Michael Kraut - Academia.edu (original) (raw)

Papers by Michael Kraut

Research paper thumbnail of Alveolar macrophages in early stage COPD show functional deviations with properties of impaired immune activation

Frontiers in Immunology

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmona... more Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD. Modeling cell-to-cell communication, signaling pathway usage, and transcription factor binding predicts TGF-β1 to be a major upstream regulator of transcriptional changes in alveolar macrophages of COPD patients. Functionally, macrophages in COPD showed reduced antigen presentation capacity, accumulation of cholesteryl ester, reduced cellular chemotaxis, and mitochondrial dysfunction, reminiscent of impaired immune activation.

Research paper thumbnail of Accession Numbers

density lipoprotein mediates anti-inflammatory transcriptional reprogramming of macrophages via t... more density lipoprotein mediates anti-inflammatory transcriptional reprogramming of macrophages via the transcriptional repressor ATF3

Research paper thumbnail of Abstract W P397: Severity of White Matter Hyperintensities Is Associated With Impaired Cerebral Autoregulation During Cardiac Surgery

Stroke, 2015

Introduction: Impaired autoregulation during cardiac surgery with cardiopulmonary bypass (CPB) is... more Introduction: Impaired autoregulation during cardiac surgery with cardiopulmonary bypass (CPB) is associated with perioperative mortality and morbidity. Identifying risk factors for impaired autoregulation during CPB surgery may facilitate risk stratification, and guide intra- and postoperative monitoring of high-risk patients. Hypothesis: We hypothesized that severity of white matter hyperintensities (WMHs) detected with MRI is associated with impaired cerebral autoregulation during CPB surgery. Methods: From a prospective cohort of 280 patients whom underwent cerebral autoregulation monitoring during CPB, 97 patients had research brain MRIs within 5-7 days of surgery. Intraoperative autoregulation monitoring was performed by generating a continuous moving Pearson’s correlation coefficient between mean arterial pressure (MAP) and cerebral blood flow velocity of the middle cerebral arteries measured with transcranial Doppler to generate the mean velocity index (Mx). Impaired autoreg...

Research paper thumbnail of Neural Basis of Semantic Memory: Preface

Research paper thumbnail of Visualizing spatially distributed hemodynamic lag times in event-related functional MRI: estimation of a characteristic visual "impulse response

Proceedings of the 20th Annual International Conference of the IEEE Engineering in Medicine and Biology Society. Vol.20 Biomedical Engineering Towards the Year 2000 and Beyond (Cat. No.98CH36286)

Research paper thumbnail of Case Report: Improving Verbal Retrieval Deficits With High Definition Transcranial Direct Current Stimulation Targeting the Pre-Supplementary Motor Area in a Patient With Chronic Traumatic Brain Injury

Frontiers in Neurology, 2021

We report a patient who has cognitive sequalae including verbal retrieval deficits after severe t... more We report a patient who has cognitive sequalae including verbal retrieval deficits after severe traumatic brain injury (TBI). The cortico-caudate-thalamic circuit involving the pre-Supplementary Motor Area (pre-SMA) has been proposed to underlie verbal retrieval functions. We hypothesized that High Definition-transcranial Direct Current Stimulation (HD-tDCS) targeting the pre-SMA would selectively modulate this circuit to remediate verbal retrieval deficits. After the patient underwent 10 sessions of 20 min of 1 mA HD-tDCS targeting the pre-SMA, we documented significant improvements for verbal fluency and naming, and for working memory and executive function tasks that involve the frontal lobes. The effects persisted for up to 14 weeks after completion of HD-tDCS treatment. We also demonstrated normalization of the event-related potentials suggesting modulation of the underlying neural circuit. Our study implicates that region-specific non-invasive brain stimulation, such as HD-tDC...

