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

Abstract

PurposeThe 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.Subjects and methodsWe 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.ResultsWe 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.ConclusionThe 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.

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

“…Once the participant responded, the temperature was rapidly reset to baseline. An average of 3 measurements for each threshold was used to determine the specific cold and heat threshold temperatures for each subject 12,24,34…”

“…The amplitude of the PPG signal derived from its raw waveform reflects changes in the peripheral vascular bed controlled by the sympathetic nervous system, with low amplitude reflecting vasoconstriction. 12,24,[34][35][36] Electrocardiogram (ECG), continuous blood pressure (Nexfin; Bmeye, Amsterdam, The Netherlands) and respiratory wave forms (thoracic and abdominal bands; zRip DuraBelt; Philips) were also recorded. The standard deviation of the cardiac beatto-beat interval (R-R interval [RRI]) derived from the ECG reflects total heart rate variability (HRV), a measure of cardiac autonomic balance.…”

“…37 As described in our previous studies, 12,13,24 signals from all devices, including thermode temperature, were recorded concurrently and continuously at subsecond sampling rates with the Biopac-Acqknowledge data-acquisition system. 12,24,34…”

“…All recorded data were exported to a browser specially designed in MatLab for processing and analysis. 12,24,34…”

“…The magnitude of vasoconstriction was assessed by calculating the percentage decrease in mean MBF from baseline, with a greater percentage decrease indicating stronger vasoconstriction. 12,24,34 To determine if the thermal stimulus pattern within each cycle produced a corresponding pattern of vasoconstriction, the thermode temperature signal (Figure 1) was cross-correlated with the corresponding blood flow signal 34 (supplemental Figure 1, available on the Blood Web site). The cross-correlation algorithm determines the point of maximum correlation between the thermode signal and the corresponding PPG amplitude signal in a 30-second window, before and after the thermal stimulation.…”