Spinal cord involvement in progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infectious demyelinating disease of the central nervous system caused by JC polyomavirus predominantly affecting immunocompromised individuals. Nowadays, HIV, hematological malignancies and iatrogenic immune suppression account for most PML cases. For unknown reasons, spinal cord is classically protected from PML lesions. Here, we report the course of a patient harboring spinal cord lesions in the context of PML with immune reconstitution inflammatory syndrome and review the eight other cases reported in the literature so far. Then, we discuss the evolving spectrum of PML over recent years, potentially making its diagnosis more challenging.

[For an integrated approach to brain health]. / Pour une approche intégrée de la santé cérébrale.

The brain is a vital organ that partly regulates our homeostasis and governs our interactions with the world (i.e. the physical, biological, and social environments). A healthy environment and a peaceful and equitable society ensure a normal brain development and promote individual (physical, mental, social, and spiritual) well-being. However, brain health is never certain and can be deteriorated, from conception until death, by exposure to multiple physical, chemical, biological, psychological, and social agents - the so-called exposome. From an integrated perspective, this article highlights the need to value, promote and protect brain health. The current challenge is to strengthen public awareness, education and research on brain health, in order to prevent neurological and psychiatric diseases.

Le cerveau est un organe vital qui règle en partie notre homéostasie et régit nos interactions avec le monde (c'est-à-dire les environnements physiques, biologiques et sociaux). Un environnement sain et une société paisible et équitable assurent son développement normal et œuvrent au bien-être individuel (physique, mental, social et spirituel). Mais la santé cérébrale n'est jamais acquise et peut être détériorée, dès la conception et jusqu'au décès, par l'exposition à de multiples agents physiques, chimiques, biologiques, psychologiques et sociaux - l'exposome. Dans une perspective intégrée, cet article souligne la nécessité fondamentale de valoriser, promouvoir et protéger la santé du cerveau. Le défi actuel est de renforcer la sensibilisation, l'éducation et la recherche sur la santé cérébrale et prévenir les maladies neurologiques et psychiatriques.

Association between sleep slow-wave activity and in-vivo estimates of myelin in healthy young men.

Sleep has been suggested to contribute to myelinogenesis and associated structural changes in the brain. As a principal hallmark of sleep, slow-wave activity (SWA) is homeostatically regulated but also differs between individuals. Besides its homeostatic function, SWA topography is suggested to reflect processes of brain maturation. Here, we assessed whether interindividual differences in sleep SWA and its homeostatic response to sleep manipulations are associated with in-vivo myelin estimates in a sample of healthy young men. Two hundred twenty-six participants (18-31 y.) underwent an in-lab protocol in which SWA was assessed at baseline (BAS), after sleep deprivation (high homeostatic sleep pressure, HSP) and after sleep saturation (low homeostatic sleep pressure, LSP). Early-night frontal SWA, the frontal-occipital SWA ratio, as well as the overnight exponential SWA decay were computed over sleep conditions. Semi-quantitative magnetization transfer saturation maps (MTsat), providing markers for myelin content, were acquired during a separate laboratory visit. Early-night frontal SWA was negatively associated with regional myelin estimates in the temporal portion of the inferior longitudinal fasciculus. By contrast, neither the responsiveness of SWA to sleep saturation or deprivation, its overnight dynamics, nor the frontal/occipital SWA ratio were associated with brain structural indices. Our results indicate that frontal SWA generation tracks inter-individual differences in continued structural brain re-organization during early adulthood. This stage of life is not only characterized by ongoing region-specific changes in myelin content, but also by a sharp decrease and a shift towards frontal predominance in SWA generation.

Immune-mediated cerebellitis following SARS-CoV-2 infection-a case report and review of the literature.

