Jennie Tsao’s research while affiliated with University of California, Los Angeles and other places

Objective: Imaging studies in adults with irritable bowel syndrome (IBS) have shown both morphological and resting state (RS) functional connectivity (FC) alterations related to cortical modulation of sensory processing. Because analogous differences have not been adequately investigated in children, this study compared gray matter volume (GMV) and RS-FC between girls with IBS and healthy controls (HC) and tested the correlation between brain metrics and laboratory-based pain thresholds (Pth). Methods: Girls with Rome III criteria IBS (n = 32) and matched HCs (n = 26) were recruited. In a subset of patients, Pth were determined using a thermode to the forearm. Structural and RS scans were acquired. A voxel-based general linear model, adjusting for age, was applied to compare differences between groups. Seeds were selected from regions with group GMV differences for a seed-to-voxel whole brain RS-FC analysis. Significance for analyses was considered at p < .05 after controlling for false discovery rate. Significant group differences were correlated with Pth. Results: Girls with IBS had lower GMV in the thalamus, caudate nucleus, nucleus accumbens, anterior midcingulate (aMCC), and dorsolateral prefrontal cortex. They also exhibited lower RS-FC between the aMCC and the precuneus, but greater connectivity between the caudate nucleus and precentral gyrus. Girls with IBS had higher Pth with a moderate effect size (t(22.81) = 1.63, p = .12, d = 0.64) and lower thalamic GMV bilaterally was correlated with higher Pth (left: r = -.62, p(FDR) = .008; right: r = -.51, p(FDR) = .08). Conclusions: Girls with IBS had lower GMV in the PFC, basal ganglia, and aMCC, as well as altered FC between multiple brain networks, suggesting that structural changes related to IBS occur early in brain development. Girls with IBS also showed altered relationships between pain sensitivity and brain structure.

Background Vaso-occlusive pain crises (VOCs) are the “hallmark” of sickle-cell disease (SCD) and can lead to sympathetic nervous system dysfunction. Increased sympathetic nervous system activation during VOCs and/or pain can result in vasoconstriction, which may increase the risk for subsequent VOCs and pain. Hypnosis is a neuromodulatory intervention that may attenuate vascular and pain responsiveness. Due to the lack of laboratory-controlled pain studies in patients with SCD and healthy controls, the specific effects of hypnosis on acute pain-associated vascular responses are unknown. The current study assessed the effects of hypnosis on peripheral blood flow, pain threshold, tolerance, and intensity in adults with and without SCD. Subjects and methods Fourteen patients with SCD and 14 healthy controls were included. Participants underwent three laboratory pain tasks before and during a 30-minute hypnosis session. Peripheral blood flow, pain threshold, tolerance, and intensity before and during hypnosis were examined. Results A single 30-minute hypnosis session decreased pain intensity by a moderate amount in patients with SCD. Pain threshold and tolerance increased following hypnosis in the control group, but not in patients with SCD. Patients with SCD exhibited lower baseline peripheral blood flow and a greater increase in blood flow following hypnosis than controls. Conclusion Given that peripheral vasoconstriction plays a role in the development of VOC, current findings provide support for further laboratory and clinical investigations of the effects of cognitive–behavioral neuromodulatory interventions on pain responses and peripheral vascular flow in patients with SCD. Current results suggest that hypnosis may increase peripheral vasodilation during both the anticipation and experience of pain in patients with SCD. These findings indicate a need for further examination of the effects of hypnosis on pain and vascular responses utilizing a randomized controlled trial design. Further evidence may help determine unique effects of hypnosis and potential benefits of integrating cognitive–behavioral neuromodulatory interventions into SCD treatment.

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.