Research paper thumbnail of Personalized Blood Pressure Management During Cardiac Surgery With Cerebral Autoregulation Monitoring: A Randomized Trial

Seminars in Thoracic and Cardiovascular Surgery, 2021

The purpose of this study was to determine if setting mean arterial pressure (MAP) targets during... more The purpose of this study was to determine if setting mean arterial pressure (MAP) targets during cardiopulmonary bypass (CPB) based on individualized cerebral autoregulation data reduces the frequency of neurological complications compared with usual care. Patients (n=460) ≥ 55 years old at risk for neurological complications were randomized to have MAP targets during CPB to be above the lower limit of transcranial Doppler determined cerebral autoregulation versus usual institutional practices. The primary outcome was the frequency of the composite endpoint of clinical stroke, or new brain MRI detected ischemic injury, or cognitive decline 4 to 6 weeks after surgery from baseline. Secondary outcomes were components of the primary composite outcome and clinically detected delirium. Complete outcome data were available from 194 patients (stroke assessments, n=460; MRI data, n=164; cognitive data n=336). There was no difference between groups in the frequency of the composite neurological end-point or its components (p=0.752). Compared with the usual care there was a 45% reduction in the frequency of clinically detected delirium in the autoregulation group (8.2% versus 14.9%, risk ratio=0.55, 95% CI=0.32, 0.93, p=0.035) and improved performance on test of memory 4 to 6 weeks after surgery from baseline (p=0.019). Basing MAP during CPB on cerebral autoregulation monitoring did not reduce the frequency of the primary neurological outcome in high-risk patients compared with usual care but it was associated with a reduction in the frequency of delirium and better performance on tests of memory 4 to 6 weeks after surgery.

Research paper thumbnail of The Influence of Pre-Supplementary Motor Area Targeted High-Definition Transcranial Direct Current Stimulation on Inhibitory Control

The neural underpinnings of inhibitory control, an executive cognitive control function, has been... more The neural underpinnings of inhibitory control, an executive cognitive control function, has been a topic of interest for several decades due to both its clinical significance and the maturation of cognitive science disciplines. Behavioral, imaging, and electrophysiological studies suggest that the pre-supplementary motor area (preSMA) serves as a primary hub in a network of regions engaged in inhibition. High-definition transcranial direct current stimulation (HD-tDCS) allows us to modulate neural function to assess cortical contribution to cognitive functioning. The present study targeted HD-tDCS modulation of preSMA to affect inhibition. Participants were randomly assigned to receive 20 min of Sham, Anodal, or Cathodal stimulation prior to completing a semantically cued go/nogo task while electroencephalography (EEG) data were recorded. Both anodal and cathodal stimulation improved inhibitory performance as measured by faster reaction times and increased (greater negative) N2 eve...

Research paper thumbnail of Swarm Learning as a privacy-preserving machine learning approach for disease classification

Identification of patients with life-threatening diseases including leukemias or infections such ... more Identification of patients with life-threatening diseases including leukemias or infections such as tuberculosis and COVID-19 is an important goal of precision medicine. We recently illustrated that leukemia patients are identified by machine learning (ML) based on their blood transcriptomes. However, there is an increasing divide between what is technically possible and what is allowed because of privacy legislation. To facilitate integration of any omics data from any data owner world-wide without violating privacy laws, we here introduce Swarm Learning (SL), a decentralized machine learning approach uniting edge computing, blockchain-based peer-to-peer networking and coordination as well as privacy protection without the need for a central coordinator thereby going beyond federated learning. Using more than 14,000 blood transcriptomes derived from over 100 individual studies with non-uniform distribution of cases and controls and significant study biases, we illustrate the feasib...

Research paper thumbnail of Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients

Genome Medicine, 2021

Background The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patient... more Background The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system. Methods In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings. Results Here, we profiled whole bloo...

Research paper thumbnail of Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Despite the epidemics of chronic obstructive pulmonary disease (COPD), the cellular and molecular... more Despite the epidemics of chronic obstructive pulmonary disease (COPD), the cellular and molecular mechanisms of this disease are far from being understood. Here, we characterize and classify the cellular composition within the alveolar space and peripheral blood of COPD patients and control donors using a clinically applicable single-cell RNA-seq technology corroborated by advanced computational approaches for: machine learning-based cell-type classification, identification of differentially expressed genes, prediction of metabolic changes, and modeling of cellular trajectories within a patient cohort. These high-resolution approaches revealed: massive transcriptional plasticity of macrophages in the alveolar space with increased levels of invading and proliferating cells, loss of MHC expression, reduced cellular motility, altered lipid metabolism, and a metabolic shift reminiscent of mitochondrial dysfunction in COPD patients. Collectively, single-cell omics of multi-tissue samples...

