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The neural mechanisms underlying motor preparation have attracted much attention, particularly because of the assertion that they are similar to the mechanisms of motor imagery (MI), a technique widely used in motor rehabilitation and brain-computer interfaces (BCIs). Here we clarified the process of visuomotor transformation for the real and imagined movements by analyzing EEG responses that were time locked to the appearance of visual targets and movement onsets. The experimental task required responding to target stimuli with button presses or imagined button presses while ignoring distractors. We examined how different components of movement-related potentials (MRPs) varied depending on the reaction time (RT) and interpreted the findings in terms of the motor noise accumulation hypothesis. Furthermore, we compared MRPs and event-related desynchronization (ERD) for overt motor actions versus motor imagery. For the MRPs, we distinguished lateralized readiness potentials (LRPs) and reafferent potentials (RAPs). While MRPs were similar for the real and imagined movements, imagery-related potentials were not lateralized. The amplitude of the late potentials that developed during motor imagery at the same time RAPs occurred during real movements was correlated with the amplitude of β-ERD. As such they could have represented sensorimotor activation triggered by the imagery. LRPs that occurred during real movements lasted longer for longer RTs, which is consistent with activity accumulation in the motor cortex prior to overt action onset. LRPs occurred for non-target stimuli, as well, but they were small and short lived. We interpret these results in terms of a visuomotor transformation, where information flows from visual to motor areas and results in a movement, a decision not to move and/or a mental image of a movement. The amplitude of the late positive peak that developed during MI was correlated with the amplitude of the β-ERD. Since the latency of this component was consistent with the timing of RAP, we suggest that it is a non-lateralized RAP-like component associated with sensorimotor activation during kinesthetic MI.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Supplementary Figure from Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition

Supplementary Data from Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition

This study investigates the movement behavior of particles of dissimilar morphology in the powder bed in Laser Powder Bed Fusion. Gas atomized (GA) and water atomized (WA) low alloy steel powders were employed to study their motion around the laser scan path. Particle velocities, entrainment distances and denudation zones were measured for both powders using high-speed imaging. The entrainment of GA powder particles in front of the laser beam towards the process area was initiated 1.6 mm from the edge of the melt pool, whereas the distance was 0.6–0.8 mm for the WA powder. The differences in observed behavior were related to the variations in particle shape of the two types of powder. The processing of WA powder resulted in a 16% narrower denudation zone (for a low volumetric energy density) compared to GA powder. However, the denudation width difference decreased with increasing volumetric energy density, most likely due to a steeper pressure gradient in the process area which diminishes the impact of powder shape. X-ray computed microtomography was utilized to estimate the drag force acting on the powder particles of various morphologies. The results showed that the radial drag force exerted on GA powder was 64% greater than when using WA powder. Moreover, if the WA powder particles were of elongated shape the drag force decreased by almost an order of magnitude, demonstrating the importance of the particle's morphology in the process dynamics.

Blown powder directed energy deposition of SS316L powder is carried out on various substrate surface conditions of SS304 such as cleaned, sand blasted, milled, oily, cold galvanised and painted to study their influence on the process. High-speed imaging is used for process observation and the deposited tracks are analysed qualitatively and quantitatively using surface images, cross sectional macrographs and x-ray images. Frames from high-speed imaging reveal the removal of additional material from the substrate surface such as paint and oil. The stages involved in their removal: peeling and evaporation are presented. EDS analysis showed that no additional elements other than powder and substrate material are found in the track volume. The quantitative results for all specimens show that the surface conditions had minor influences on track width, track height, wetting angle, dilution and deposited cross sectional area. Defects such as porosity, inclusions and cracking were not observed related to the surface conditions. These findings could significantly reduce processing time by skipping the cleaning step before directed energy deposition such as laser cladding or repair in industrial applications.

