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

Abstract

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.

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

“…The height of the PPG pulses was extracted (photoplethysmograph amplitude [PPGamp]), followed by the same pre-processing steps for the LDF signal. 2 , 3 , 21 We observed that the LDF and PPGamp signals were usually correlated well (not shown). We also computed R, Tr, and Pr indices to pain, using the PPGamp signal, which showed no statistical differences compared with the indices obtained using the LDF ( Table S1 ).…”

“…To overcome this limitation, we assumed we were obtaining another cycle of unique oscillatory response in every 10 seconds of blood flow. 3 , 19 Based on this effective unit of time, we would need another 40×10 seconds=400 seconds=~7 minutes of baseline data in addition to the length of the task stimulation to obtain bootstrap P -value with reasonable robustness and resolution. For this reason, we constructed the null distribution by combining the 5-minute silent baseline recording and 10–15 minutes of the extended baseline recording periods ( Figure 2 ).…”

“…Previously, we have shown that the peripheral vaso-constriction responses to heat pain occurred rapidly and were detectable using the pulses described here. 3 …”

A dual role for peripheral GDNF signaling in nociception and cardiovascular reflexes

“…Patients that experience pathologies characterized by musculoskeletal ischemic injury, such as sickle cell disease, PVD, or complex regional pain syndrome (CRPS) often present both pain and altered autonomic vasomotor responses to tissue ischemia 36,57,58,59 . Our data suggests that muscle GDNF, combined with GFRα1 upregulation can sensitize muscle primary afferents after I/R.…”

Convergence of physiological responses to pain during face-to-face interaction

“…BVP has been used to assess rapid stimuliinduced autonomic responses 16 , and is suitable for capturing an individual's acute physiological response to a pain-provoking stimulus. Specifically, a reduction in BVP amplitude from the baseline in response to a stimulus reflects peripheral vasoconstriction in the finger and is known to be associated with sympathetic arousal caused by acute stress 16,17 and thermal pain 18 . We thus used the constriction percentages of BVP amplitude after stimulus onset as an index of physiological pain response (see Methods for details).…”