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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.

Laser hardening is a very efficient technique for local surface treatment, however, in case of complex and large components robust processing is highly challenging due to limitations in terms of the absolute size of the overall heat-affected zone. As is shown in the present work, an increased in-depth effect can be achieved by tailoring the laser parameters without melting the surface layer. Optimization of process parameters leads to an elaborate test design demanding numerous verification measurements to determine essential material properties. In this context, the evaluation of compressive residual stress values in the surface layer is very important, e.g. in case of fatigue loaded components. However, residual stress profile measurements obtained by X-ray diffraction are very time-consuming and, thus, can significantly impair the laser parameter development cycle. For this reason, the present study introduces a novel pragmatic approach allowing for qualitative evaluation of laser-induced compressive residual stress states, in particular for multiple laser pass processes based on a Gaussian-like intensity profile. Based on straightforward analytical evaluation, several characteristic features of the affected surface layer, e.g. the position of the residual stress transition zone, can be correlated to a change of the local energy input. A novel parameter referred to as modified area energy is established in present work for this purpose. This novel energy approach provides for an essential contribution to the field of laser hardening to considerably shorten the experimental effort within the laser parameter search.

Purpose This paper aims to gain an understanding of the behaviour of iron ore when melted by a laser beam in a continuous manner. This fundamental knowledge is essential to further develop additive manufacturing routes such as production of low cost parts and in-situ reduction of the ore during processing. Design/methodology/approach Blown powder directed energy deposition was used as the processing method. The process was observed through high-speed imaging, and computed tomography was used to analyse the specimens. Findings The experimental trials give preliminary results showing potential for the processability of iron ore for additive manufacturing. A large and stable melt pool is formed in spite of the inhomogeneous material used. Single and multilayer tracks could be deposited. Although smooth and even on the surface, the single layer tracks displayed porosity. In case of multilayered tracks, delamination from the substrate material and deformation can be seen. High-speed videos of the process reveal various process phenomena such as melting of ore powder during feeding, cloud formation, melt pool size, melt flow and spatter formation. Originality/value Very little literature is available that studies the possible use of ore in additive manufacturing. Although the process studied here is not industrially useable as is, it is a step towards processing cheap unprocessed material with a laser beam.

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

Filler wire metallurgy was modified through temporally shaped laser pulses, controlling cooling cycles in a recently developed method. Trends were identified through efficient mapping while maintaining representative thermal cycles of welding processes. A primary pulse melted preplaced filler wires while a secondary, linearly ramped-down pulse elevated the nugget to re-austenization temperatures. Ramped-down pulses resulted in linear cooling rates comparable with and exceeding furnace-based methods, between 50 and 300∘C/s. The linear decay of laser output power guided the temperature through a regime to obtain desired microstructures. For three very high-strength steel filler wire chemistries, quenching resulted in smaller plates with cross-hatched microstructures, accompanied by grain boundary ferrite. Finer bainite microstructures started forming for fast linear temperature decay, about 250∘C/s. Slower decay or a weaker third cycle formed coarser microstructures with coalescent sheaves and less cross-hatching.

Sleep disorders are among the most debilitating comorbidities of Parkinson’s disease (PD) and affect the majority of patients. Of these, the most common is insomnia, the difficulty to initiate and maintain sleep. The degree of insomnia correlates with PD severity and it responds to treatments that decrease pathological basal ganglia (BG) beta oscillations (10–17 Hz in primates), suggesting that beta activity in the BG may contribute to insomnia. We used multiple electrodes to record BG spiking and field potentials during normal sleep and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in nonhuman primates. MPTP intoxication resulted in severe insomnia with delayed sleep onset, sleep fragmentation, and increased wakefulness. Insomnia was accompanied by the onset of nonrapid eye movement (NREM) sleep beta oscillations that were synchronized across the BG and cerebral cortex. The BG beta oscillatory activity was associated with a decrease in slow oscillations (0.1–2 Hz) throughout the cortex, and spontaneous awakenings were preceded by an increase in BG beta activity and cortico-BG beta coherence. Finally, the increase in beta oscillations in the basal ganglia during sleep paralleled decreased NREM sleep, increased wakefulness, and more frequent awakenings. These results identify NREM sleep beta oscillation in the BG as a neural correlate of PD insomnia and suggest a mechanism by which this disorder could emerge.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.