It is well known that both the movement of the hand itself and the mental representation of it lead to event-related desynchronization (ERD) of EEG recorded over the corresponding motor areas of the cerebral cortex. Similarly, in somatosensory cortical areas, ERD occurs upon tactile stimulation of the hand, but whether this effect is caused by mental representation of sensations from tactile stimulation remains poorly understood. In the present study, the effects on the EEG of imaginary vibrotactile sensations on the right hand were compared with the effects of real vibrotactile stimulation. Both actual vibrotactile stimulation and mental representation of it have been found to elicit contralateral ERD patterns, particularly prominent in theμ-band and most pronounced in the C3 region. The paper discusses tactile imagery as a part of the complex sensorimotor mental image and its prospects for using EEG patterns of imagery-induced tactile sensations as control signals in BCI circuits independently and when combined with ERD based on movement imagination to improve the efficiency of neurointerface technologies in rehabilitation medicine, in particular, to restore movements after a stroke and neurotrauma.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Meningeal solitary fibrous tumor (SFT) is a rare tumor with high propensity to recur and metastasize, even late in the course of disease. The WHO 2021 classification of CNS tumors divides SFT in 3 grades, based on mitotic index and necrosis. We re-examined our cohort of 126 patients (57 F, 69 M; mean age 53.0 years) with SFT, confirmed by STAT6 nuclear positivity and/or NAB2::STAT6 fusion, with extended follow-up (median 7.6 years; range 4 days-26.6 years). Tumors included 76 grade 1, 36 grade 2 and 14 grade 3 according to 2021 WHO criteria, evaluated at primary resection (n=90), recurrence (n=35), or metastasis (n=1). Fifty-six patients had one or more post-surgical events, the earliest event being local recurrence (n=41) or metastasis (n=15). Forty patients died (29 of disease; 9 of other causes; 2 unknown). Overall survival (OS), and progression-free survival (PFS, recurrence and/or metastasis) from time of primary resection (n=90) were not significantly associated with grade; however, risk of metastasis differed significantly (5-year estimates: 4.1%, 15.3%, and 37.8% for grades 1, 2, and 3 SFT, respectively; p=0.005). NAB2::STAT6 fusion status was known in 101 cases (51 = ex5-7-ex16-17, 26 = ex4_ex2-3; 12 = ex2-3_exANY/other and 12 =no fusion). Disease specific 5-year survival in primary tumors with molecular data (n = 75) was 80.0% in patients whose tumors harbored ex5-7_ex16-17 compared to 93.3% in all others combined (p=0.014). Targeted TERT promoter mutation testing was performed in 98 patients, revealing patients with tumors lacking TERT promoter mutation (n = 88) were younger at time of surgery than those harboring a mutation (n=10; p = 0.022), and none with a mutation harboring concurrent ex5-7_ex16-17 fusion (p = 0.0009). In summary, WHO 2021 grade is associated with risk of metastasis. Patients whose tumors harbor ex5-7_ex16-17 fusion have a higher risk of dying from the disease.

Spontaneous pauses in firing are the hallmark of external pallidum (GPe) neurons. However, the role of GPe pauses in the basal ganglia network remains unknown. Pupil size and saccadic eye movements have been linked to attention and exploration. Here, we recorded GPe spiking activity and the corresponding pupil sizes and eye positions in non-human primates. We show that pauses, rather than the GPe discharge rate per se, were associated with dilated pupils. In addition, following pause initiation there was a considerable increase in the rate of spontaneous saccades. These results suggest that pauses are a powerful mechanism by which the GPe may influence basal ganglia downstream structures and play a role in exploratory behavior.