The coronavirus disease 2019 (COVID-19) can be associated with a wide variety of neurological manifestations. Some of these manifestations might result from the ongoing systemic inflammatory state, but the pathophysiology of specific neurologic involvement is still unclear. In this article, we report a patient who developed an isolated cerebellar syndrome 9 weeks after an episode of COVID-19. The reverse-transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 was positive on cerebrospinal fluid (CSF). A post-infectious-autoimmune-cerebellitis following COVID-19 was suspected, and the patient was treated with corticosteroids, leading to a complete recovery within a few weeks. We review the other cases of COVID-19-associated cerebellar syndrome reported so far and discuss the potential pathophysiological mechanisms underlying this neurologic manifestation.

Genetic risk for insomnia is associated with objective sleep measures in young and healthy good sleepers.

Insomnia disorder (ID) is the second most common neuropsychiatric disorder. Its socioeconomic burden is enormous while diagnosis and treatment are difficult. A novel approach that reveals associations between insomnia genetic propensity and sleep phenotypes in youth may help understand the core of the disease isolated from comorbidities and pave the way for new treatments. We obtained quantitative nocturnal sleep electroencephalogram (EEG) features in 456 participants (18-31y, 49 women). Sleep EEG was recorded during a baseline night following at least 7 days of regular sleep times. We then assessed daytime sleep onset latency in a subsample of N = 359 men exposed to manipulations affecting sleep pressure. We sampled saliva or blood for polygenic risk score (PRS) determination. The PRS for ID was computed based on genome-wide common single nucleotide polymorphism assessments. Participants also completed a battery of behavioral and cognitive tests. The analyses revealed that the PRS for ID was negatively associated with cumulated EEG power in the delta (0.5-4 Hz) and theta (4-8 Hz) bands across rapid eye movement (REM) and non-REM sleep (p ≤ .0026; ß ≥ -0.13) controlling for age, sex and BMI. The PRS for ID was also negatively associated with daytime likelihood of falling asleep (ß = -0.19, p = .0009). Other explorations for associations with non-baseline-nights, cognitive measures, and mood did not yield significant results. These results propose that the need or the ability to fall asleep and to generate slow brain activity during sleep may constitute the core sleep-related risk factors for developing ID.

Atezolizumab Treatment for Progressive Multifocal Leukoencephalopathy.

Atezolizumab successfully reinvigorated JC virus immunity in a patient in Belgium with progressive multifocal leukoencephalopathy, as demonstrated by clinical, virologic, and radiologic response to treatment. However, the treatment also resulted in immune reconstitution inflammatory syndrome and life-threatening immune-related adverse events. These conditions were treated with corticosteroids, leading to treatment resistance.

Daytime rest: Association with 24-h rest-activity cycles, circadian timing and cognition in older adults.

Growing epidemiological evidence points toward an association between fragmented 24-h rest-activity cycles and cognition in the aged. Alterations in the circadian timing system might at least partially account for these observations. Here, we tested whether daytime rest (DTR) is associated with changes in concomitant 24-h rest probability profiles, circadian timing and neurobehavioural outcomes in healthy older adults. Sixty-three individuals (59-82 years) underwent field actigraphy monitoring, in-lab dim light melatonin onset assessment and an extensive cognitive test battery. Actimetry recordings were used to measure DTR frequency, duration and timing and to extract 24-h rest probability profiles. As expected, increasing DTR frequency was associated not only with higher rest probabilities during the day, but also with lower rest probabilities during the night, suggesting more fragmented night-time rest. Higher DTR frequency was also associated with lower episodic memory performance. Moreover, later DTR timing went along with an advanced circadian phase as well as with an altered phase angle of entrainment between the rest-activity cycle and circadian phase. Our results suggest that different DTR characteristics, as reflective indices of wake fragmentation, are not only underlined by functional consequences on cognition, but also by circadian alteration in the aged.

Voxel-Based quantitative MRI reveals spatial patterns of grey matter alteration in multiple sclerosis.