Research paper thumbnail of Disrupted neural synchrony mediates the relationship between white matter integrity and cognitive performance in older adults

Our main goal was to determine the influence of white matter integrity on the dynamic coupling be... more Our main goal was to determine the influence of white matter integrity on the dynamic coupling between brain regions and the individual variability of cognitive performance in older adults. EEG was recorded while participants performed a task specifically designed to engage working memory and inhibitory processes, and the associations among functional activity, structural integrity, and cognitive performance were assessed. We found that the association between white matter microstructural integrity and cognitive functioning with aging is mediated by time-varying alpha and gamma phase-locking value (PLV). Specifically, older individuals with better preservation of the inferior fronto-occipital fasciculus showed greater task-related modulations of alpha and gamma long-range PLV between the inferior frontal gyrus and occipital lobe, lower local phase-amplitude coupling in occipital lobes, and better cognitive control performance. Our results help delineate the role of individual variab...

Research paper thumbnail of Identification of selection and inhibition components in a go/nogo task from EEG spectra using a machine learning model

Prior Go/NoGo studies have localized specific regions and EEG spectra for which traditional appro... more Prior Go/NoGo studies have localized specific regions and EEG spectra for which traditional approaches have distinguished between Go and NoGo conditions. A more detailed characterization of the spatial distribution and timing of the synchronization of frequency bands would contribute substantially to the clarification of neural mechanisms that underlie performance of the Go/NoGo task. The present study used a machine learning approach to learn the features that distinguish between ERSPs involved in selection and inhibition in a Go/NoGo task. A neural network classifier was used to predict task conditions for each subject to characterize ERSPs associated with Go versus NoGo trials. The final model accurately identified individual task conditions at an overall rate of 92%, estimated by 5-fold cross-validation. The detailed accounting of EEG time-frequency patterns localized to brain sources (i.e., thalamus, preSMA, orbitofrontal cortex, and superior parietal cortex) provides elaborati...

Research paper thumbnail of Cellular reprogramming of human monocytes is regulated by time-dependent IL4 signalling and NCOR2

The clinical and therapeutic value of humanin vitrogenerated monocyte-derived dendritic cell (moD... more The clinical and therapeutic value of humanin vitrogenerated monocyte-derived dendritic cell (moDC) and macrophages is well established. However, in line with recent findings regarding myeloid cell ontogeny and due to our limited understanding of their physiological counterparts, transcriptional regulation and heterogeneity, the full potential of these important cellular systems is still underestimated.In this study, we use cutting edge high-dimensional analysis methods to better understand the transcriptional organization, phenotypic heterogeneity and functional differences between humanex vivoisolated andin vitrogenerated mononuclear phagocytes with the aim to better realize their full potential in the clinic.We demonstrate that human monocytes activated by MCSF or GMCSF most closely resemble inflammatory macrophages identifiedin vivo, while IL4 signalling in the presence of GMCSF generates moDCs resembling inflammatory DCsin vivo, but not steady state cDC1 or cDC2. Moreover, thes...

Research paper thumbnail of SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function During Aging

Journal of Alzheimer's disease : JAD, 2018

We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzhei... more We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed inci...

Research paper thumbnail of Trial-Level Regressor Modulation for Functional Magnetic Resonance Imaging Designs Requiring Strict Periodicity of Stimulus Presentations: Illustrated Using a Go/No-Go Task

Magnetic resonance insights, 2017

Computer-based assessment of many cognitive processes (eg, anticipatory and response readiness pr... more Computer-based assessment of many cognitive processes (eg, anticipatory and response readiness processes) requires the use of invariant stimulus display times (SDT) and intertrial intervals (ITI). Although designs with invariant SDTs and ITIs have been used in functional magnetic resonance imaging (fMRI) research, such designs are problematic for fMRI studies because of collinearity issues. This study examined regressor modulation with trial-level reaction times (RT) as a method for improving signal detection in a/task with invariant SDTs and ITIs. The effects of modulating theregressor were evaluated with respect to the detection of BOLD signal-change for thecondition. BOLD signal-change towas examined when theregressor was based on a (a) canonical hemodynamic response function (HRF), (b) RT-based amplitude-modulated (AM) HRF, and (c) RT-based amplitude and duration modulated (A&DM) HRF. Reaction time-based modulation reduced the collinearity between theandregressors, with A&DM pro...

