Deep brain stimulation in the ALIC-BNST region targeting the bed nucleus of stria terminalis in patients with obsessive-compulsive disorder: effects on cognition after 12 months.

PURPOSE: The aim of this study was to evaluate cognitive effects 12 months after Deep Brain Stimulation (DBS) of the Bed Nucleus of Stria Terminalis (BNST) in patients with refractory Obsessive-Compulsive Disorder (OCD). METHODS: Eight patients (5 female; mean ± SD age 36 ± 15) with OCD were included. A neuropsychological test battery covering verbal and spatial episodic memory, executive function, and attention was administered preoperatively and 12 months after surgery. Medical records were used as a source for descriptive data to probe for any changes not covered by standardized checklists and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the primary outcome measure. RESULTS: At 12 months, seven patients showed response to DBS: three were full responders (i.e., Y-BOCS ≥ 35% improvement), and four were partial responders (Y-BOCS 25-34% improvement). Relative to baseline, there was a slight decline on visuo-spatial learning (p = 0.027), and improved performance on the Color-Word Interference inhibition/switching subtest (p = 0.041), suggesting improvement in cognitive flexibility. CONCLUSIONS: DBS in the BNST for treatment refractory OCD generates very few adverse cognitive effects and improves cognitive flexibility after 12 months of stimulation. The improvement in Y-BOCS and the absence of major cognitive side effects support the BNST as a potential target for DBS in severe OCD.

Effect of the ABCA1 agonist CS-6253 on amyloid-ß and lipoprotein metabolism in cynomolgus monkeys.

BACKGROUND: Inducing brain ATP-binding cassette 1 (ABCA1) activity in Alzheimer's disease (AD) mouse models is associated with improvement in AD pathology. The purpose of this study was to investigate the effects of the ABCA1 agonist peptide CS-6253 on amyloid-ß peptides (Aß) and lipoproteins in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys, a species with amyloid and lipoprotein metabolism similar to humans. METHODS: CS-6253 peptide was injected intravenously into cynomolgus monkeys at various doses in three different studies. Plasma and CSF samples were collected at several time points before and after treatment. Levels of cholesterol, triglyceride (TG), lipoprotein particles, apolipoproteins, and Aß were measured using ELISA, ion-mobility analysis, and asymmetric-flow field-flow fractionation (AF4). The relationship between the change in levels of these biomarkers was analyzed using multiple linear regression models and linear mixed-effects models. RESULTS: Following CS-6253 intravenous injection, within minutes, small plasma high-density lipoprotein (HDL) particles were increased. In two independent experiments, plasma TG, apolipoprotein E (apoE), and Aß42/40 ratio were transiently increased following CS-6253 intravenous injection. This change was associated with a non-significant decrease in CSF Aß42. Both plasma total cholesterol and HDL-cholesterol levels were reduced following treatment. AF4 fractionation revealed that CS-6253 treatment displaced apoE from HDL to intermediate-density- and low density-lipoprotein (IDL/LDL)-sized particles in plasma. In contrast to plasma, CS-6253 had no effect on the assessed CSF apolipoproteins or lipids. CONCLUSIONS: Treatment with the ABCA1 agonist CS-6253 appears to favor Aß clearance from the brain.

Estimation of electric field impact in deep brain stimulation from axon diameter distribution in the human brain.

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 levelEFt0 = 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.

Comparison between patient-specific deep brain stimulation simulations and commercial system SureTune3.

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).

Postoperative Lead Movement after Deep Brain Stimulation Surgery and the Change of Stimulation Volume.