Communication between the basal ganglia (BG) and cortex is crucial for behavior as it allows learning through external reinforcement. Non-REM sleep benefits learning in the corticostriatal system through the sleep spindle-associated reactivation of previously active neuronal ensembles and the subsequent modification of synaptic weights. However, how sleep spindles coordinate cross-region spiking, and whether spindle-driven reactivation occurs in other BG structures, remains unknown. We recorded field potentials (FP) and spiking activity in cortex and BG during sleep in two non-human primates immediately following a task that involved the learning of new cue-reward contingencies. FP sleep spindles were widespread in the BG, and they were similar to cortical spindles in morphology, spectral content and response to learning prior to sleep. Further, BG FP spindles were concordant with EEG spindles and associated with increased cortico-BG correlation. However, spindles across the BG differed markedly in their entrainment of local spiking. The spiking activity of striatal projection neurons exhibited consistent phase locking to striatal FP spindles and EEG spindles, producing phase windows of peaked cross-region spindling. In contrast, in the subthalamic nucleus (STN), which like the striatum receives substantial thalamocortical input, and in BG nuclei downstream to the striatum and STN, neuronal firing was not entrained to either local or EEG sleep spindles. These results dissociate striatal projection neurons from the rest of the BG, and suggest corticostriatal synapses as the main hub for offline communication between cortex and BG.

BackgroundOcular toxoplasmosis is common across all regions of the world. Understanding of the epidemiology and approach to diagnosis and treatment have evolved recently. In November 2020, an international group of uveitis-specialised ophthalmologists formed the International Ocular Toxoplasmosis Study Group to define current practice.Methods192 Study Group members from 48 countries completed a 36-item survey on clinical features, use of investigations, indications for treatment, systemic and intravitreal treatment with antiparasitic drugs and corticosteroids, and approach to follow-up and preventive therapy.ResultsFor 77.1% of members, unilateral retinochoroiditis adjacent to a pigmented scar accounted for over 60% of presentations, but diverse atypical presentations were also reported. Common complications included persistent vitreous opacities, epiretinal membrane, cataract, and ocular hypertension or glaucoma. Most members used clinical examination with (56.8%) or without (35.9%) serology to diagnose typical disease but relied on intraocular fluid testing—usually PCR—in atypical cases (68.8%). 66.1% of members treated all non-pregnant patients, while 33.9% treated selected patients. Oral trimethoprim–sulfamethoxazole was first-line therapy for 66.7% of members, and 60.9% had experience using intravitreal clindamycin. Corticosteroid drugs were administered systemically by 97.4%; 24.7% also injected corticosteroid intravitreally, almost always in combination with an antimicrobial drug (72.3%). The majority of members followed up all (60.4%) or selected (35.9%) patients after resolution of acute disease, and prophylaxis against recurrence with trimethoprim–sulfamethoxazole was prescribed to selected patients by 69.8%.ConclusionOur report presents a current management approach for ocular toxoplasmosis, as practised by a large international group of uveitis-specialised ophthalmologists.

Brain Computer Interface (BCIs) strive to provide a communication channel between the human brain and the environment without using overt actions. To achieve this goal, BCIs convert recordings of neural activity into commands to an external device. One of the most common BCI methods is based on matching of spectral characteristics of EEG sensorimotor rhythms (SMR) to motor imagery attempts. While such motor-imagery BCI have been extensively studied, little is known about the possibility of using tactile imagery as a BCI component. Here we studied EEG modulations associated with tactile imagery and obtained results suggesting that this approach could improve BCI operations.METHODS. 12 healthy naïve volunteers participated in the study. After vibrotactile stimulation was applied several times to the right hand, participants imagined the same sensations in the absence of actual vibration. During this tactile imagery task, 30 channels of EEG were recorded. The effects of tactile imagery were assessed as changes of the SMR in mu and beta bands, which were quantified using EEG desynchronization/synchronization (ERD/S) ratios. An offline classification was conducted for three states: resting, tactile imagery of the right hand, and tactile imagery of the left hand. The classification was based on common spatial pattern (CSP) filtering and linear discriminant analysis.RESULTS. The participants exhibited consistent contralateral ERD patterns over sensorimotor areas during tactile imagery of each hand. Statistically significant differences (p