Research paper thumbnail of Repetitive TMS to augment cognitive processing therapy in combat veterans of recent conflicts with PTSD: A randomized clinical trial

Journal of affective disorders, Jan 15, 2018

The objective was to test whether repetitive Transcranial Magnetic Stimulation (rTMS) just prior ... more The objective was to test whether repetitive Transcranial Magnetic Stimulation (rTMS) just prior to Cognitive Processing Therapy (CPT) would significantly improve the clinical outcome compared to sham rTMS prior to CPT in veterans with PTSD. Veterans 18-60 years of age with current combat-related PTSD symptoms were randomized, using a 1:1 ratio in a parallel design, to active (rTMS+CPT) versus sham (sham+CPT) rTMS just prior to weekly CPT for 12-15 sessions. Blinded raters evaluated veterans at baseline, after the 5th and 9th treatments, and at 1, 3, and 6 months post-treatment. Clinician Administered PTSD Scale (CAPS) was the primary outcome measure with the PTSD Checklist (PCL) as a secondary outcome measure. The TMS coil (active or sham) was positioned over the right dorsolateral prefrontal cortex (110% MT, 1Hz continuously for 30min, 1800 pulses/treatment). Of the 515 individuals screened for the study, 103 participants were randomized to either active (n = 54) or sham rTMS (n =...

Research paper thumbnail of Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2

Immunity, Dec 19, 2017

Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinic... more Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High-dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM-CSF and IL-4 stimulation combinatorically and temporally, resulting in a mode- and time-d...

Research paper thumbnail of Neurodegenerative Dementias After Traumatic Brain Injury

The Journal of neuropsychiatry and clinical neurosciences, Jan 24, 2017

Traumatic brain injury (TBI) is often considered to be a risk factor for the later development of... more Traumatic brain injury (TBI) is often considered to be a risk factor for the later development of neurodegenerative conditions, but some findings do not support a link. Differences in research methods, clinical samples, and limitations encountered when assessing and documenting TBI details likely contribute to the mixed reports in the literature. Despite some variability in findings, a review of the literature does provide support for the notion that TBI appears to be associated with earlier onset of some neurodegenerative disorders, although clearly not everyone with a TBI appears to be at an increased risk. Whereas a mechanistic link remains unknown, TBI has been found to initiate an accumulation of pathological processes related to several neurodegenerative disorders. The authors propose a hypothetical model that relates TBI to the development of pathological burden overlapping with some neurodegenerative conditions, in which onset of cognitive/behavioral impairments is hastened ...

Research paper thumbnail of Theta and Alpha Alterations in Amnestic Mild Cognitive Impairment in Semantic Go/NoGo Tasks

Frontiers in aging neuroscience, 2017

Growing evidence suggests that cognitive control processes are impaired in amnestic mild cognitiv... more Growing evidence suggests that cognitive control processes are impaired in amnestic mild cognitive impairment (aMCI); however the nature of these alterations needs further examination. The current study examined differences in electroencephalographic theta and alpha power related to cognitive control processes involving response execution and response inhibition in 22 individuals with aMCI and 22 age-, sex-, and education-matched cognitively normal controls. Two Go/NoGo tasks involving semantic categorization were used. In the basic categorization task, Go/NoGo responses were made based on exemplars of a single car (Go) and a single dog (NoGo). In the superordinate categorization task, responses were made based on multiple exemplars of objects (Go) and animals (NoGo). Behavioral data showed that the aMCI group had more false alarms during the NoGo trials compared to controls. The EEG data revealed between group differences related to response type in theta (4-7 Hz) and low-frequency...

