Integrating Machine Learning with Biomedical Signal Processing and Systems Analysis: An Applications-based Course.

The growing importance of data analytics in biomedicine is increasingly becoming recognized in biomedical engineering curricula through the introduction of machine learning classes that generally run in parallel to, but separately from, more traditional engineering courses, such as signal and systems analysis. We propose a new approach that systematically integrates signal processing and systems analysis with key techniques in machine learning. In the proposed course, the student obtains hands-on experience in applying algorithms that can be applied to practical problems of physiological signal conditioning, analysis and interpretation.

McDAPS: A multi-channel physiological signals display and analysis system for clinical researchers.

We introduce McDAPS, an interactive software for assessing autonomic imbalance from non-invasive multi-channel physiological recordings. McDAPS provides a graphical user interface for data visualization, beat-to-beat processing and interactive analyses. The software extracts beat-to-beat RR interval systolic blood pressure, diastolic blood pressure, the pulse amplitude of photoplethysmogram and the pulse-to-pulse interval.

Functional near-infrared spectroscopy-based prefrontal cortex oxygenation during working memory tasks in sickle cell disease.

Significance: Sickle cell disease (SCD), characterized by painful vaso-occlusive crises, is associated with cognitive decline. However, objective quantification of cognitive decline in SCD remains a challenge, and the associated hemodynamics are unknown.

Aim: To address this, we utilized functional near-infrared spectroscopy (fNIRS) to measure prefrontal cortex (PFC) oxygenation responses to -back working memory tasks in SCD patients and compared them with healthy controls.

Identifying elevated risk for future pain crises in sickle-cell disease using photoplethysmogram patterns measured during sleep: A machine learning approach.

Transient increases in peripheral vasoconstriction frequently occur in obstructive sleep apnea and periodic leg movement disorder, both of which are common in sickle cell disease (SCD). These events reduce microvascular blood flow and increase the likelihood of triggering painful vaso-occlusive crises (VOC) that are the hallmark of SCD. We recently reported a significant association between the magnitude of vasoconstriction, inferred from the finger photoplethysmogram (PPG) during sleep, and the frequency of future VOC in 212 children with SCD.

Nocturnal peripheral vasoconstriction predicts the frequency of severe acute pain episodes in children with sickle cell disease.

The basic model of SCD physiology states that vaso-occlusion occurs when hemoglobin S-containing red blood cells (RBC) undergo sickling before they escape the capillary into a larger vessel. We have shown that mental stress, pain and cold, and events reported by patients to trigger SCD vaso-occlusive crisis (VOC), cause rapid and significant decrease in blood flow, reducing the likelihood that RBC could transit the microvasculature before sickling occurs. However, the critical link between decrease in microvascular blood flow and the incidence of future sickle VOC has never been established experimentally in humans.

Tricuspid regurgitant jet velocity and myocardial tissue Doppler parameters predict mortality in a cohort of patients with sickle cell disease spanning from pediatric to adult age groups - revisiting this controversial concept after 16 years of additional evidence.

Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young adult mortality in SCD. To better understand the clinical importance of multi-level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S') and diastole (E'), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD.

Progressive vasoconstriction with sequential thermal stimulation indicates vascular dysautonomia in sickle cell disease.

Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction.

Vaso-Occlusion in Sickle Cell Disease: Is Autonomic Dysregulation of the Microvasculature the Trigger?

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain.

Erythrocyte and plasma oxidative stress appears to be compensated in patients with sickle cell disease during a period of relative health, despite the presence of known oxidative agents.

Sickle cell disease (SCD) is a monogenetic disease that results in the formation of hemoglobin S. Due to more rapid oxidation of hemoglobin S due to intracellular heme and adventitious iron in SCD, it has been thought that an inherent property of SCD red cells would be an imbalance in antioxidant defenses and oxidant production. Less deformable and fragile RBC in SCD results in intravascular hemolysis and release of free hemoglobin (PFHb) in the plasma, which might be expected to produce oxidative stress in the plasma.

Respiratory modulation of peripheral vasoconstriction: a modeling perspective.

Although respiratory sinus arrhythmia and blood pressure variability have been investigated extensively, there have been far fewer studies of the respiratory modulation of peripheral blood flow in humans. Existing studies have been based primarily on noninvasive measurements using digit photoplethysmography and laser-Doppler flowmetry. The cumulative knowledge derived from these studies suggests that respiration can contribute to fluctuations in peripheral blood flow and volume through a combination of mechanical, hemodynamic, and neural mechanisms.

Sickle Cell Disease Subjects Have a Distinct Abnormal Autonomic Phenotype Characterized by Peripheral Vasoconstriction With Blunted Cardiac Response to Head-Up Tilt.

In sickle cell disease (SCD), prolonged capillary transit times, resulting from reduced peripheral blood flow, increase the likelihood of rigid red cells entrapment in the microvasculature, predisposing to vaso-occlusive crisis. Since changes in peripheral flow are mediated by the autonomic nervous system (ANS), we tested the hypothesis that the cardiac and peripheral vascular responses to head-up tilt (HUT) are abnormal in SCD. Heart rate, respiration, non-invasive continuous blood pressure and finger photoplethysmogram (PPG) were monitored before, during, and after HUT in SCD, anemic controls and healthy subjects.

Mental stress causes vasoconstriction in subjects with sickle cell disease and in normal controls.

Vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD) and occurs when deoxygenated sickled red blood cells occlude the microvasculature. Any stimulus, such as mental stress, which decreases microvascular blood flow will increase the likelihood of red cell entrapment resulting in local vaso-occlusion and progression to VOC. Neurally mediated vasoconstriction might be the physiological link between crisis triggers and vaso-occlusion.

A novel cross-correlation methodology for assessing biophysical responses associated with pain.

Purpose: The purpose of this work was to noninvasively detect and quantify microvascular blood flow changes in response to externally applied pain in humans. The responsiveness of the microvasculature to pain stimulation might serve as an objective biomarker in diseases associated with altered pain perception and dysregulated vascular functions. The availability of such a biomarker may be useful as a tool for predicting outcome and response to treatments, particularly in diseases like sickle cell anemia where clinical manifestations are directly linked to microvascular perfusion.

Autonomic nervous system involvement in sickle cell disease.

Sickle cell disease (SCD) is a genetic disorder of hemoglobin producing hemoglobin-S (HbS) and resulting in recurrent severe episodes of pain, organ damage and premature death due to vaso- occlusion. Deoxy HbS polymerizes, causing red cells to become rigid and lodge in the microvasculature if they do not escape into larger vessels before this transformation occurs. The mechanism that triggers this transition from steady state to vaso-occlusive crisis (VOC) is not known.

Individuals with sickle cell disease have a significantly greater vasoconstriction response to thermal pain than controls and have significant vasoconstriction in response to anticipation of pain.

The painful vaso-occlusive crises (VOC) that characterize sickle cell disease (SCD) progress over hours from the asymptomatic steady-state. SCD patients report that VOC can be triggered by stress, cold exposure, and, pain itself. We anticipated that pain could cause neural-mediated vasoconstriction, decreasing regional blood flow and promoting entrapment of sickle cells in the microvasculature.

Biophysical markers of the peripheral vasoconstriction response to pain in sickle cell disease.

Painful vaso-occlusive crisis (VOC), a complication of sickle cell disease (SCD), occurs when sickled red blood cells obstruct flow in the microvasculature. We postulated that exaggerated sympathetically mediated vasoconstriction, endothelial dysfunction and the synergistic interaction between these two factors act together to reduce microvascular flow, promoting regional vaso-occlusions, setting the stage for VOC. We previously found that SCD subjects had stronger vasoconstriction response to pulses of heat-induced pain compared to controls but the relative degrees to which autonomic dysregulation, peripheral vascular dysfunction and their interaction are present in SCD remain unknown.

Model-Derived Markers of Autonomic Cardiovascular Dysfunction in Sleep-Disordered Breathing.

Evidence indicates that sleep-disordered breathing leads to elevated sympathetic tone and impaired vagal activity, promoting hypertension and cardiometabolic disease. Low-cost but accurate monitoring of autonomic function is useful for the aggressive management of sleep apnea. This article reviews the development and application of multivariate dynamic biophysical models that enable the causal dependencies among respiration, blood pressure, heart rate variability, and peripheral vascular resistance to be quantified.

Modeling of deep breath vasoconstriction reflex.

Deep breaths akin to sighs have been reported to cause peripheral vasoconstriction. Our previous simulation studies have shown that this phenomenon cannot be reproduced in existing circulatory control models without inclusion of a respiratory-vascular coupling mechanism. To better understand this "sigh-vasoconstriction reflex", we investigated the effect of spontaneous and passively induced sighs as well as spontaneous breathing on peripheral vasoconstriction during wakefulness and non-rapid eye movement sleep in human subjects.

Autonomic responses to cold face stimulation in sickle cell disease: a time-varying model analysis.

Sickle cell disease (SCD) is characterized by sudden onset of painful vaso-occlusive crises (VOC), which occur on top of the underlying chronic blood disorder. The mechanisms that trigger VOC remain elusive, but recent work suggests that autonomic dysfunction may be an important predisposing factor. Heart-rate variability has been employed in previous studies, but the derived indices have provided only limited univariate information about autonomic cardiovascular control in SCD.

Estimating the baroreflex and respiratory modulation of peripheral vascular resistance.

The peripheral vascular resistance (RPV) control is known to be largely sympathetically-mediated; thus assessment of the RPV control would allow us to infer valuable information regarding sympathetic nervous activity. The linear and 2nd-order nonlinear minimal models were used to capture the influences of blood pressure (baroreflex) and respiration (respiratory-coupling) on fluctuations of RPV. To validate the minimal models, they were applied on the "data" generated by the simulation model developed in our previous study.

An extended model of blood pressure variability: incorporating the respiratory modulation of vascular resistance.

Short-term blood pressure variability is generally attributed to the baroreflex feedback control on heart rate and systemic vascular resistance (SVR), and the mechanical effect of respiration on stroke volume. Although it is known that respiration affects sympathetic outflow and deep breaths can lead to peripheral vasoconstriction, the respiratory modulation of SVR has been little studied. In the present study, we investigated the dynamics resulting from the respiratory modulation of SVR and its effect on blood pressure variability by employing structured and minimal modeling approaches.

Monitoring ultradian changes in cardiorespiratory control in obstructive sleep apnea syndrome.

Spectral analysis of heart rate variability (HRV) is commonly employed to track changes in autonomic nervous system and respiratory activity during sleep. However, conventional HRV spectral indices can be seriously confounded by inter-subject differences or intra-individual changes in ventilation and ventilatory pattern, especially in subjects with obstructive sleep apnea syndrome (OSAS). We highlight the approach we have undertaken to circumvent this problem by introducing "respiration-adjusted" spectral indices of HRV.