Quantifying the Relationship of Bilateral Blood Flow in Glabrous Skin at Rest and During Sympathetic Perturbations

Sympathetic nervous system regulation of blood flow within glabrous skin occurs through control of vasoconstrictor tone, with vasodilation being a passive process. As bursts of sympathetic vasoconstrictor activity occur simultaneously at separate sites of the body, blood flow patterns should also be closely matched due to the direct connection between sympathetic nerves and peripheral microvessels. With sympathetic activity difficult and invasive to measure directly, the possibility of using blood conductance as an indirect measure seems promising. We investigated the relationship of bilateral blood conductance recordings of both middle fingers in ten (7M, 3F) healthy participants, while at rest and in response to perturbations known to elicit sympathetic activity. Cutaneous vascular conductance was measured from both middle fingers via laser Doppler flowmetry, while at rest in a thermoneutral room for 20 minutes and in response to 4 randomized sympathetic perturbations (2 breath holds and 2 cold stimuli) while centrally vasodilated via heating of the back. Correlation coefficients while at thermoneutral rest were high (0.80 ± 0.22) demonstrating a strong temporal relationship for blood conductance in both fingers. During the sympathetic perturbations, blood conductance in both fingers were more related during (0.93 ± 0.11) and post (0.87 ± 0.11) administration of the sympathetic perturbation than prior (0.67 ± 0.25) to the administration (p = 0.002). Taken together, these findings indicate that blood conductance patterns at separate sites of the body are significantly more related during vasoconstrictor activity and that blood conductance may have potential as a non-invasive measure of sympathetic activity

Laser doppler perfusion imaging of the normal and diseased vulva.

Vulval lichen sclerosus (LS) and high-grade intraepithelial neoplasia (VIN 3) are two common and distressing diseases. Significant morbidity is caused by symptoms of persistent pruritus and surgical treatment of skin areas suspicious of malignancy. The risk of developing cancer in a background of LS and VIN 3 is poorly defined. The methods currently available for clinical assessment of the vulva are limited. There is abundant research on the application of the LASER Doppler technique - laser Doppler Flowmetry (LDF) - showing changes in perfusion within the small blood vessels of the skin as a useful parameter for more accurate disease classification. There is also research on immunohistochemical microvessel density (MVD) studies showing increases in blood supply in tissues prone to develop cancer or as a prognostic marker of cancer outcome. The Laser Doppler perfusion imager (LDPI) provides a rapid, real time, non-invasive and non-contact method to measure skin blood flow in an area as opposed to a single point by the LDF, making the LDPI more suitable for application to the vulva. This thesis reports for the first time, the application of the LDPI to the vulva. Initially the LDPI was applied to the clinically normal vulva to study perfusion variance related to menstrual cycle, age and local skin temperature provocation. The application was then extended to vulval disease, LS and VIN 3, and validated against morphological differences in MVD. The LDPI and MVD studies suggest that in VIN 3 there is an actual increase in skin perfusion. In LS the situation is more complex and suggests that the LDPI measured perfusion at a greater depth than the MVD. Studies on base line perfusion variance of vulval LS to topical therapy show that there is no overall difference in baseline perfusion in spite of symptom improvement. Temperature provocation studies suggest differences in skin blood flow response in diseased compared to the normal vulva

The development of biomedical instrumentation using backscattered laser light

This thesis is concerned with the measurement of blood flow and oxygen saturation in the microcirculation using the techniques of laser Doppler flowmetry and pulse oximetry. An investigation of the responses of Doppler flowmeters using different signal processing bandwidths and laser sources revealed two major findings. Firstly, that careful choice of processing bandwidth is required in order to sample the whole range of possible Doppler frequencies present in the backscattered light. Secondly, that the choice of laser source is important in governing the output stability of a flowmeter. Another investigation focused on the evaluation of a dual channel laser Doppler flowmeter using both in vitro and in vivo models. It was demonstrated that the instrument permitted a useful method of obtaining flow information by comparing simultaneous responses at experimental and control sites. The choice of laser wavelength was investigated in a study to determine whether blood flow measurements are obtained from different depths within the skin tissue. The results indicate that some depth discrimination is obtainable using instruments operating at different wavelengths, however it is difficult to demonstrate the effect in vivo. In a separate study it was shown that pressure applied to the skin surface greatly affects the underlying blood flow. It is recommended that care has to be taken when positioning Doppler probes on the skin. A reflection pulse oximeter was developed using laser light backscattered from the skin. The instrument was evaluated in vitro and in vivo by comparing desaturation responses with a commercial transmission pulse oximeter. The reflection oximeter was demonstrated to reliably follow trends in oxygen saturation but several problems prevented instrument calibration. Finally, a device combining laser Doppler flowmetry with reflection pulse oximetry was developed and used in vivo to follow trends in blood flow and oxygen saturation from the same tissue sample