Research paper thumbnail of Alveolar macrophages in early stage COPD show functional deviations with properties of impaired immune activation

Frontiers in Immunology

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmona... more Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD. Modeling cell-to-cell communication, signaling pathway usage, and transcription factor binding predicts TGF-β1 to be a major upstream regulator of transcriptional changes in alveolar macrophages of COPD patients. Functionally, macrophages in COPD showed reduced antigen presentation capacity, accumulation of cholesteryl ester, reduced cellular chemotaxis, and mitochondrial dysfunction, reminiscent of impaired immune activation.

Research paper thumbnail of Accession Numbers

density lipoprotein mediates anti-inflammatory transcriptional reprogramming of macrophages via t... more density lipoprotein mediates anti-inflammatory transcriptional reprogramming of macrophages via the transcriptional repressor ATF3

Research paper thumbnail of Abstract W P397: Severity of White Matter Hyperintensities Is Associated With Impaired Cerebral Autoregulation During Cardiac Surgery

Stroke, 2015

Introduction: Impaired autoregulation during cardiac surgery with cardiopulmonary bypass (CPB) is... more Introduction: Impaired autoregulation during cardiac surgery with cardiopulmonary bypass (CPB) is associated with perioperative mortality and morbidity. Identifying risk factors for impaired autoregulation during CPB surgery may facilitate risk stratification, and guide intra- and postoperative monitoring of high-risk patients. Hypothesis: We hypothesized that severity of white matter hyperintensities (WMHs) detected with MRI is associated with impaired cerebral autoregulation during CPB surgery. Methods: From a prospective cohort of 280 patients whom underwent cerebral autoregulation monitoring during CPB, 97 patients had research brain MRIs within 5-7 days of surgery. Intraoperative autoregulation monitoring was performed by generating a continuous moving Pearson’s correlation coefficient between mean arterial pressure (MAP) and cerebral blood flow velocity of the middle cerebral arteries measured with transcranial Doppler to generate the mean velocity index (Mx). Impaired autoreg...

Research paper thumbnail of Neural Basis of Semantic Memory: Preface

Research paper thumbnail of Visualizing spatially distributed hemodynamic lag times in event-related functional MRI: estimation of a characteristic visual "impulse response

Proceedings of the 20th Annual International Conference of the IEEE Engineering in Medicine and Biology Society. Vol.20 Biomedical Engineering Towards the Year 2000 and Beyond (Cat. No.98CH36286)

Research paper thumbnail of Case Report: Improving Verbal Retrieval Deficits With High Definition Transcranial Direct Current Stimulation Targeting the Pre-Supplementary Motor Area in a Patient With Chronic Traumatic Brain Injury

Frontiers in Neurology, 2021

We report a patient who has cognitive sequalae including verbal retrieval deficits after severe t... more We report a patient who has cognitive sequalae including verbal retrieval deficits after severe traumatic brain injury (TBI). The cortico-caudate-thalamic circuit involving the pre-Supplementary Motor Area (pre-SMA) has been proposed to underlie verbal retrieval functions. We hypothesized that High Definition-transcranial Direct Current Stimulation (HD-tDCS) targeting the pre-SMA would selectively modulate this circuit to remediate verbal retrieval deficits. After the patient underwent 10 sessions of 20 min of 1 mA HD-tDCS targeting the pre-SMA, we documented significant improvements for verbal fluency and naming, and for working memory and executive function tasks that involve the frontal lobes. The effects persisted for up to 14 weeks after completion of HD-tDCS treatment. We also demonstrated normalization of the event-related potentials suggesting modulation of the underlying neural circuit. Our study implicates that region-specific non-invasive brain stimulation, such as HD-tDC...

