Myocardial infarction augments sleep to limit cardiac inflammation and damage.

Sleep is integral to cardiovascular health1,2. Yet, the circuits that connect cardiovascular pathology and sleep are incompletely understood. It remains unclear whether cardiac injury influences sleep and whether sleep-mediated neural outputs contribute to heart healing and inflammation. Here we report that in humans and mice, monocytes are actively recruited to the brain after myocardial infarction (MI) to augment sleep, which suppresses sympathetic outflow to the heart, limiting inflammation and promoting healing. After MI, microglia rapidly recruit circulating monocytes to the brain's thalamic lateral posterior nucleus (LPN) via the choroid plexus, where they are reprogrammed to generate tumour necrosis factor (TNF). In the thalamic LPN, monocytic TNF engages Tnfrsf1a-expressing glutamatergic neurons to increase slow wave sleep pressure and abundance. Disrupting sleep after MI worsens cardiac function, decreases heart rate variability and causes spontaneous ventricular tachycardia. After MI, disrupting or curtailing sleep by manipulating glutamatergic TNF signalling in the thalamic LPN increases cardiac sympathetic input which signals through the ß2-adrenergic receptor of macrophages to promote a chemotactic signature that increases monocyte influx. Poor sleep in the weeks following acute coronary syndrome increases susceptibility to secondary cardiovascular events and reduces the heart's functional recovery. In parallel, insufficient sleep in humans reprogrammes ß2-adrenergic receptor-expressing monocytes towards a chemotactic phenotype, enhancing their migratory capacity. Collectively, our data uncover cardiogenic regulation of sleep after heart injury, which restricts cardiac sympathetic input, limiting inflammation and damage.

A program for real-time surveillance of SARS-CoV-2 genetics.

The COVID-19 pandemic brought forth an urgent need for widespread genomic surveillance for rapid detection and monitoring of emerging SARS-CoV-2 variants. It necessitated design, development, and deployment of a nationwide infrastructure designed for sequestration, consolidation, and characterization of patient samples that disseminates de-identified information to public authorities in tight turnaround times. Here, we describe our development of such an infrastructure, which sequenced 594,832 high coverage SARS-CoV-2 genomes from isolates we collected in the United States (U.S.) from March 13th 2020 to July 3rd 2023. Our sequencing protocol ('Virseq') utilizes wet and dry lab procedures to generate mutation-resistant sequencing of the entire SARS-CoV-2 genome, capturing all major lineages. We also characterize 379 clinically relevant SARS-CoV-2 multi-strain co-infections and ensure robust detection of emerging lineages via simulation. The modular infrastructure, sequencing, and analysis capabilities we describe support the U.S. Centers for Disease Control and Prevention national surveillance program and serve as a model for rapid response to emerging pandemics at a national scale.

Obstructive sleep apnea alters microRNA levels: Effects of continuous positive airway pressure.

Background: Obstructive sleep apnea (OSA) has been linked to cytokine-mediated chronic inflammatory states. Continuous positive airway pressure (CPAP) is an established therapy for OSA, but its effects on inflammation remain unclear. A recent study from our group identified soluble cytokine receptors altered in OSA patients and modified by CPAP adherence. However, the upstream regulatory pathways responsible for these shifts in proinflammatory cascades with OSA and CPAP therapy remained unknown. Accordingly, this study mapped OSA and CPAP-modulated soluble cytokine receptors to specific microRNAs and then tested the hypothesis that OSA and CPAP adherence shift cytokine-related microRNA expression profiles. Study Design: Plasma samples were collected from patients with OSA (n=50) at baseline and approximately 90 days after CPAP initiation and compared to referent control subjects (n=10). Patients with OSA were further divided into cohorts defined by adherence vs nonadherence to CPAP therapy. The microRNAs that mapped to soluble cytokine receptors of interest were subjected to quantitative polymerase chain reaction. Results: At baseline, increased hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-5p, hsa-miR-195-5p, hsa-miR-424-5p, hsa-miR-223-3p, and hsa-miR-223-5p were observed in patients with OSA compared to controls (p<0.05). In CPAP adherent patients (n=22), hsa-miR233-3p and hsa-miR233-5p decreased at follow-up (p<0.05) whereas there was no change in miR levels from baseline in non-adherent CPAP patients (n=28). The miRs hsa-miR233-3p and hsa-miR233-5p mapped to both proinflammatory and innate immunity activation; the inflammasome. Conclusion: A specific set of microRNAs, including hsa-miR233-3p and hsa-miR233-5p, may serve as a marker of inflammatory responses in patients with OSA, and be used to assess attenuation of inflammasome activation by CPAP.