Despite robust postmortem evidence and potential clinical importance of gray matter (GM) pathology in multiple sclerosis (MS), assessing GM damage by conventional magnetic resonance imaging (MRI) remains challenging. This prospective cross-sectional study aimed at characterizing the topography of GM microstructural and volumetric alteration in MS using, in addition to brain atrophy measures, three quantitative MRI (qMRI) parameters-magnetization transfer (MT) saturation, longitudinal (R1), and effective transverse (R2*) relaxation rates, derived from data acquired during a single scanning session. Our study involved 35 MS patients (14 relapsing-remitting MS; 21 primary or secondary progressive MS) and 36 age-matched healthy controls (HC). The qMRI maps were computed and segmented in different tissue classes. Voxel-based quantification (VBQ) and voxel-based morphometry (VBM) statistical analyses were carried out using multiple linear regression models. In MS patients compared with HC, three configurations of GM microstructural/volumetric alterations were identified. (a) Co-localization of GM atrophy with significant reduction of MT, R1, and/or R2*, usually observed in primary cortices. (b) Microstructural modifications without significant GM loss: hippocampus and paralimbic cortices, showing reduced MT and/or R1 values without significant atrophy. (c) Atrophy without significant change in microstructure, identified in deep GM nuclei. In conclusion, this quantitative multiparametric voxel-based approach reveals three different spatially-segregated combinations of GM microstructural/volumetric alterations in MS that might be associated with different neuropathology.

Immune checkpoint inhibitors for progressive multifocal leukoencephalopathy: Identifying relevant outcome factors.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is an infectious brain disease caused by JC virus in immunocompromised individuals. Immune checkpoint inhibitors (ICIs) recently emerged as a therapeutic hope for these patients but identification of those likely to respond to the treatment is still an unmet need. METHOD: We performed a systematic PubMed search for reports of patients treated for PML using an ICI. Clinical, biological and radiological characteristics were contrasted between patients who responded to the treatment (RP) and those who did not (NRP). RESULTS: Thirty-five patients were included in the present study. Twenty-one of them reportedly benefited from the treatment. Age, blood CD4+ cells count, pretreatment viral load in the cerebrospinal fluid (CSF), PML lesions localization, treatment delay since first PML symptoms, type of ICI used and immune-related adverse events (irAEs) occurrence did not significantly differ between RP and NRP. By contrast, a history of therapeutic immune suppression and the use of an immunosuppressive therapy at treatment initiation were significantly associated with a poor response. Besides, reaching an undetectable viral load in the CSF and reduction of the lesion load on magnetic resonance imaging after ICI administration was associated with a good clinical response. CONCLUSION: Current data suggest that patients with PML under immunosuppressive therapy are less likely to respond to ICIs and raises the issue of the optimal management of irAEs during ICI treatment in this setting.

Lung and liver sarcoidosis-like reaction induced by tocilizumab.

A drug-induced sarcoidosis-like reaction is a systemic granulomatous reaction indistinguishable from sarcoidosis and occurring in temporal relationship with a drug initiation. In this article, we report a patient who developed lung and liver granulomatous lesions following tocilizumab initiation for a giant cell arteritis. Infectious, toxic, neoplastic and inflammatory differential diagnoses were ruled out and lesions regressed after treatment cessation, leading to the diagnosis of tocilizumab induced sarcoidosis-like reaction. We review the 6 cases reported so far and emphasize the value of a prompt diagnosis. Finally, we discuss the potential pathophysiological mechanisms underlying this rare reaction, which could help to better understand the pathophysiology of sarcoidosis.

Relationship between brain AD biomarkers and episodic memory performance in healthy aging.

The presence of brain biomarkers can be observed decades before the first clinical symptoms of Alzheimer's disease (AD). We aimed to determine whether associations between biomarkers and episodic memory performance already exist in a healthy late middle-aged population or only in participants over 60 years old. Performance at the Free and Cued Selective Reminding Test [FCSRT], the Logical Memory test and the Mnemonic Similarity Task [MST] was determined in sixty healthy participants (50-70 y.) with a negative status for amyloid-beta (Aß) biomarker. We assessed Aß cortical level and tau/neuroinflammation burden using PET scanner, and hippocampal atrophy with MRI scanner. Generalized linear mixed models showed that MST scores (recognition and pattern separation) were positively associated with hippocampal volume in participants over 60 years. No association between memory performance and Aß and tau/neuroinflammation burden was found in the older or in the younger age group. This suggests that visual recognition memory and discrimination of lures may constitute early cognitive markers of memory decline in an older population.