Research paper thumbnail of Personalized Blood Pressure Management During Cardiac Surgery With Cerebral Autoregulation Monitoring: A Randomized Trial

Seminars in Thoracic and Cardiovascular Surgery, 2021

The purpose of this study was to determine if setting mean arterial pressure (MAP) targets during... more The purpose of this study was to determine if setting mean arterial pressure (MAP) targets during cardiopulmonary bypass (CPB) based on individualized cerebral autoregulation data reduces the frequency of neurological complications compared with usual care. Patients (n=460) ≥ 55 years old at risk for neurological complications were randomized to have MAP targets during CPB to be above the lower limit of transcranial Doppler determined cerebral autoregulation versus usual institutional practices. The primary outcome was the frequency of the composite endpoint of clinical stroke, or new brain MRI detected ischemic injury, or cognitive decline 4 to 6 weeks after surgery from baseline. Secondary outcomes were components of the primary composite outcome and clinically detected delirium. Complete outcome data were available from 194 patients (stroke assessments, n=460; MRI data, n=164; cognitive data n=336). There was no difference between groups in the frequency of the composite neurological end-point or its components (p=0.752). Compared with the usual care there was a 45% reduction in the frequency of clinically detected delirium in the autoregulation group (8.2% versus 14.9%, risk ratio=0.55, 95% CI=0.32, 0.93, p=0.035) and improved performance on test of memory 4 to 6 weeks after surgery from baseline (p=0.019). Basing MAP during CPB on cerebral autoregulation monitoring did not reduce the frequency of the primary neurological outcome in high-risk patients compared with usual care but it was associated with a reduction in the frequency of delirium and better performance on tests of memory 4 to 6 weeks after surgery.

Research paper thumbnail of The Influence of Pre-Supplementary Motor Area Targeted High-Definition Transcranial Direct Current Stimulation on Inhibitory Control

The neural underpinnings of inhibitory control, an executive cognitive control function, has been... more The neural underpinnings of inhibitory control, an executive cognitive control function, has been a topic of interest for several decades due to both its clinical significance and the maturation of cognitive science disciplines. Behavioral, imaging, and electrophysiological studies suggest that the pre-supplementary motor area (preSMA) serves as a primary hub in a network of regions engaged in inhibition. High-definition transcranial direct current stimulation (HD-tDCS) allows us to modulate neural function to assess cortical contribution to cognitive functioning. The present study targeted HD-tDCS modulation of preSMA to affect inhibition. Participants were randomly assigned to receive 20 min of Sham, Anodal, or Cathodal stimulation prior to completing a semantically cued go/nogo task while electroencephalography (EEG) data were recorded. Both anodal and cathodal stimulation improved inhibitory performance as measured by faster reaction times and increased (greater negative) N2 eve...

Research paper thumbnail of Swarm Learning as a privacy-preserving machine learning approach for disease classification

Identification of patients with life-threatening diseases including leukemias or infections such ... more Identification of patients with life-threatening diseases including leukemias or infections such as tuberculosis and COVID-19 is an important goal of precision medicine. We recently illustrated that leukemia patients are identified by machine learning (ML) based on their blood transcriptomes. However, there is an increasing divide between what is technically possible and what is allowed because of privacy legislation. To facilitate integration of any omics data from any data owner world-wide without violating privacy laws, we here introduce Swarm Learning (SL), a decentralized machine learning approach uniting edge computing, blockchain-based peer-to-peer networking and coordination as well as privacy protection without the need for a central coordinator thereby going beyond federated learning. Using more than 14,000 blood transcriptomes derived from over 100 individual studies with non-uniform distribution of cases and controls and significant study biases, we illustrate the feasib...

Research paper thumbnail of Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients

Genome Medicine, 2021

Background The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patient... more Background The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system. Methods In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings. Results Here, we profiled whole bloo...

Research paper thumbnail of Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Despite the epidemics of chronic obstructive pulmonary disease (COPD), the cellular and molecular... more Despite the epidemics of chronic obstructive pulmonary disease (COPD), the cellular and molecular mechanisms of this disease are far from being understood. Here, we characterize and classify the cellular composition within the alveolar space and peripheral blood of COPD patients and control donors using a clinically applicable single-cell RNA-seq technology corroborated by advanced computational approaches for: machine learning-based cell-type classification, identification of differentially expressed genes, prediction of metabolic changes, and modeling of cellular trajectories within a patient cohort. These high-resolution approaches revealed: massive transcriptional plasticity of macrophages in the alveolar space with increased levels of invading and proliferating cells, loss of MHC expression, reduced cellular motility, altered lipid metabolism, and a metabolic shift reminiscent of mitochondrial dysfunction in COPD patients. Collectively, single-cell omics of multi-tissue samples...

