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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. In the present study, we employed a mathematical model to decompose the total vasoconstriction response to pain into: 1) the neurogenic component, 2) the vascular response to blood pressure, 3) respiratory coupling and 4) neurogenic-vascular interaction. The model allowed us to quantify the contribution of each component to the total vasoconstriction response. The most salient features of the components were extracted to represent biophysical markers of autonomic and vascular impairment in SCD and controls. These markers provide a means of phenotyping severity of disease in sickle-cell anemia that is based more on underlying physiology than on genotype. The marker of the vascular component (BMv) showed stronger contribution to vasoconstriction in SCD than controls (p = 0.0409), suggesting a dominant myogenic response in the SCD subjects as a consequence of endothelial dysfunction. The marker of neurogenic-vascular interaction (BMn-v) revealed that the interaction reinforced vasoconstriction in SCD but produced vasodilatory response in controls (p = 0.0167). This marked difference in BMn-v suggests that it is the most sensitive marker for quantifying combined alterations in autonomic and vascular function in SCD in response to heat-induced pain.

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. In this study, we present an improved predictive model of VOC frequency by employing a two-level stacking machine learning (ML) model that incorporates detailed features extracted from the PPG signals in the same database. The first level contains seven different base ML algorithms predicting each subject's pain category based on the input PPG characteristics and other clinical information, while the second level is a meta model which uses the inputs to the first-level model along with the outputs of the base models to produce the final prediction. Model performance in predicting future VOC was significantly higher than in predicting VOC prior to each sleep study (F1-score of 0.43 vs. 0.35, p -value <0.0001), consistent with our hypothesis of a causal relationship between vasoconstriction and future pain incidence, rather than past pain leading to greater propensity for vasoconstriction. The model also performed much better than our previous conventional statistical model (F1 = 0.33), as well as all other algorithms that used only the base-models for predicting VOC without the second tier meta model. The modest F1 score of the present predictive model was due in part to the relatively small database with substantial imbalance (176:36) between low-pain and high-pain subjects, as well as other factors not captured by the sleep data alone. This report represents the first attempt ever to use non-invasive finger PPG measurements during sleep and a ML-based approach to predict increased propensity for VOC crises in SCD. The promising results suggest the future possibility of embedding an improved version of this model in a low-cost wearable system to assist clinicians in managing long-term therapy for SCD patients.

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. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.

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. 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. We quantified the PFC oxygenation rate as an index of cognitive activity in each group and compared them. In half of the participants, a Stroop test was administered before they started -back to elevate their baseline stress level. In SCD compared to healthy controls, we found that (1) under a high baseline stress level, there were significantly greater oxygenation responses during the 2-back task, further elevated with histories of stroke; (2) there was a marginally slower -back response time, and it was even slower with a history of stroke; and (3) the task accuracy was not different. Additional requirements for processing time, PFC resources, and PFC oxygenation in SCD patients offer an important basis for understanding their cognitive decline and highlight the potential of fNIRS for evaluating cognitive functions.