INTRODUCTION: Lead movement after deep brain stimulation may occur and influence the affected volume of stimulation. The aim of the study was to investigate differences in lead position between the day after surgery and approximately 1 month postoperatively and also simulate the electric field (EF) around the active contacts in order to investigate the impact of displacement on affected volume. METHODS: Twenty-three patients with movement disorders underwent deep brain stimulation surgery (37 leads). Computed tomography at the 2 time points were co-fused respectively with the stereotactic images in Surgiplan. The coordinates (x, y, and z) of the lead tips were compared between the 2 dates. Eleven of these patients were selected for the EF simulation in Comsol Multiphysics. Postoperative changes of EF spread in the tissue due to conductivity changes in perielectrode space and due to displacement were evaluated by calculating the coverage coefficient and the Sørensen-Dice coefficient. RESULTS: There was a significant displacement (mean ± SD) on the left lead: x (0.44 ± 0.72, p < 0.01), y (0.64 ± 0.54, p < 0.001), and z (0.62 ± 0.71, p < 0.001). On the right lead, corresponding values were: x (-0.11 ± 0.61, ns), y (0.71 ± 0.54, p < 0.001), and z (0.49 ± 0.81, p < 0.05). The anchoring technique was a statistically significant variable associated with displacement. No correlation was found between bilateral (n = 14) versus unilateral deep brain stimulation, gender (n = 17 male), age <60 years (n = 8), and calculated air volume. The simulated stimulation volume was reduced after 1 month because of the perielectrode space. When considering perielectrode space and displacement, the volumes calculated the day after surgery and approximately 1 month later were partly overlapped. CONCLUSION: The left lead tip displayed a tendency to move lateral, anterior, and inferior and the right a tendency to move anterior and inferior. The anchoring technique was associated to displacement. New brain territory was affected due to the displacement despite considering the reduced stimulated volume after 1 month. Postoperative changes in perielectrode space and small lead movements are reasons for delaying programming to 4 weeks following surgery.

Non-invasive and quantitative in vivo monitoring of gold nanoparticle concentration and tissue hemodynamics by hybrid optical spectroscopies.

Owing to their unique combination of chemical and physical properties, inorganic nanoparticles show a great deal of potential as suitable agents for early diagnostics and less invasive therapies. Yet, their translation to the clinic has been hindered, in part, by the lack of non-invasive methods to quantify their concentration in vivo while also assessing their effect on the tissue physiology. In this work, we demonstrate that diffuse optical techniques, employing near-infrared light, have the potential to address this need in the case of gold nanoparticles which support localized surface plasmons. An orthoxenograft mouse model of clear cell renal cell carcinoma was non-invasively assessed by diffuse reflectance and correlation spectroscopies before and over several days following a single intravenous tail vein injection of polyethylene glycol-coated gold nanorods (AuNRs-PEG). Our platform enables to resolve the kinetics of the AuNR-PEG uptake by the tumor in quantitative agreement with ex vivo inductively coupled plasma mass spectroscopy. Furthermore, it allows for the simultaneous monitoring of local tissue hemodynamics, enabling us to conclude that AuNRs-PEG do not significantly alter the animal physiology. We note that the penetration depth of this current probe was a few millimeters but can readily be extended to centimeters, hence gaining clinical relevance. This study and the methodology presented here complement the nanomedicine toolbox by providing a flexible platform, extendable to other absorbing agents that can potentially be translated to human trials.

Patient-Specific Simulations of Deep Brain Stimulation Electric Field with Aid of In-house Software ELMA.

Deep brain stimulation (DBS) is an established technique for reduction of symptoms in movement disorders. Finite element method (FEM) simulations of the electric field magnitude (EF) are useful for estimating the affected tissue around the DBS lead and this can help optimize the therapy. This paper describes how patient-specific FEM models can be set up with the aid of the Matlab-based in-house software tool ELMA. Electrode placement is determined from two coordinates in postoperative medical imaging and electric conductivity is assigned from preoperative magnetic resonance imaging (MRI) and patient-specific DBS data. Simulations are performed using the equation for steady currents in Comsol Multiphysics (CM). The simulated EF is superimposed on the preoperative MRI for evaluation of affected structures. The method is demonstrated with patient-specific simulations in the zona incerta and a globus pallidus example containing cysts with higher conductive which causes considerable distortion of the EF. The improved software modules and precise lead positioning simplifies and reduces the time for DBS EF modelling and simulation.

Pre-clinical longitudinal monitoring of hemodynamic response to anti-vascular chemotherapy by hybrid diffuse optics.

The longitudinal effect of an anti-vascular endothelial growth factor receptor 2 (VEGFR-2) antibody (DC 101) therapy on a xenografted renal cell carcinoma (RCC) mouse model was monitored using hybrid diffuse optics. Two groups of immunosuppressed male nude mice (seven treated, seven controls) were measured. Tumor microvascular blood flow, total hemoglobin concentration and blood oxygenation were investigated as potential biomarkers for the monitoring of the therapy effect twice a week and were related to the final treatment outcome. These hemodynamic biomarkers have shown a clear differentiation between two groups by day four. Moreover, we have observed that pre-treatment values and early changes in hemodynamics are highly correlated with the therapeutic outcome demonstrating the potential of diffuse optics to predict the therapy response at an early time point.

A method for monitoring of oxygen saturation changes in brain tissue using diffuse reflectance spectroscopy.