Research paper thumbnail of Disrupted neural synchrony mediates the relationship between white matter integrity and cognitive performance in older adults

Our main goal was to determine the influence of white matter integrity on the dynamic coupling be... more Our main goal was to determine the influence of white matter integrity on the dynamic coupling between brain regions and the individual variability of cognitive performance in older adults. EEG was recorded while participants performed a task specifically designed to engage working memory and inhibitory processes, and the associations among functional activity, structural integrity, and cognitive performance were assessed. We found that the association between white matter microstructural integrity and cognitive functioning with aging is mediated by time-varying alpha and gamma phase-locking value (PLV). Specifically, older individuals with better preservation of the inferior fronto-occipital fasciculus showed greater task-related modulations of alpha and gamma long-range PLV between the inferior frontal gyrus and occipital lobe, lower local phase-amplitude coupling in occipital lobes, and better cognitive control performance. Our results help delineate the role of individual variab...

Research paper thumbnail of Identification of selection and inhibition components in a go/nogo task from EEG spectra using a machine learning model

Prior Go/NoGo studies have localized specific regions and EEG spectra for which traditional appro... more Prior Go/NoGo studies have localized specific regions and EEG spectra for which traditional approaches have distinguished between Go and NoGo conditions. A more detailed characterization of the spatial distribution and timing of the synchronization of frequency bands would contribute substantially to the clarification of neural mechanisms that underlie performance of the Go/NoGo task. The present study used a machine learning approach to learn the features that distinguish between ERSPs involved in selection and inhibition in a Go/NoGo task. A neural network classifier was used to predict task conditions for each subject to characterize ERSPs associated with Go versus NoGo trials. The final model accurately identified individual task conditions at an overall rate of 92%, estimated by 5-fold cross-validation. The detailed accounting of EEG time-frequency patterns localized to brain sources (i.e., thalamus, preSMA, orbitofrontal cortex, and superior parietal cortex) provides elaborati...

Research paper thumbnail of Cellular reprogramming of human monocytes is regulated by time-dependent IL4 signalling and NCOR2

The clinical and therapeutic value of humanin vitrogenerated monocyte-derived dendritic cell (moD... more The clinical and therapeutic value of humanin vitrogenerated monocyte-derived dendritic cell (moDC) and macrophages is well established. However, in line with recent findings regarding myeloid cell ontogeny and due to our limited understanding of their physiological counterparts, transcriptional regulation and heterogeneity, the full potential of these important cellular systems is still underestimated.In this study, we use cutting edge high-dimensional analysis methods to better understand the transcriptional organization, phenotypic heterogeneity and functional differences between humanex vivoisolated andin vitrogenerated mononuclear phagocytes with the aim to better realize their full potential in the clinic.We demonstrate that human monocytes activated by MCSF or GMCSF most closely resemble inflammatory macrophages identifiedin vivo, while IL4 signalling in the presence of GMCSF generates moDCs resembling inflammatory DCsin vivo, but not steady state cDC1 or cDC2. Moreover, thes...

Research paper thumbnail of SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function During Aging

Journal of Alzheimer's disease : JAD, 2018

We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzhei... more We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed inci...

Research paper thumbnail of Trial-Level Regressor Modulation for Functional Magnetic Resonance Imaging Designs Requiring Strict Periodicity of Stimulus Presentations: Illustrated Using a Go/No-Go Task

Magnetic resonance insights, 2017

Computer-based assessment of many cognitive processes (eg, anticipatory and response readiness pr... more Computer-based assessment of many cognitive processes (eg, anticipatory and response readiness processes) requires the use of invariant stimulus display times (SDT) and intertrial intervals (ITI). Although designs with invariant SDTs and ITIs have been used in functional magnetic resonance imaging (fMRI) research, such designs are problematic for fMRI studies because of collinearity issues. This study examined regressor modulation with trial-level reaction times (RT) as a method for improving signal detection in a/task with invariant SDTs and ITIs. The effects of modulating theregressor were evaluated with respect to the detection of BOLD signal-change for thecondition. BOLD signal-change towas examined when theregressor was based on a (a) canonical hemodynamic response function (HRF), (b) RT-based amplitude-modulated (AM) HRF, and (c) RT-based amplitude and duration modulated (A&DM) HRF. Reaction time-based modulation reduced the collinearity between theandregressors, with A&DM pro...