The regulation of peripheral vascular resistance (RPV) is believed to be largely sympathetically-mediated. Thus assessment of R PV control would allow us to infer valuable information regarding sympathetic nervous activity. Variability in RPV is generally attributed to the baroreflex control of total peripheral resistance (TPR). Although it is known that respiration affects sympathetic outflow and deep breaths, akin to sighs, can lead to peripheral vasoconstriction, the respiratory modulation of TPR has been little studied. In the present study, we utilized noninvasive surrogate measures of RPV to examine the two mechanisms that influence its variability: the baroreflex control of peripheral vascular resistance and the respiratory-peripheral vascular resistance coupling. The first surrogate measure was obtained from peripheral arterial tonometry (PAT). PAT measured the changes in volume at the finger tip, reflecting the vasoconstriction response as the reduction in its signal amplitude. The other surrogate measure was obtained from laser Doppler flowmetry, which monitors microvascular perfusion. The results of this study suggest that RPV fluctuations were directly modulated by respiration rather than through indirect effect of respiratory modulation of arterial blood pressure (ABP). The simulation model developed based on previous literatures pertinent to short-term blood pressure regulation could not reproduce the sigh-vasoconstriction response as observed in the experimental data. The minimal modeling approach was employed to estimate this respiratory coupling effect, which would be incorporated into the simulation model. By means of both modeling approaches, we demonstrated that only after the direct respiratory modulation mechanism was added to the simulation model that a similar vasoconstriction response following a sigh could be reproduced. The linear and nonlinear dynamics as well as the interaction effect involved in the modulation of RPV through changes in ABP and respiration were investigated in obese pediatric subjects exposed to orthostatic stress and subjects with sickle cell disease before and after blood transfusion treatment. In the obese pediatric subject group, we found that the linear gains of both the TPR baroreflex as well as the respiratory coupling mechanisms diminished as a result of orthostatic stress. The reduction in these gains suggests that sympathetic modulation of TPR decreased in spite of a rise in sympathetic tone. Orthostatic stress was found to lead also to a reduction in the strength of the nonlinear behavior in obese pediatric subjects. Subjects with more severe degrees of metabolic syndrome and obstructive sleep apnea syndrome showed larger reduction in nonlinear TPR baroreflex gain. Transfusion therapy in the sickle cell disease subjects led to an increase in nonlinear TPR baroreflex gain as well as the interaction between ABP and respiration. In conclusion, through a combination of the structured and the minimal modeling approaches, we have developed an extended model of blood pressure variability that incorporates the respiratory modulation effect on R PV. Taking this respiratory modulation effect into account is important for achieving accurate TPR baroreflex estimation. Finally, the system gains derived from the estimated kernels may constitute potentially useful biomarkers of sympathetic nervous system function.

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. We, therefore, developed a method to distinguish the blood flow response due to the test stimulus from the blood flow measurement that also includes concurrent flow changes from unknown origins. We measured the microvascular blood flow response in 24 healthy subjects in response to a train of randomly spaced and scaled heat pulses on the anterior forearm. The fingertip microvascular perfusion was measured using laser Doppler flowmetry. The cross-correlation between the heat pulses and the blood flow response was computed and tested for significance against the null distribution obtained from the baseline recording using bootstrapping method. We estimated correlation coefficients, response time, response significance, and the magnitude of vasoreactivity from microvascular blood flow responses. Based on these pain response indices, we identified strong responders and subjects who did not show significant responses. The cross-correlation of a random pattern of painful stimuli with directly measured microvascular flow can detect vasoconstriction responses in a noisy blood flow signal, determine the time between stimulus and response, and quantify the magnitude of this response. This approach provided an objective measurement of vascular response to pain that may be an inherent characteristic of individual human subjects, and may also be related to the severity of vascular disorders.

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. To circumvent this limitation, a time‐varying modeling approach was applied to investigate the functional mechanisms relating blood pressure (BP) and respiration to heart rate and peripheral vascular resistance in healthy controls, untreated SCD subjects and SCD subjects undergoing chronic transfusion therapy. Measurements of respiration, heart rate, continuous noninvasive BP and peripheral vascular resistance were made before, during and after the application of cold face stimulation (CFS), which perturbs both the parasympathetic and sympathetic nervous systems. Cardiac baroreflex sensitivity estimated from the model was found to be impaired in nontransfused SCD subjects, but partially restored in SCD subjects undergoing transfusion therapy. Respiratory‐cardiac coupling gain was decreased in SCD and remained unchanged by chronic transfusion. These results are consistent with autonomic dysfunction in the form of impaired parasympathetic control and sympathetic overactivity. As well, CFS led to a significant reduction in vascular resistance baroreflex sensitivity in the nontransfused SCD subjects but not in the other groups. This blunting of the baroreflex control of peripheral vascular resistance during elevated sympathetic drive could be a potential factor contributing to the triggering of VOC in SCD. This study investigated the effect of cold face stimulation (CFS) on autonomic function in subjects with sickle cell disease (SCD), chronically transfused SCD subjects, and healthy controls. Using a time‐varying computational model, we found that cardiac baroreflex sensitivity was impaired in nontransfused SCD subjects, but partially restored toward healthy control levels in SCD subjects undergoing transfusion therapy. As well, CFS reduced vascular resistance baroreflex sensitivity in the nontransfused SCD subjects but not in the other groups.