Achieving Better Understanding of Obstructive Sleep Apnea Treatment Effects on Cardiovascular Disease Outcomes through Machine Learning Approaches: A Narrative Review.

Obstructive sleep apnea (OSA) affects almost a billion people worldwide and is associated with a myriad of adverse health outcomes. Among the most prevalent and morbid are cardiovascular diseases (CVDs). Nonetheless, randomized controlled trials (RCTs) of OSA treatment have failed to show improvements in CVD outcomes. A major limitation in our field is the lack of precision in defining OSA and specifically subgroups with the potential to benefit from therapy. Further, this has called into question the validity of using the time-honored apnea-hypopnea index as the ultimate defining criteria for OSA. Recent applications of advanced statistical methods and machine learning have brought to light a variety of OSA endotypes and phenotypes. These methods also provide an opportunity to understand the interaction between OSA and comorbid diseases for better CVD risk stratification. Lastly, machine learning and specifically heterogeneous treatment effects modeling can help uncover subgroups with differential outcomes after treatment initiation. In an era of data sharing and big data, these techniques will be at the forefront of OSA research. Advanced data science methods, such as machine-learning analyses and artificial intelligence, will improve our ability to determine the unique influence of OSA on CVD outcomes and ultimately allow us to better determine precision medicine approaches in OSA patients for CVD risk reduction. In this narrative review, we will highlight how team science via machine learning and artificial intelligence applied to existing clinical data, polysomnography, proteomics, and imaging can do just that.

Unsupervised physics-informed deep learning-based reconstruction for time-resolved imaging by multiplexed ptychography.

We explore numerically an unsupervised, physics-informed, deep learning-based reconstruction technique for time-resolved imaging by multiplexed ptychography. In our method, the untrained deep learning model replaces the iterative algorithm's update step, yielding superior reconstructions of multiple dynamic object frames compared to conventional methodologies. More precisely, we demonstrate improvements in image quality and resolution, while reducing sensitivity to the number of recorded frames, the mutual orthogonality of different probe modes, overlap between neighboring probe beams and the cutoff frequency of the ptychographic microscope - properties that are generally of paramount importance for ptychographic reconstruction algorithms.

Heterogeneous Effects of Continuous Positive Airway Pressure in Non-Sleepy Obstructive Sleep Apnea on Cardiovascular Disease Outcomes: Post Hoc Machine Learning Analysis of the ISAACC Trial (ECSACT Study).

Rationale: Randomized controlled trials of continuous positive airway pressure (CPAP) therapy for cardiovascular disease (CVD) prevention among patients with obstructive sleep apnea (OSA) have been largely neutral. However, given that OSA is a heterogeneous disease, there may be unidentified subgroups demonstrating differential treatment effects. Objectives: We sought to apply a novel data-drive approach to identify nonsleepy OSA subgroups with heterogeneous effects of CPAP on CVD outcomes within the Impact of Sleep Apnea Syndrome in the Evolution of Acute Coronary Syndrome (ISAACC) study. Methods: Participants were randomly partitioned into two datasets. One for training (70%) our machine-learning model and a second (30%) for validation of significant findings. Model-based recursive partitioning was applied to identify subgroups with heterogeneous treatment effects. Survival analysis was conducted to compare treatment (CPAP vs. usual care [UC]) outcomes within subgroups. Results: A total of 1,224 nonsleepy OSA participants were included. Of 55 features entered into our model, only two appeared in the final model (i.e., average OSA event duration and hypercholesterolemia). Among participants at or below the model-derived average event duration threshold (19.5 s), CPAP was protective for a composite of CVD events (training hazard ratio [HR], 0.46; P = 0.002). For those with longer event duration (>19.5 s), an additional split occurred by hypercholesterolemia status. Among participants with longer event duration and hypercholesterolemia, CPAP resulted in more CVD events compared with UC (training HR, 2.24; P = 0.011). The point estimate for this harmful signal was also replicated in the testing dataset (HR, 1.83; P = 0.118). Conclusions: We discovered subgroups of nonsleepy OSA participants within the ISAACC study with heterogeneous effects of CPAP. Among the training dataset, those with longer OSA event duration and hypercholesterolemia had nearly 2.5 times more CVD events with CPAP compared with UC, whereas those with shorter OSA event duration had roughly half the rate of CVD events if randomized to CPAP.

