Johannes D. Johansson

In this work, broadband diffuse reflectance spectroscopy (DRS) and diffuse correlation spectroscopy (DCS) were used to quantify deep tissue hemodynamics in a patient-derived orthotopic xenograft mouse model of clear cell renal cancer undergoing antiangiogenic treatment. A cohort of twenty-two mice were treated with sunitinib and compared to thirteen control untreated mice, and monitored by DRS/DCS. A reduction in total hemoglobin concentration (THC, p = 0.03), oxygen saturation (SO_2, p = 0.03) and blood flow index (BFI, p = 0.02) was observed over the treatment course. Early changes in tumor microvascular blood flow and total hemoglobin concentration were correlated with the final microvessel density (p = 0.014) and tumor weight (p = 0.024), respectively. Higher pre-treatment tumor microvascular blood flow was observed in non-responder mice with respect to responder mice, which was statistically predictive of the tumor intrinsic resistance (p = 0.01). This hybrid diffuse optical technique provides a method for predicting tumor intrinsic resistance to antiangiogenic therapy and could be used as predictive biomarker of response to antiangiogenic therapies in pre-clinical models.

Partial-thickness burn wounds extend partially through the dermis, leaving many pain receptors intact and making the injuries very painful. Due to the painfulness, quick assessment of the burn depth is important to not delay surgery of the wound if needed. Laser speckle imaging (LSI) of skin blood flow can be helpful in finding severe coagulation zones with impaired blood flow. However, LSI measurements are typically too superficial to properly reach the full depth of the adult dermis and cannot resolve the flow in depth. Diffuse correlation spectroscopy (DCS) uses varying source-detector separations to allow differentiation of flow depths but requires time-consuming 2D scanning to form an image of the burn area. We here present a prototype for a hybrid DCS and LSI technique called speckle contrast diffuse correlation spectroscopy (scDCS) with the novel approach of using a laser line as a source and using the speckle contrast of averaged images to obtain an estimate of static scattering in the tissue. This will allow for fast non-contact 1D scanning to perform 3D tomographic imaging, making quantitative estimates of the depth and area of the coagulation zone from burn wounds. Simulations and experimental results from a volumetric flow phantom and a gelatin wedge phantom show promise to determine coagulation depth. The aim is to develop a method that, in the future, could provide more quantitative estimates of coagulation depth in partial thickness burn wounds to better estimate when surgery is needed.

Partial thickness burn wounds extend partially through the dermis, leaving many pain receptors intact and making the injuries very painful. Due to the painfulness, quick assessment of the burn depth is important to not delay surgery of the wound if needed. Laser speckle imaging (LSI) of skin blood flow can be helpful in finding severe coagulation zones with impaired blood flow. However, LSI measurements are typically too superficial to properly reach the full depth of adult dermis and cannot resolve the flow in depth. Diffuse correlation spectroscopy (DCS) uses varying source-detector separations to allow differentiation of flow depths but requires time-consuming 2D scanning to form an image of the burn area. We here present a prototype for a hybrid DCS and LSI technique called speckle contrast Diffuse Correlation Spectroscopy (scDCS) with the novel approach of using a laser line as a source and using the speckle contrast of averaged images to obtain an estimate of static scattering in the tissue. This will allow for fast non-contact 1D scanning to perform 3D tomographic imaging, making quantitative estimates of the depth and area of the coagulation zone from burn wounds. Simulations and experimental results from a volumetric flow phantom and a gelatin wedge phantom show promise to determine coagulation depth. The aim is to develop a method that in the future could provide more quantitative estimates of coagulation depth in partial thickness burn wounds to better estimate when surgery is needed.

Partial thickness burn wounds extend partially through the dermis, leaving many pain receptors intact and making the injuries very painful. Due to the painfulness, quick assessment of the burn depth is important to not delay surgery of the wound if needed. Laser speckle imaging (LSI) of skin blood flow can be helpful in finding severe coagulation zones with impaired blood flow. However, LSI measurements are typically too superficial to properly reach the full depth of adult dermis and cannot resolve the flow in depth. Diffuse correlation spectroscopy (DCS) uses varying source-detector separations to allow differentiation of flow depths but requires time-consuming 2D scanning to form an image of the burn area. We here present a prototype for a hybrid DCS and LSI technique called speckle contrast Diffuse Correlation Spectroscopy (scDCS) with the novel approach of using a laser line as a source and using the speckle contrast of averaged images to obtain an estimate of static scattering in the tissue. This will allow for fast non-contact 1D scanning to perform 3D tomographic imaging, making quantitative estimates of the depth and area of the coagulation zone from burn wounds. Simulations and experimental results from a volumetric flow phantom and a gelatin wedge phantom show promise to determine coagulation depth. The aim is to develop a method that in the future could provide more quantitative estimates of coagulation depth in partial thickness burn wounds to better estimate when surgery is needed.

A novel system and method for 3D laser speckle imaging of coagulation depth in partial thickness burn wounds using a line laser to provide depth-varying imaging is presented.

