoclonal antibodies, tocilizumab and satralizumab, in the treatment of NMOSD.Expert opinion: A better understanding of the role of cytokines in NMOSD may provide the neurologist with novel therapies for this disease. IL-6 R appears to be a central hub to NMOSD pathogenesis and a relevant therapeutic target.

Wilhelm Uhthoff and Uhthoff's phenomenon.

Wilhelm Uhthoff, known for his contributions to both neurology and neuro-ophthalmology, was a German ophthalmologist who specialized in neurologic disorders. The eponym "Uhthoff's phenomenon" was first used to describe the reversible, transient blurring of vision in patients with multiple sclerosis during exercise. Subsequently, it was discovered that this neurologic sign not only was triggered by physical exertion but also by other homeostatic disruptions such as hot baths, menstruation, and high external temperatures. Here, we take a look at the life and career of Wilhelm Uhthoff and discuss the basis behind this phenomenon.

Association Between Cigarette Smoking and Multiple Sclerosis: A Review.

Importance: Cigarette smoking is a common environmental exposure and addiction, which has severe health consequences. Smoking is a risk factor for multiple sclerosis (MS); also, smoking has been associated with disease activity and overall prognosis for patients with MS. Observations: Cigarette smoking is an irritative agent on the lungs, in which a proinflammatory cascade starts that culminates in autoimmunity. Inflammation may increase the risk of MS in some individuals, in a process driven by antigen cross-reactivity between lung antigens and myelin antigens. Genetics plays a central role in the individual predisposition to mounting an autoimmune reaction. Also, free radicals, cyanates, and carbon monoxide in cigarette smoke may be directly toxic to neurons. Patients with MS who smoke have higher rates of disease activity, faster rates of brain atrophy, and a greater disability burden. Some of the outcomes of smoking were found to be reversible, which makes counseling key. Conclusions and Relevance: The pathways involved in cigarette smoking should be further analyzed to understand the mechanisms whereby smoking worsens MS prognosis. The proinflammatory and neurotoxic outcomes of cigarette smoking may be shared by other environmental exposures, such as pollution and organic solvents. From a global perspective, efforts should be made to diminish the prevalence of cigarette smoking in patients with MS.