Motion of charged particles in bright squeezed vacuum.

The motion of laser-driven electrons quivers with an average energy termed pondermotive energy. We explore electron dynamics driven by bright squeezed vacuum (BSV), finding that BSV induces width oscillations, akin to electron quivering in laser light, with an equivalent ponderomotive energy. We identify closed and open trajectories of the electronic width that are associated with high harmonic generation and above-threshold ionization, respectively, similarly to trajectories of the electron position when its motion is driven by coherent light. In the case of bound electrons, the width oscillations may lead to ionization with noisy sub-cycle structure. Our results are foundational for strong-field and free-electron quantum optics, as they shed light on ionization, high harmonic generation, and nonlinear Compton scattering in BSV.

Single-shot ptychographic imaging of non-repetitive ultrafast events.

We demonstrate experimentally high-speed ptychographic imaging of non-repetitive complex-valued events. Three time-resolved complex-valued frames are reconstructed from data recorded in a single camera snapshot. The temporal resolution of the microscope is determined by delays between illuminating pulses. The ability to image amplitude and phase of nonrepetitive events with ultrafast temporal resolution will open new opportunities in science and technology.

Sensory disturbances in Creutzfeldt-Jakob disease.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease characterized by rapidly progressive dementia, motor impairments, and psychiatric symptoms. Sensory disturbances were occasionally reported as well. The study aims to describe the sensory symptoms of the disease. METHODS: The CJD Israeli National Database was screened for patients who presented sensory symptoms throughout the disease course. Symptoms, characteristics, and distribution were reviewed and the demographic and clinical data (sex, etiologies of the disease, age of onset, disease duration, neurological exam finding, tau protein level, EEG and MRI findings) were compared with the demographics and clinical data of CJD without sensory symptoms. Then, the patients with sensory symptoms were divided into patients with symptom distribution consistent with peripheral nervous system (PNS) involvement and central nervous system (CNS) involvement. The demographics and clinical data of the 2 groups were compared. RESULTS: Eighty-four CJD patients with sensory symptoms and 645 CJD patients without sensory symptoms were included in the study. Sensory symptoms were more common in genetic E200K CJD patients (14.6% vs. 5.6% respectively, p = 0.0005) (chi-squared test). Numbness and neuropathic pain were the most common symptoms and distribution of symptoms of "stocking gloves" with decreased deep tendon reflexes suggesting peripheral neuropathy in 44% of the patients. In these patients, the classical EEG findings of Periodic Sharp Wave Complexes were less often found (58% vs. 22%, p = 0.02) (chi-squared test). CONCLUSIONS: Sensory symptoms are more common in E200K patients and often follow peripheral neuropathy distribution that suggests PNS involvement.

Revealing the Interplay between Strong Field Selection Rules and Crystal Symmetries.

Symmetries are ubiquitous in condensed matter physics, playing an important role in the appearance of different phases of matter. Nonlinear light matter interactions serve as a coherent probe for resolving symmetries and symmetry breaking via their link to selection rules of the interaction. In the extreme nonlinear regime, high harmonic generation (HHG) spectroscopy offers a unique spectroscopic approach to study this link, probing the crystal spatial properties with high sensitivity while opening new paths for selection rules in the XUV regime. In this Letter we establish an advanced HHG polarimetry scheme, driven by a multicolor strong laser field, to observe the structural symmetries of solids and their interplay with the HHG selection rules. By controlling the crystal symmetries, we resolve nontrivial polarization states associated with new spectral features in the HHG spectrum. Our scheme opens new opportunities in resolving the symmetries of quantum materials, as well as ultrafast light driven symmetries in condensed matter systems.

The epidemiological and clinical characteristics of patients with young-onset genetic Creutzfeldt-Jakob disease.