Spatial frequency domain techniques use spatially modulated illumination patterns to quantify absorption and scattering properties of tissue and other diffusive media across visible and/or near-infrared ranges.^{1 – 4} These techniques can be implemented in a variety of ways such as spatial frequency domain imaging (SFDI)² or spatial frequency domain spectroscopy (SFDS).³ Through the quantification of these optical properties, SFDI/S has demonstrated the potential to non-invasively assess skin cancers,^5,6 wound severity,^7,8 and tissue structure and viability^9,10 in the skin. In many of these clinical applications, such as burn wound assessment and melanin quantification, depth sensitivity and subsurface discrimination approaches enabled by SFDI/S are critical features toward accurate characterization of specific tissue volumes.^{11 – 15}

Objective.Finite element method (FEM) simulations of the electric field magnitude (EF) are commonly used to estimate the affected tissue surrounding the active contact of deep brain stimulation (DBS) leads. Previous studies have found that DBS starts to noticeably activate axons at approximately 0.2 V mm^-1, corresponding to activation of 3.4μm axons in simulations of individual axon triggering. Most axons in the brain are considerably smaller however, and the effect of the electric field is thus expected to be stronger with increasing EF as more and more axons become activated. The objective of this study is to estimate the fraction of activated axons as a function of electric field magnitude.Approach. The EF thresholds required for axon stimulation of myelinated axon diameters between 1 and 5μm were obtained from a combined cable and Hodgkin-Huxley model in a FEM-simulated electric field from a Medtronic 3389 lead. These thresholds were compared with the average axon diameter distribution from literature from several structures in the human brain to obtain an estimate of the fraction of axons activated at EF levels between 0.1 and 1.8 V mm^-1.Main results. The effect of DBS is estimated to be 47·EF-8.8% starting at a threshold levelEF_t0 = 0.19 V mm^-1.Significance. The fraction of activated axons from DBS in a voxel is estimated to increase linearly with EF above the threshold level of 0.19 V mm^-1. This means linear regression between EF above 0.19 V mm^-1and clinical outcome is a suitable statistical method when doing improvement maps for DBS.

Objective. Software to visualize estimated volume of tissue activated (VTA) in deep brain stimulation assuming a homogeneous tissue surrounding such as SureTune3 has recently become available for clinical use. The objective of this study is to compare SureTune3 with homogeneous and heterogeneous patient-specific finite element method (FEM) simulations of the VTA to elucidate how well they coincide in their estimates. Approach. FEM simulations of the VTA were performed in COMSOL Multiphysics and compared with VTA from SureTune3 with variation of voltage and current amplitude, pulse width, axon diameter, number of active contacts, and surrounding homogeneous grey or white matter. Patient-specific simulations with heterogeneous tissue were also performed. Main results. The VTAs corresponded well for voltage control in homogeneous tissue, though with the smallest VTAs being slightly larger in SureTune3 and the largest VTAs being slightly larger in the FEM simulations. In current control, FEM estimated larger VTAs in white matter and smaller VTAs in grey matter compared to SureTune3 as grey matter has higher electric conductivity than white matter and requires less voltage to reach the same current. The VTAs also corresponded well in the patient-specific cases except for one case with a cyst of highly conductive cerebrospinal fluid (CSF) near the active contacts. Significance. The VTA estimates without taking the surrounding tissue into account in SureTune3 are in good agreement with patient-specific FEM simulations when using voltage control in the absence of CSF-filled cyst. In current control or when CSF is present near the active contacts, the tissue characteristics are important for the VTA and needs consideration. Clinical. trial ethical approval: Local ethics committee at Linköping University (2012/434-31).

Background: Finite element method (FEM) simulations of the electric field magnitude (EF) are commonly used to estimate the affected tissue surrounding the active contact of deep brain stimulation (DBS) leads. Previous studies have found that DBS starts to noticeably activate axons at approximately 0.2 V/mm, corresponding to activation of 3.4 $\mu$m axons in simulations of individual axon triggering. Most axons in the brain are considerably smaller however, and the effect of the electric field is thus expected to be stronger with increasing EF as more and more axons become activated. Objective: To estimate the fraction of activated axons as a function of electric field magnitude. Methods: The EF thresholds required for axon stimulation of myelinated axon diameters between 1 and 5 $\mu$m were obtained from a combined cable and Hodgkin-Huxley model in a FEM-simulated electric field from a Medtronic 3389 lead. These thresholds were compared with the average axon diameter distribution from literature from several structures in the human brain to obtain an estimate of the fraction of axons activated at EF levels between 0.1 and 1.8 V/mm. Results: The effect of DBS is estimated to be 41$\cdot$EF - 7.4 % starting at a threshold level EFt0 = 0.18 V/mm. Conclusion: The fraction of activated axons from DBS in a voxel is estimated to increase linearly with EF above the threshold level of 0.18 V/mm. This means linear regression between EF above 0.18 V/mm and clinical outcome is a suitable statistical method when doing improvement maps for DBS.