Design of a thermal diffusion sensor for noninvasive assessment of skin surface perfusion and endothelial dysfunction

Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2008.Includes bibliographical references (p. 105-121).The skin microcirculation performs a range of vital functions, such as maintaining nutritional perfusion to the tissues and overall thermoregulation. Not only does impairment to the skin blood supply lead to tissue necrosis and other disease complications, increasing evidence shows that dysfunctional vasoreactivity in the skin microcirculation is associated with multiple disease states, including hypertension, diabetes mellitus, hypercholesterolemia, peripheral vascular disease, and coronary artery disease, and it is one of the earliest indicators of systemic endothelial dysfunction, the precursor to atherosclerotic disease. Endothelial dysfunction is functionally characterized by abnormal vasomotor response to either a pharmacological or flow-mediated stimulus and can be demonstrated in the skin by measuring reperfusion following a period of ischemia, a phenomenon known as post-occlusive reactive hyperemia (PORH). In my research, I have reviewed the literature regarding endothelial dysfunction and its association with a wide range of cardiovascular risk factors. I have also described the mechanisms thought to link endothelial function in the central vascular beds (i.e. coronary) to that of peripheral conduit vessels and the microcirculation. The knowledge thus gathered confirmed that the microcirculation of the skin is an appropriate site for endothelial function assessment. The ultimate goal of my thesis is to design a noninvasive sensor that is capable of obtaining a quantitative measure of skin perfusion, continuously and in real-time, using the principle of thermal diffusion in perfused tissue. I performed preliminary noninvasive endothelial function testing with a modified Thermal Diffusion Probe (TDP), which has been previously validated for absolute perfusion measurement in an invasive setting.(cont.) Based on an initial analysis, I have shown that thermal surface perfusion measurements are feasible and reflect the natural perfusion and temperature fluctuations intrinsic to skin tissue. I also established guidelines for determining quantitative parameters of reactivity from tests of PORH as well as temporal parameters of perfusion variations over time through a spectral analysis of resting blood flow. After establishing the necessary thermal boundary conditions for obtaining surface perfusion measurements, I embarked on a process of computer-assisted modeling and rapid prototyping of various design iterations on an insulated sensor housing, with subsequent fabrication of first generation noninvasive sensors. As a result of these initial sensor designs, specifications for the sensor housing were created to ensure that the appropriate thermal field would be established at the skin measurement site - an important step as it permits the most accurate determination of tissue thermal properties. Finally, I propose a candidate design for an ideal sensor capable of improving the reproducibility of noninvasive perfusion measurements on skin. The development of a noninvasive measure of endothelial dysfunction in the skin is of great value in the early identification of individuals at risk for atherosclerotic complications. Furthermore, the nature of such a technique would provide quantitative information on the presence of a disorder, the extent of dysfunction, and the effectiveness of treatment interventions.by Vivian V. Li.M.Eng