OBJECTIVES: The onset of Creutzfeldt-Jakob disease (CJD) is usually around the age of 60, but younger patients have been described as well. Our study characterizes the demographic and clinical features of young-onset CJD patients. METHODS: The CJD Israeli National Database was reviewed, and the patients were divided into groups of young (<40-year-old) (Y|) and older disease onset (>40-year-old) (O). Each group was further divided into sporadic (sCJD) and genetic (gCJD) patients. Clinical and demographic parameters were compared between the groups. RESULTS: The study included 731 patients (Y- 18 patients, O- 713 patients). MRI showed classical features more often in the older population (O-76.9%, Y-36%, p = 0.006). Rapidly progressive dementia as a presenting feature was more common in the older group (O = 58%, Y = 27.7%, p = 0.019) whereas cerebellar onset (gait instability, dysarthria) was more common in the younger group (O = 6.7%, Y = 27.7%, p = 0.036)). Among gCJD patients, rapidly progressive dementia was commonly seen in older patients (O = 54%, Y = 21% p = 0.008) whereas cerebellar symptoms were seen in young patients (O = 7%, Y = 30% p = 0.01) Typical MRI findings were seen in 37% of young people compared to 87% of older patients (p = 0.002). No significant differences were between young and older patients in the sCJD group. CONCLUSION: Young-onset gCJD patients have unique disease features including less typical brain MRI changes, a lower prevalence of dementia, and a higher prevalence of cerebellar signs at disease onset.

Multiscale dynamical symmetries and selection rules in nonlinear optics.

Symmetries and their associated selection rules are extremely useful in many fields of science. For systems of electromagnetic (EM) fields interacting with matter, the symmetries of matter and the EM fields' time-dependent polarization determine the properties of the nonlinear responses, and they can be facilitated for controlling light emission and enabling ultrafast symmetry breaking spectroscopy of various properties. Here, we formulate a general theory that describes the macroscopic and microscopic dynamical symmetries (including quasicrystal-like symmetries) of EM vector fields, revealing many previously unidentified symmetries and selection rules in light-matter interactions. We demonstrate an example of multiscale selection rules experimentally in the framework of high harmonic generation. This work paves the way for novel spectroscopic techniques in multiscale systems and for imprinting complex structures in extreme ultraviolet-x-ray beams, attosecond pulses, or the interacting medium itself.

Risk of and duration of protection from SARS-CoV-2 reinfection assessed with real-world data.

This retrospective observational study aimed to gain a better understanding of the protective duration of prior SARS-CoV-2 infection against reinfection. The objectives were two-fold: to assess the durability of immunity to SARS-CoV-2 reinfection among initially unvaccinated individuals with previous SARS-CoV-2 infection, and to evaluate the crude SARS-CoV-2 reinfection rate and associated risk factors. During the pandemic era time period from February 29, 2020, through April 30, 2021, 144,678,382 individuals with SARS-CoV-2 molecular diagnostic or antibody test results were studied. Rates of reinfection among index-positive individuals were compared to rates of infection among index-negative individuals. Factors associated with reinfection were evaluated using multivariable logistic regression. For both objectives, the outcome was a subsequent positive molecular diagnostic test result. Consistent with prior findings, the risk of reinfection among index-positive individuals was 87% lower than the risk of infection among index-negative individuals. The duration of protection against reinfection was stable over the median 5 months and up to 1-year follow-up interval. Factors associated with an increased reinfection risk included older age, comorbid immunologic conditions, and living in congregate care settings; healthcare workers had a decreased reinfection risk. This large US population-based study suggests that infection induced immunity is durable for variants circulating pre-Delta predominance.

Advanced Proteomics and Cluster Analysis for Identifying Novel Obstructive Sleep Apnea Subtypes before and after Continuous Positive Airway Pressure Therapy.

Rationale: Studies have shown elevated inflammatory biomarkers in obstructive sleep apnea (OSA), but data after continuous positive airway pressure (CPAP) treatment are inconsistent. Objectives: We used the Olink proteomics panel to identify unique OSA clusters on the basis of inflammatory protein expression and assess the impact of CPAP therapy. Methods: Adults with newly diagnosed OSA had blood drawn at baseline and three to four months after CPAP. Samples were analyzed using the Olink proteomics platform, which measures 92 prespecified inflammatory proteins using proximity extension assay. Linear mixed-effects models were used to model changes in protein expression during the period of CPAP use, adjusting for batch, age, and sex. Unsupervised hierarchical clustering was performed to identify unique inflammatory OSA clusters on the basis of inflammatory biomarkers. Within-cluster impact of CPAP on inflammatory protein expression was assessed. Results: Among 46 patients, the mean age was 46 ± 12 years (22% women), mean body mass index was 31 ± 5 kg/m2, and mean respiratory disturbance index was 33 ± 17 events/hour. Unsupervised cluster and heatmap analysis revealed three unique proteomic clusters, with low (n = 21), intermediate (n = 19), and high (n = 6) inflammatory protein expression. After CPAP, there were significant within-cluster differences in protein expression. The low inflammatory cluster had a significant increase in protein expression (16%; P = 0.02), and the high inflammatory cluster had a significant decrease in protein expression (-20%; P = 0.003), more significant among those compliant with CPAP in the low (25%; P = 0.04) and high (-22%; P = 0.01) clusters. Conclusions: We identified three unique inflammatory clusters in patients with OSA using plasma proteomics, with a differential response to CPAP by cluster. Our results are hypothesis generating and require further investigation in larger longitudinal studies for enhanced cardiovascular risk profiling in OSA.