Subject characteristics, baseline physiological measurements and biophysical markers of the study cohort. (XLSX)

Representative data recorded during a test procedure in (a) a non-SCD subject and (b) a SCD subject showing similarity between changes finger blood volume and microvascular blood flow. The top row shows changes in temperature (ΔTemp, °C). 0°C indicates no heat was delivered. Row 2 shows changes in beat-averaged blood pressure (MAP, mmHg). Row 3 shows changes in tidal volume (ΔVT, L). Row 4 shows corresponding changes in finger blood volume (ΔFBV, %). The bottom row shows microvascular blood flow measured by laser Doppler flowmetry (ΔPU, perfusion unit). (TIF)

Details on modeling FBV response to heat-induced pain and model estimation. (DOCX)

Introduction: Sickle cell disease (SCD) is a genetic disorder characterized by sudden onset of painful vaso-occlusive episodes (VOC) which can be triggered by stress as reported by sickle cell patients. The exact mechanism of VOC origin is not well understood; however, it could result as a progression of microvascular blockade with rigid sickled red blood cells (RBC). Anything that decreases regional blood flow (RBF) will increase the transit time that it takes the RBC to escape the microvasculature before it gets rigid and entrapped, thus increasing the chances of vaso-occlusion that may progress to VOC. The RBF is controlled by the autonomic nervous system (ANS) which is modulated by stress, and as we have previously shown, SCD patients have augmented autonomic mediated vasoconstriction response (VCR) to sigh and pain. Our studies showed significant VCR when subjects were told they were about to experience pain, suggesting that VCR might be the physiologic link between common VOC triggers like stress and sickled RBC retention in the microvasculature. Objectives: To study the effect of mental stress on autonomic parameters peripheral blood flow (PBF) and heart rate variability (HRV) in SCD. Methods: 19 SCD and 16 control (healthy and sickle cell trait) subjects were studied. Two standard mental stress tasks with graded levels of difficulty (N-back test and Stroop test) were presented to subjects using E-prime (Psychological software). Subjects were also exposed to a novel pain anticipation task, previously shown to induce VCR. PBF was measured using photo-plethysmography (PPG) on the left thumb. Reduction in PPG amplitude indicates vasoconstriction. Cardiac beat-to-beat variability (R-to-R interval;RRI) was extracted from electrocardiogram. ANS balance was derived from the following spectral indices of the RRI: high frequency power (HFP) ≈ parasympathetic activity, low frequency power (LFP), and the low/high ratio (LFP/HFP) representing sympathovagal balance. Average changes in PBF and HRV from the baseline were taken as the responses to the mental tasks. Results: There was a significant decrease in mean PBF, RRI and HFP during all the mental stressors (N-back test, Stroop test and pain fear) compared to the baseline (p<0.01). Based on task accuracy scores, there was clear difference in sublevels of task difficulty (p<0.0001). While PBF decreased during all the sublevels of N-back and Stroop compared to baseline (p<0.01), there was no PBF difference between the task sublevels. However, when subjects were told that they were about to experience severe pain from heat applied to their arm in a sham pain instruction that was given after N-back and Stroop, there was a significant decrease in PBF compared to baseline (p<0.001) and compared to the response during N-back (p<0.01). The parasympathetic withdrawal in response to mental tasks and fear of pain followed a similar pattern. Conclusions: Graded mental stress and fear of pain causes significant decrease in regional blood flow and parasympathetic withdrawal in SCD subjects and normal controls. The vasoconstriction response to "fear of pain" was significantly greater than the VRC caused by N-back and to a lesser extent in Stroop. The pattern of responses were not significantly different between SCD and controls however the consequences of decreased blood flow could be quite different because of the resulted entrapment of sickle cells in the microvasculature. This could explain how stress may play a role in the initiation of VOC in SCD by enhancing ANS mediated vasoconstriction, prolonging microvascular transit time and increasing the likelihood of vaso-occlusion. The 1st signal is mental tasks event marker, 2nd signal is photo-plethysmography (PPG) and the 3rd signal is heart rate variability derived from the electrocardiogram signal. Peripheral blood flow and heart rate variability during baseline and various mental tasks Peripheral blood flow and heart rate variability during baseline and various mental tasks Box plot of mean peripheral blood flow (PBF) during baseline, mental tasks and fear of pain. Box plot of mean peripheral blood flow (PBF) during baseline, mental tasks and fear of pain. Disclosures Wood: Celgene: Consultancy; AMAG: Consultancy; Ionis Pharmaceuticals: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Biomed Informatics: Consultancy; Vifor: Consultancy; World Care Clinical: Consultancy; World Care Clinical: Consultancy; Celgene: Consultancy; AMAG: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy; Biomed Informatics: Consultancy.