Exploring scoring methods for research studies: Accuracy and variability of visual and automated sleep scoring.

Sleep studies face new challenges in terms of data, objectives and metrics. This requires reappraising the adequacy of existing analysis methods, including scoring methods. Visual and automatic sleep scoring of healthy individuals were compared in terms of reliability (i.e., accuracy and stability) to find a scoring method capable of giving access to the actual data variability without adding exogenous variability. A first dataset (DS1, four recordings) scored by six experts plus an autoscoring algorithm was used to characterize inter-scoring variability. A second dataset (DS2, 88 recordings) scored a few weeks later was used to explore intra-expert variability. Percentage agreements and Conger's kappa were derived from epoch-by-epoch comparisons on pairwise and consensus scorings. On DS1 the number of epochs of agreement decreased when the number of experts increased, ranging from 86% (pairwise) to 69% (all experts). Adding autoscoring to visual scorings changed the kappa value from 0.81 to 0.79. Agreement between expert consensus and autoscoring was 93%. On DS2 the hypothesis of intra-expert variability was supported by a systematic decrease in kappa scores between autoscoring used as reference and each single expert between datasets (.75-.70). Although visual scoring induces inter- and intra-expert variability, autoscoring methods can cope with intra-scorer variability, making them a sensible option to reduce exogenous variability and give access to the endogenous variability in the data.

Cortical reactivations during sleep spindles following declarative learning.

Increasing evidence suggests that sleep spindles are involved in memory consolidation, but few studies have investigated the effects of learning on brain responses associated with spindles in humans. Here we used simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) during sleep to assess haemodynamic brain responses related to spindles after learning. Twenty young healthy participants were scanned with EEG/fMRI during (i) a declarative memory face sequence learning task, (ii) subsequent sleep, and (iii) recall after sleep (learning night). As a control condition an identical EEG/fMRI scanning protocol was performed after participants over-learned the face sequence task to complete mastery (control night). Results demonstrated increased responses in the fusiform gyrus both during encoding before sleep and during successful recall after sleep, in the learning night compared to the control night. During sleep, a larger response in the fusiform gyrus was observed in the presence of fast spindles during the learning as compared to the control night. Our findings support a cortical reactivation during fast spindles of brain regions previously involved in declarative learning and subsequently activated during memory recall, thereby promoting the cortical consolidation of memory traces.

Seasonality in human cognitive brain responses.

Daily variations in the environment have shaped life on Earth, with circadian cycles identified in most living organisms. Likewise, seasons correspond to annual environmental fluctuations to which organisms have adapted. However, little is known about seasonal variations in human brain physiology. We investigated annual rhythms of brain activity in a cross-sectional study of healthy young participants. They were maintained in an environment free of seasonal cues for 4.5 d, after which brain responses were assessed using functional magnetic resonance imaging (fMRI) while they performed two different cognitive tasks. Brain responses to both tasks varied significantly across seasons, but the phase of these annual rhythms was strikingly different, speaking for a complex impact of season on human brain function. For the sustained attention task, the maximum and minimum responses were located around summer and winter solstices, respectively, whereas for the working memory task, maximum and minimum responses were observed around autumn and spring equinoxes. These findings reveal previously unappreciated process-specific seasonality in human cognitive brain function that could contribute to intraindividual cognitive changes at specific times of year and changes in affective control in vulnerable populations.

Influence of COMT Genotype on Antero-posterior Cortical Functional Connectivity Underlying Interference Resolution.