Antibody titer levels and the effect on subsequent SARS-CoV-2 infection in a large US-based cohort.

Despite a growing amount of data around the kinetics and durability of the antibody response induced by vaccination and previous infection, there is little understanding of whether or not a given quantitative level of antibodies correlates to protection against SARS-CoV-2 infection or reinfection. In this study, we examine SARS-CoV-2 anti-spike receptor binding domain (RBD) antibody titers and subsequent SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) tests in a large cohort of US-based patients. We analyzed antibody test results in a cohort of 22,204 individuals, 6.8% (n = 1,509) of whom eventually tested positive for SARS-CoV-2 RNA, suggesting infection or reinfection. Kaplan-Meier curves were plotted to understand the effect of various levels of anti-spike RBD antibody titers (classified into discrete ranges) on subsequent RT-PCR positivity rates. Statistical analyses included fitting a Cox proportional hazards model to estimate the age-, sex- and exposure-adjusted hazard ratios for S antibody titer, using zip-code positivity rates by week as a proxy for COVID-19 exposure. It was found that the best models of the temporally associated infection risk were those based on log antibody titer level (HR = 0.836 (p < 0.05)). When titers were binned, the hazard ratio associated with antibody titer >250 Binding Antibody Units (BAU) was 0.27 (p < 0.05, 95% CI [0.18, 0.41]), while the hazard ratio associated with previous infection was 0.20 (p < 0.05, 95% CI [0.10, 0.39]). Fisher exact odds ratio (OR) for Ab titers <250 BAU showed OR = 2.84 (p < 0.05; 95% CI: [2.30, 3.53]) for predicting the outcome of a subsequent PCR test. Antibody titer levels correlate with protection against subsequent SARS-CoV-2 infection or reinfection when examining a cohort of real-world patients who had the spike RBD antibody assay performed.

Pharyngeal Inflammation on Positron Emission Tomography/Magnetic Resonance Imaging Before and After Obstructive Sleep Apnea Treatment.

Rationale: There is upper airway inflammation in patients with obstructive sleep apnea (OSA), which reduces with continuous positive airway pressure (CPAP) therapy. Objectives: Validate the use of positron emission tomography (PET)/magnetic resonance imaging (MRI) to quantify metabolic activity within the pharyngeal mucosa of patients with OSA against nasal lavage proteomics and assess the impact of CPAP therapy. Methods: Adults with OSA underwent [18F]-Fluoro-2-deoxy-D-glucose PET/MRI of the neck before and 3 months after initiating CPAP. Nasal lavage samples were collected. Inflammatory protein expression from samples was analyzed using the Olink platform. Upper airway imaging segmentation was performed. Target-to-background ratio (TBRmax) was calculated from target pharyngeal maximum standard uptake values (SUV) and personalized background mean SUV. Most-diseased segment TBRmax was identified per participant at locations with the highest PET avidity. Correlation analysis was performed between baseline TBRmax and nasal lavage proteomics. TBRmax was compared before and after CPAP using linear mixed-effect models. Results: Among 38 participants, the baseline mean age was 46.3 years (standard deviation [SD], 12.5), 21% were female, the mean body mass index was 30.9 kg/m2 (SD, 4.6), and the mean respiratory disturbance index measured by peripheral arterial tonometry was 31 events/h (SD, 16.4). There was a significant positive correlation between pharyngeal mucosa most-diseased segment TBRmax and nasal lavage proteomic inflammation (r = 0.41 [P < 0.001, false discovery rate = 0.002]). Primary analysis revealed a reduction in the most-diseased segment TBRmax after a median of 2.91 months of CPAP therapy (-0.86 [standard error (SE) ± 0.30; P = 0.007]). Stratified analysis by smoking status revealed a significantly decreased most-diseased segment TBRmax after CPAP therapy among never-smokers but not among ever-smokers (-1.01 [SE ± 0.39; P = 0.015] vs. -0.64 [SE ± 0.49; P = 0.201]). Conclusions: CPAP therapy reduces metabolic activity measured by PET/MRI within the upper airway of adults with OSA. Furthermore, PET/MRI measures of upper airway metabolic activity correlate with a noninvasive marker of inflammation (i.e., nasal lavage inflammatory protein expression).