Investigating Hemodynamic Responses to Electrical Neurostimulation

Since the 1900s, the number of deaths attributable to cardiovascular disease has steadily risen. With the advent of antihypertensive drugs and non-invasive surgical procedures, such as intravascular stenting, these numbers have begun to level off. Despite this trend, the number of patients diagnosed with some form of cardiovascular disease has only increased. By 2030, prevalence of coronary heart disease is expected to increase approximately by 18% in the United States. By 2050, prevalence of peripheral arterial occlusive disease is expected to increase approximately by 98% in the U.S. No single drug or surgical intervention offers a complete solution to these problems. Thus, a multi-faceted regimen of lifestyle changes, medication, and device or surgical interventions is usually necessary. A potential adjunct therapy and cost-effective solution for treating cardiovascular disease that has been overlooked is neurostimulation. Recent studies show that using neurostimulation techniques, such as transcutaneous electrical nerve stimulation (TENS), can help to reduce ischemic pain, lower blood pressure, increase blood flow to the periphery, and decrease systemic vascular resistance. The mechanisms by which these hemodynamic changes occur is still under investigation. The primary aim of this thesis is to elucidate these mechanisms through a thorough synthesis of the existing literature on this subject. Neurostimulation, specifically TENS, is thought to modulate both the metaboreflex and norepinephrine release from sympathetic nerve terminals. To test the hypothesis that TENS increases local blood flow, decreases mean arterial pressure, and decreases cutaneous vascular resistance compared to placebo, in which the electrodes are attached but no electrical stimulation is applied, a protocol was developed to test the effect of neurostimulation on healthy subjects. Implementation of this protocol in a pilot study will determine if neurostimulation causes significant changes in blood flow using the most relevant perfusion measurement instrumentation. Before conducting this study, pre-pilot comparison studies of interferential current therapy (IFC) versus TENS, low frequency (4 Hz) TENS versus high frequency (100 Hz) TENS, and electrode placement on the back versus the forearm were conducted. The only statistically significant difference found was that the application of IFC on the back decreased the reperfusion time, meaning that the time required to reach the average baseline perfusion unit value after occlusion decreased. Further pre-pilot work investigating these different modalities and parameters is necessary to ensure that favorable hemodynamic changes can be detected in the pilot study

Cutaneous vascular haemodynamics in diabetes mellitus.

In this thesis the laser Doppler flowmeter and other microvascular methods were used to investigate the skin microcirculation in non-diabetic and diabetic subjects in order to gain a greater understanding of the normal microcirculation and to define abnormalities relevant to the diabetic state. The principle findings were- 1. The normal skin microvascular response to thermal and mechanical injury is a substantial increase in blood flow. In diabetic subjects with and without complications this hyperaemic response was reduced and degree of impairment was found to be greatest in those with the severest complications. 2. In diabetic patients, the diameter of foot skin capillaries was reduced and the basement membrane width was found to increase progressively with increasing severity of complications. These structural changes may partly explain the reduced hyperaemic responses and their relationship with severity of complications. These structural and functional abnormalities may be implicated in the pathogenesis and impaired healing of diabetic foot lesions. 3. In normal subjects, blood flow in the toe pulp fell by 80% when the foot was lowered 50 cm below the heart. Toe blood flow in neuropathic diabetic subjects was three fold higher than in normal subjects, and on lowering the foot this difference was even greater; dependent flow was seven fold higher and the fall in blood flow was only 50%. These findings are compatible with reduced central sympathetic tone and/or peripheral sympathetic nerve failure. 4. In young non-neuropathic diabetic subjects, the more severe stress of sitting still for 50 minutes with the foot 1 meter below heart level, also revealed an increase in toe pulp blood flow. This was associated with elevated capillary pressure, failure in the expected rise in plasma osmotic pressure, and increased foot swelling. These results provide evidence of capillary hypertension and impairment of oedema preventing mechanisms in the dependent foot of diabetic subjects. These abnormalities may be important in initiating structural and functional damage to the skin microcirculation

Contactless photoplethysmography for assessment of small fiber neuropathy

Chronic pain is a prevalent condition affecting approximately one-fifth of the global population, with significant impacts on quality of life and work productivity. Small fiber neuropathies are a common cause of chronic pain, and current diagnostic methods rely on subjective self-assessment or invasive skin biopsies, highlighting the need for objective noninvasive assessment methods. The study aims to develop a modular prototype of a contactless photoplethysmography system with three spectral bands (420, 540, and 800 nm) and evaluate its potential for assessing peripheral neuropathy patients via a skin topical heating test and spectral analyses of cutaneous flowmotions. The foot topical skin heating test was conducted on thirty volunteers, including fifteen healthy subjects and fifteen neuropathic patients. Four cutaneous nerve fiber characterizing parameters were evaluated at different wavelengths, including vasomotor response trend, flare area, flare intensity index, and the spectral power of cutaneous flowmotions. The results show that neuropathic patients had significantly lower vasomotor response (50%), flare area (63%), flare intensity index (19%), and neurogenic component (54%) of cutaneous flowmotions compared to the control group, independent of photoplethysmography spectral band. An absolute value of perfusion was 20%–30% higher in the 420 nm band. Imaging photoplethysmography shows potential as a cost-effective alternative for objective and non-invasive assessment of neuropathic patients, but further research is needed to enhance photoplethysmography signal quality and establish diagnostic criteria