Research paper thumbnail of Repetitive TMS to augment cognitive processing therapy in combat veterans of recent conflicts with PTSD: A randomized clinical trial

Journal of affective disorders, Jan 15, 2018

The objective was to test whether repetitive Transcranial Magnetic Stimulation (rTMS) just prior ... more The objective was to test whether repetitive Transcranial Magnetic Stimulation (rTMS) just prior to Cognitive Processing Therapy (CPT) would significantly improve the clinical outcome compared to sham rTMS prior to CPT in veterans with PTSD. Veterans 18-60 years of age with current combat-related PTSD symptoms were randomized, using a 1:1 ratio in a parallel design, to active (rTMS+CPT) versus sham (sham+CPT) rTMS just prior to weekly CPT for 12-15 sessions. Blinded raters evaluated veterans at baseline, after the 5th and 9th treatments, and at 1, 3, and 6 months post-treatment. Clinician Administered PTSD Scale (CAPS) was the primary outcome measure with the PTSD Checklist (PCL) as a secondary outcome measure. The TMS coil (active or sham) was positioned over the right dorsolateral prefrontal cortex (110% MT, 1Hz continuously for 30min, 1800 pulses/treatment). Of the 515 individuals screened for the study, 103 participants were randomized to either active (n = 54) or sham rTMS (n =...

Research paper thumbnail of Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2

Immunity, Dec 19, 2017

Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinic... more Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High-dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM-CSF and IL-4 stimulation combinatorically and temporally, resulting in a mode- and time-d...

Research paper thumbnail of Neurodegenerative Dementias After Traumatic Brain Injury

The Journal of neuropsychiatry and clinical neurosciences, Jan 24, 2017

Traumatic brain injury (TBI) is often considered to be a risk factor for the later development of... more Traumatic brain injury (TBI) is often considered to be a risk factor for the later development of neurodegenerative conditions, but some findings do not support a link. Differences in research methods, clinical samples, and limitations encountered when assessing and documenting TBI details likely contribute to the mixed reports in the literature. Despite some variability in findings, a review of the literature does provide support for the notion that TBI appears to be associated with earlier onset of some neurodegenerative disorders, although clearly not everyone with a TBI appears to be at an increased risk. Whereas a mechanistic link remains unknown, TBI has been found to initiate an accumulation of pathological processes related to several neurodegenerative disorders. The authors propose a hypothetical model that relates TBI to the development of pathological burden overlapping with some neurodegenerative conditions, in which onset of cognitive/behavioral impairments is hastened ...

Research paper thumbnail of Theta and Alpha Alterations in Amnestic Mild Cognitive Impairment in Semantic Go/NoGo Tasks

Frontiers in aging neuroscience, 2017

Growing evidence suggests that cognitive control processes are impaired in amnestic mild cognitiv... more Growing evidence suggests that cognitive control processes are impaired in amnestic mild cognitive impairment (aMCI); however the nature of these alterations needs further examination. The current study examined differences in electroencephalographic theta and alpha power related to cognitive control processes involving response execution and response inhibition in 22 individuals with aMCI and 22 age-, sex-, and education-matched cognitively normal controls. Two Go/NoGo tasks involving semantic categorization were used. In the basic categorization task, Go/NoGo responses were made based on exemplars of a single car (Go) and a single dog (NoGo). In the superordinate categorization task, responses were made based on multiple exemplars of objects (Go) and animals (NoGo). Behavioral data showed that the aMCI group had more false alarms during the NoGo trials compared to controls. The EEG data revealed between group differences related to response type in theta (4-7 Hz) and low-frequency...