Management of advanced Parkinson's disease in Israel: Clinicians viewpoint and action items.

Parkinson's disease (PD) is taking a staggering toll on healthcare systems worldwide, with the bulk of the expenditures invested in the late stages of the disease. Considering the rising life expectancy and the increasing prevalence of PD across the globe, a clear understanding of the early signs and treatment options available for advanced PD (APD), will facilitate tailoring management programs and support services. This task is complicated by the lack of both global consensus in defining APD and standardized care guidelines. This perspective prepared by a panel of movement disorder specialists, proposes to extend and optimize currently accepted PD coding to better reflect the diverse disease manifestations, with emphasis on non-motor features. The panel seeks to promote timely diagnosis by adjustment of evaluation tools for use by community neurologists and suggests modification of eligibility criteria for advanced therapy. Moreover, it advocates multidisciplinary assessments of APD patients to drive personalized, patient-centered and holistic management. Overall, earlier and more targeted intervention is expected to markedly improve patient quality of life.

Genetic Creutzfeldt-Jakob disease in Turkish Jews-demographic and clinical features.

BACKGROUND: The largest cluster of genetic Creutzfeldt- Jakob Disease (CJD) exists in Libyan Jews carrying the E200K mutation in the PRNP gene. However, there is another cluster of genetic CJD with E200K mutation in families of Turkish-Jewish origin. AIMS: In this retrospective study, we aim to describe the demographic and clinical features of this population of patients. MATERIAL AND METHODS: The Israeli National CJD database was searched for demographic, clinical, imaging, and laboratory data of genetic CJD patients of Libyan and Turkish ancestry with the E200K mutation. The data of Libyan and Turkish patients were compared with notice similar or different demographic or clinical courses. RESULTS: Four hundred and twenty-three patients with CJD of Libyan (L) ancestry and 27 patients with CJD of Turkish (T) ancestry were identified. There were no significant differences in demographic and clinical data between the two populations (age of onset: T = 62 ± 8.8, L = 60 ± 9.7; age of death: T = 63 ± 8.6, L = 61 ± 9.7; and disease duration: T = 7.8 ± 8.4 months, L = 9.6 ± 13.6 months). Rapidly progressive dementia was the most common presentation in both groups, followed by pure cerebellar onset. The levels of tau protein in CSF did not differ between groups (T = 1290 ± 397.6 pg/ml, L = 1276 ± 594.2 pg/ml). MRI and EEG showed classical CJD features in most patients in both groups. DISCUSSION: The E200K mutation is the most common mutation among gCJD patients and was reported in different ethnical populations, suggesting several independent haplotypes of the mutation. The Turkish-Jew cluster, first described in this study, shares similar demographic and clinical features with the bigger cluster of Libyan-Jews CJD patients. CONCLUSION: E200K gCJD patients of Turkish ancestry share similar demographic and clinical features to patients of Libyan descent, suggesting a common origin of both populations.

A cerebellar origin of feedforward inhibition to the motor cortex in non-human primates.

Voluntary movements are driven by coordinated activity across a large population of motor cortical neurons. Formation of this activity is controlled by local interactions and long-range inputs. How remote areas of the brain communicate with motor cortical neurons to effectively drive movement remains unclear. We address this question by studying the cerebellar-thalamocortical system. We find that thalamic input to the motor cortex triggers feedforward inhibition by contacting inhibitory cells via highly effective GluR2-lacking AMPA receptors and that, during task performance, the activity of parvalbumin (PV) and pyramidal cells exhibits relations comparable with movement parameters. We also find that the movement-related activity of PV interneurons precedes firing of pyramidal cells. This counterintuitive sequence of events, where inhibitory cells are recruited more strongly and before excitatory cells, may amplify the cortical effect of cerebellar signals in a way that exceeds their sheer synaptic efficacy by suppressing other inputs.