The tonic activity of striatal cholinergic interneurons (CINs) is modified differentially by their afferent inputs. Although their unitary synaptic currents are identical, in most CINs cortical inputs onto distal dendrites only weakly entrain them, whereas proximal thalamic inputs trigger abrupt pauses in discharge in response to salient external stimuli. To test whether the dendritic expression of the active conductances that drive autonomous discharge contribute to the CINs’ capacity to dissociate cortical from thalamic inputs, we used an optogenetics-based method to quantify dendritic excitability. We found that the persistent sodium (NaP) current gave rise to dendritic boosting, and that the hyperpolarization-activated cyclic nucleotide-gated (HCN) current gave rise to a subhertz membrane resonance. This resonance may underlie our novel finding of an association between CIN pauses and internally-generated slow wave events in sleeping non-human primates. Moreover, our method indicated that dendritic NaP and HCN currents were preferentially expressed in proximal dendrites. We validated the non-uniform distribution of NaP currents pharmacologically; with two-photon imaging of dendritic back-propagating action potentials; and by demonstrating boosting of thalamic, but not cortical, inputs by NaP currents. Thus, the localization of active dendritic conductances in CIN dendrites mirrors the spatial distribution of afferent terminals and may promote their differential responses to thalamic vs. cortical inputs.

Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research., Leptomeningeal disease (LMD) is a serious complication of metastatic solid tumors with a poor prognosis. Here, by using single-cell RNA sequencing of cerebrospinal fluid, the authors report genomic and immune correlates of response to immunotherapy in two cohorts of patients with LMD treated with immune checkpoint inhibitors.

In this work, the EEG mu-rhythm desynchronization was studied during motor imagery (MI) combined with functional electrical stimulation (FES) of an imaginary hand. The aim of the study is to estimate the effect of (FES) on mu-rhythm event related desynchronization/synchronization (ERD/ERDS) patterns during and after motor imagery. The study involved 13 healthy participants, which were asked to imagine the right hand grasping while EEG was recorded. Evaluation of the cortical activation was performed by mu-rhythm ERD/ERDS estimation. ERD/ERDS was assessed in experimental conditions before, during and after FES. Statistically significant changes (Friedman test) in the central mu-rhythm ERD during MI+FES comparing “before” condition was obtained. Our results suggest a direct effect of the peripheral electric stimulation on the cortical activation level, which is especially expressed in combination with the motor imagery.

Movement observation (MO) modulates activity of brain regions involved in motor control. It is mentioned that this phenomenon is evoked by the mirror neurons system activity and reflects processes of action understanding, action recognition and covert imitation of observed movements. Desynchronization of sensorimotor EEG oscillations and increase in corticospinal excitability assessed by transcranial magnetic stimulation (TMS) are invasive markers of motor and somatosensory cortices activation. Despite the fact that numerous studies show sensitivity of these markers to movements observation, little is known about the dynamics of the EEG activity and corticospinal excitability during evaluating the anatomically correctness of observed actions. We designed a TMS-EEG experiment with passive observation of simple aimless movements, in which subjects observed natural and unnatural flexions of fingers. Spatially separated sensorimotor EEG oscillations and TMS evoked myographic potentials were studied. The results revealed sensitivity of mu/beta oscillations to the anatomical correctness of movement. No correlations between mu/beta desynchronization and motor evoked potentials (MEPs) were found, but a weak link between beta synchronization and MEPs was shown. It might be proposed that ERD reflects activity of rather somatosensory but not motor cortex. Our findings demonstrate that activity of the sensorimotor cortex is modulated by action observation and action recognition, whereas EEG activity from different frequency ranges is modulated in different ways. Importantly, no significant changes in MEPs amplitude during MO was found. This result is discussed with regard to the impact of experimental instructions and participant's mental state during the MO task.

Motor imagery training is commonly used for sport and neurorehabilitation, improving human motor performance. In our previous works we have shown that motor imagery can be an effective way to reach higher performance in some sensorimotor tasks, technically related to esports. In this work reaction time of 10 participants was measured in the mouse aim task before and after motor imagery training session, while EEG was recorded. Statistically significant decrease in reaction time between before and after motor imagery training was obtained, while stable contralateral central ERD patterns during motor imagery were presented. A high correlation between baseline reactions’ time of participants and their levels of progress was observed. We believe that motor imagery training associated with sensorimotor rhythms desynchronization in EEG has great potential for esports training programs.