Introduction: Vaso-occlusive pain crises are considered the "hallmark" of sickle cell disease (SCD). Persistent occurrence is thought to lead to changes in the peripheral and central nervous system, which can then in turn lead to changes in pain sensitivity. Imaging studies have shown that hypnotic analgesia can reduce activity in supraspinal areas of the "pain matrix." To date there are no published studies looking at the effectiveness of hypnosis in altering pain perception in patients with SCD. The purpose of this study was to investigate changes in peripheral blood flow in response to a 30-minute hypnosis intervention and its relationship to pain sensitivity. Methods: To assess the effectiveness of increasing vasodilation, a laboratory based, single session hypnosis protocol was administered to a sample of 14 SCD patients and 14 healthy controls. Continuous readings for SpO2, pulse rate and pulse waveform was monitored using a pulse oximetry transducer placed on the left thumb. Bio-behavioral pain measures were collected during a standardized pain protocol before and after a hypnosis session, performed by a trained therapist. The protocol consisted of assessing pain tolerance and threshold via a heat probe (˚C) for "pain task 1", preceded by an anticipation period. "Pain task 2" consisted of assessing pain intensity via the same heat probe (˚C) on a 1-100 visual analog scale (VAS), preceded by another anticipation period. Results: To investigate blood-flow responses to their respective baseline (baseline vs. hypnosis), all recorded signal following these two periods was normalized respectively. Independent sample t-tests between both normalized anticipation and pain responses periods revealed controls showed no response to hypnosis for anticipation period 1(t(23.42) = .184, p = .855, d = .072), but SCD patients showed a large increase in blood flow (t(16.99) = 4.189, p = .0006, d = 1.79). Neither controls (t(21.05) = .00, p = .994, d = .003) or SCD patients (t(19.99) =.718, p = .481, d = .305) showed an effect of hypnosis in response to pain task 1. Neither controls (t(23.96) = -.139, p = .890, d = -.05) or SCD patients (t(18.82) = 1.035, p = .313, d = .441) showed a response to anticipation period 2, but the effect size reveals that this may be due to a lack of power. Neither controls (t(16.52) = .258, p = .799, d = .101) or SCD patients (t(19.63) = p = .5375, d = .268) showed no changes in response to hypnosis for pain task 2. Independent sample t-tests revealed no significant difference in pain threshold (t(13) = 0.941, p = .364, d = .251) or tolerance (t(13) = 0.937, p = 0.366, d = 0.250) in SCD patients before and after hypnosis. Differences in pain ratings were marginal but showed a decrease with medium effect (t(13) = -1.5315, p = 0.150, d = 0.409). The same tests revealed significant decreases in controls for pain threshold (t(13) = 2.825, p = 0.01, d = .755), pain tolerance (t(13) = 2.482, p = 0.02, d = 0.664), and pain rating (t(13) = 2.950, p = 0.01, d = .789). Conclusion: Results revealed that hypnosis may be an effective treatment in helping manage vasoconstriction in SCD as a response to cognitive appraisals about pain, as well as reducing pain sensitivity. The data presented provide preliminary clinical evidence of the use of hypnosis as a treatment method to improve vasodilation in SCD patients and decreasing pain crises, thus increasing overall quality of life. Disclosures No relevant conflicts of interest to declare.