Genetic variability related to the catechol-O-methyltransferase (COMT) gene (Val(158)Met) has received increasing attention as a possible modulator of executive functioning and its neural correlates. However, this attention has generally centered on the prefrontal cortices because of the well-known direct impact of COMT enzyme on these cerebral regions. In this study, we were interested in the modulating effect of COMT genotype on anterior and posterior brain areas underlying interference resolution during a Stroop task. More specifically, we were interested in the functional connectivity between the right inferior frontal operculum (IFop), an area frequently associated with inhibitory efficiency, and posterior brain regions involved in reading/naming processes (the 2 main non-executive determinants of the Stroop effect). The Stroop task was administered during functional magnetic resonance imaging scanning to 3 groups of 15 young adults divided according to their COMT Val(158)Met genotype [Val/Val (VV), Val/Met (VM), and Met/Met (MM)]. Results indicate greater activity in the right IFop and the left middle temporal gyrus in homozygous VV individuals than in Met allele carriers. In addition, the VV group exhibited stronger positive functional connectivity between these 2 brain regions and stronger negative connectivity between the right IFop and left lingual gyrus. These results confirm the impact of COMT genotype on frontal functions. They also strongly suggest that differences in frontal activity influence posterior brain regions related to a non-executive component of the task. Particularly, changes in functional connectivity between anterior and posterior brain areas might correspond to compensatory processes for performing the task efficiently when the available dopamine level is low.

Resting-state Network-specific Breakdown of Functional Connectivity during Ketamine Alteration of Consciousness in Volunteers.

BACKGROUND: Consciousness-altering anesthetic agents disturb connectivity between brain regions composing the resting-state consciousness networks (RSNs). The default mode network (DMn), executive control network, salience network (SALn), auditory network, sensorimotor network (SMn), and visual network sustain mentation. Ketamine modifies consciousness differently from other agents, producing psychedelic dreaming and no apparent interaction with the environment. The authors used functional magnetic resonance imaging to explore ketamine-induced changes in RSNs connectivity. METHODS: Fourteen healthy volunteers received stepwise intravenous infusions of ketamine up to loss of responsiveness. Because of agitation, data from six subjects were excluded from analysis. RSNs connectivity was compared between absence of ketamine (wake state [W1]), light ketamine sedation, and ketamine-induced unresponsiveness (deep sedation [S2]). RESULTS: Increasing the depth of ketamine sedation from W1 to S2 altered DMn and SALn connectivity and suppressed the anticorrelated activity between DMn and other brain regions. During S2, DMn connectivity, particularly between the medial prefrontal cortex and the remaining network (effect size ß [95% CI]: W1 = 0.20 [0.18 to 0.22]; S2 = 0.07 [0.04 to 0.09]), and DMn anticorrelated activity (e.g., right sensory cortex: W1 = -0.07 [-0.09 to -0.04]; S2 = 0.04 [0.01 to 0.06]) were broken down. SALn connectivity was nonuniformly suppressed (e.g., left parietal operculum: W1 = 0.08 [0.06 to 0.09]; S2 = 0.05 [0.02 to 0.07]). Executive control networks, auditory network, SMn, and visual network were minimally affected. CONCLUSIONS: Ketamine induces specific changes in connectivity within and between RSNs. Breakdown of frontoparietal DMn connectivity and DMn anticorrelation and sensory and SMn connectivity preservation are common to ketamine and propofol-induced alterations of consciousness.

Multimodal evoked potentials for functional quantification and prognosis in multiple sclerosis.