Background. Motor imagery engages much of the same neural circuits as an overt movement. Therefore, the mental rehearsal of movements is often used to supplement physical training and might aid motor neurorehabilitation after stroke. One attempt to capture the brain’s involvement in imagery involves the use, as a marker, of the depression or event-related desynchronization (ERD) of thalamocortical sensorimotor rhythms found in a human electroencephalogram (EEG). Using fast real-time processing, it is possible to make the subject aware of their own brain reactions or—even better—to turn them into actions through a technology called the brain–computer interface (BCI). However, it remains unclear whether BCI-enabled imagery facilitates a stronger or qualitatively different brain response compared to the open-loop training. Methods. Seven healthy volunteers who were experienced in both closed and open-loop motor imagery took part in six experimental sessions over a period of 4.5 months, in which they performed kinesthetic imagery of a previously known set of finger and arm movements with simultaneous 30-channel EEG acquisition. The first and the last session mostly consisted of feedback trials in which the subjects were presented with the classification results of the EEG patterns in real time, during the other sessions, no feedback was provided. Spatiotemporal and amplitude features of the ERD patterns concomitant with imagery were compared across experimental days and between feedback conditions using linear mixed-effects modeling. Results. The main spatial sources of ERD appeared to be highly stable across the six experimental days, remaining nearly identical in five of seven subjects (Pearson’s ρ &gt, 0.94). Only in one subject did the spatial pattern of activation statistically significantly differ (p = 0.009) between the feedback and no-feedback conditions. Real-time visual feedback delivered through the BCI did not significantly increase the ERD strength. Conclusion. The results imply that the potential benefits of MI could be yielded by well-habituated subjects with a simplified open-loop setup, e.g., through at-home self-practice.

Leptomeningeal disease is a devastating complication of cancer that is frequently underdiagnosed due to the low sensitivity of cerebrospinal fluid cytology, the current gold-standard diagnostic method. We performed genomic sequencing on cerebrospinal fluid specimens obtained from patients with suspected or confirmed leptomeningeal disease to identify tumor-derived cell-free DNA. From the same fluid draw, cerebrospinal fluid cytology was assayed for comparison. 30 patients underwent cytology and cell-free DNA analysis. This study consisted of two patient populations: 22 patients with cytology-confirmed leptomeningeal disease without parenchymal tumors abutting their cerebrospinal fluid and 8 patients with parenchymal brain metastases with no evidence of leptomeningeal disease. The primary outcome was the diagnostic accuracy of cell-free DNA, defined as the number of correct diagnoses out of the total number of tests assayed. A total of 30 patients, 23 female and 7 male, with a median age of 51 participated in this study. Participants mostly presented with metastatic solid malignancies. In patients previously diagnosed with leptomeningeal disease via cytology with no parenchymal tumor abutting cerebrospinal fluid, cell-free DNA was accurate in diagnosis of leptomeningeal disease in 45 of 48 follow-up samples (94%; 95% CI, 83%-99%). Cytology was accurate in 36 of 48 follow-up samples (75%; 95% CI, 60%-86%). Cell-free DNA was significantly more accurate (P=.02) and sensitive (P=.02) than cytology in patients without parenchymal tumors abutting the cerebrospinal fluid. In three patients with parenchymal brain metastases abutting the cerebrospinal fluid and no suspicion for leptomeningeal disease, cytology was negative in all three patients; whereas, cell-free DNA was positive in all three. This study demonstrates the improved sensitivity and accuracy of cell-free DNA in diagnosing leptomeningeal disease with the exception of parenchymal tumors abutting cerebrospinal fluid. Overall, these results will lead to improved diagnosis of leptomeningeal disease and potentially earlier intervention and clinical trial enrollment.