BACKGROUND: Functional biomarkers able to identify multiple sclerosis (MS) patients at high risk of fast disability progression are lacking. The aim of this study was to evaluate the ability of multimodal (upper and lower limbs motor, visual, lower limbs somatosensory) evoked potentials (EP) to monitor disease course and identify patients exposed to unfavourable evolution. METHODS: One hundred MS patients were assessed with visual, somatosensory and motor EP and rated on the Expanded Disability Status Scale (EDSS) at baseline (T0) and about 6 years later (T1). The Spearman correlation (rS) was used to evaluate the relationship between conventional EP scores and clinical findings. Multiple (logistic) regression analysis estimated the predictive value of baseline electrophysiological data for three clinical outcomes: EDSS, annual EDSS progression, and the risk of EDSS worsening. RESULTS: In contrast to longitudinal correlations, cross-sectional correlations between the different EP scores and EDSS were all significant (0.33 ≤ rS < 0.67, p < 0.001). Baseline global EP score and EDSS were highly significant predictors (p < 0.0001) of EDSS progression 6 years later. The baseline global EP score was found to be an independent predictor of the EDSS annual progression rate (p < 0.001), and of the risk of disability progression over time (p < 0.005). Based on a ROC curve determination, we defined a Global EP Score cut off point (17/30) to identify patients at high risk of disability progression illustrated by a positive predictive value of 70%. CONCLUSION: This study provides a proof of the concept that electrophysiology could be added to MRI and used as another complementary prognostic tool in MS patients.

Sleep Spindles as an Electrographic Element: Description and Automatic Detection Methods.

Sleep spindle is a peculiar oscillatory brain pattern which has been associated with a number of sleep (isolation from exteroceptive stimuli, memory consolidation) and individual characteristics (intellectual quotient). Oddly enough, the definition of a spindle is both incomplete and restrictive. In consequence, there is no consensus about how to detect spindles. Visual scoring is cumbersome and user dependent. To analyze spindle activity in a more robust way, automatic sleep spindle detection methods are essential. Various algorithms were developed, depending on individual research interest, which hampers direct comparisons and meta-analyses. In this review, sleep spindle is first defined physically and topographically. From this general description, we tentatively extract the main characteristics to be detected and analyzed. A nonexhaustive list of automatic spindle detection methods is provided along with a description of their main processing principles. Finally, we propose a technique to assess the detection methods in a robust and comparable way.

Modulating effect of COMT Val(158)Met polymorphism on interference resolution during a working memory task.

Genetic variability related to the catechol-O-methyltransferase (COMT) gene has received increasing attention in the last 15years, in particular as a potential modulator of the neural substrates underlying inhibitory processes and updating in working memory (WM). In an event-related functional magnetic resonance imaging (fMRI) study, we administered a modified version of the Sternberg probe recency task (Sternberg, 1966) to 43 young healthy volunteers, varying the level of interference across successive items. The task was divided into two parts (high vs. low interference) to induce either proactive or reactive control processes. The participants were separated into three groups according to their COMT Val(158)Met genotype [Val/Val (VV); Val/Met (VM); Met/Met (MM)]. The general aim of the study was to determine whether COMT polymorphism has a modulating effect on the neural substrates of interference resolution during WM processing. Results indicate that interfering trials were associated with greater involvement of frontal cortices (bilateral medial frontal gyrus, left precentral and superior frontal gyri, right inferior frontal gyrus) in VV homozygous subjects (by comparison to Met allele carriers) only in the proactive condition of the task. In addition, analysis of peristimulus haemodynamic responses (PSTH) revealed that the genotype-related difference observed in the left SFG was specifically driven by a larger increase in activity from the storage to the recognition phase of the interfering trials in VV homozygous subjects. These results confirm the impact of COMT genotype on inhibitory processes during a WM task, with an advantage for Met allele carriers. Interestingly, this impact on frontal areas is present only when the level of interference is high, and especially during the transition from storage to recognition in the left superior frontal gyrus.

Hierarchical clustering of brain activity during human nonrapid eye movement sleep.

Consciousness is reduced during nonrapid eye movement (NREM) sleep due to changes in brain function that are still poorly understood. Here, we tested the hypothesis that impaired consciousness during NREM sleep is associated with an increased modularity of brain activity. Cerebral connectivity was quantified in resting-state functional magnetic resonance imaging times series acquired in 13 healthy volunteers during wakefulness and NREM sleep. The analysis revealed a modification of the hierarchical organization of large-scale networks into smaller independent modules during NREM sleep, independently from EEG markers of the slow oscillation. Such modifications in brain connectivity, possibly driven by sleep ultraslow oscillations, could hinder the brain's ability to integrate information and account for decreased consciousness during NREM sleep.