Continuous measurement of local brain oxygen saturation (SO2 ) can be used to monitor the status of brain trauma patients in the neurocritical care unit. Currently, micro-oxygen-electrodes are considered as the "gold standard" in measuring cerebral oxygen pressure (pO2 ), which is closely related to SO2 through the oxygen dissociation curve (ODC) of hemoglobin, but with the drawback of slow in response time. The present study suggests estimation of SO2 in brain tissue using diffuse reflectance spectroscopy (DRS) for finding an analytical relation between measured spectra and the SO2 for different blood concentrations. The P3 diffusion approximation is used to generate a set of spectra simulating brain tissue for various levels of blood concentrations in order to estimate SO2 . The algorithm is evaluated on optical phantoms mimicking white brain matter (blood volume of 0.5-2%) where pO2 and temperature is controlled and on clinical data collected during brain surgery. The suggested method is capable of estimating the blood fraction and oxygen saturation changes from the spectroscopic signal and the hemoglobin absorption profile.

Scanning, non-contact, hybrid broadband diffuse optical spectroscopy and diffuse correlation spectroscopy system.

A scanning system for small animal imaging using non-contact, hybrid broadband diffuse optical spectroscopy (ncDOS) and diffuse correlation spectroscopy (ncDCS) is presented. The ncDOS uses a two-dimensional spectrophotometer retrieving broadband (610-900 nm) spectral information from up to fifty-seven source-detector distances between 2 and 5 mm. The ncDCS data is simultaneously acquired from four source-detector pairs. The sample is scanned in two dimensions while tracking variations in height. The system has been validated with liquid phantoms, demonstrated in vivo on a human fingertip during an arm cuff occlusion and on a group of mice with xenoimplanted renal cell carcinoma.

Diffuse Optical Characterization of the Healthy Human Thyroid Tissue and Two Pathological Case Studies.

The in vivo optical and hemodynamic properties of the healthy (n = 22) and pathological (n = 2) human thyroid tissue were measured non-invasively using a custom time-resolved spectroscopy (TRS) and diffuse correlation spectroscopy (DCS) system. Medical ultrasound was used to guide the placement of the hand-held hybrid optical probe. TRS measured the absorption and reduced scattering coefficients (µa, µs') at three wavelengths (690, 785 and 830 nm) to derive total hemoglobin concentration (THC) and oxygen saturation (StO2). DCS measured the microvascular blood flow index (BFI). Their dependencies on physiological and clinical parameters and positions along the thyroid were investigated and compared to the surrounding sternocleidomastoid muscle. The THC in the thyroid ranged from 131.9 µM to 144.8 µM, showing a 25-44% increase compared to the surrounding sternocleidomastoid muscle tissue. The blood flow was significantly higher in the thyroid (BFIthyroid = 16.0 × 10-9 cm2/s) compared to the muscle (BFImuscle = 7.8 × 10-9 cm2/s), while StO2 showed a small (StO2, muscle = 63.8% to StO2, thyroid = 68.4%), yet significant difference. Two case studies with thyroid nodules underwent the same measurement protocol prior to thyroidectomy. Their THC and BFI reached values around 226.5 µM and 62.8 × 10-9 cm2/s respectively showing a clear contrast to the nodule-free thyroid tissue as well as the general population. The initial characterization of the healthy and pathologic human thyroid tissue lays the ground work for the future investigation on the use of diffuse optics in thyroid cancer screening.

Spectroscopic method for determination of the absorption coefficient in brain tissue.

I use Monte Carlo simulations and phantom measurements to characterize a probe with adjacent optical fibres for diffuse reflectance spectroscopy during stereotactic surgery in the brain. Simulations and measurements have been fitted to a modified Beer-Lambert model for light transport in order to be able to quantify chromophore content based on clinically measured spectra in brain tissue. It was found that it is important to take the impact of the light absorption into account when calculating the apparent optical path length, lp, for the photons in order to get good estimates of the absorption coefficient, µa. The optical path length was found to be well fitted to the equation lp=a+b ln(Is)+c ln(µa)+d ln(Is)ln(µa), where Is is the reflected light intensity for scattering alone (i.e., zero absorption). Although coefficients a-d calculated in this study are specific to the probe used here, the general form of the equation should be applicable to similar probes.

Simulation of reflected light intensity changes during navigation and radio-frequency lesioning in the brain.

An electrode with adjacent optical fibers for measurements during navigation and radio frequency lesioning in the brain is modeled for Monte Carlo simulations of light transport in brain tissue. Relative reflected light intensity at 780 nm, I780, from this electrode and probes with identical fiber configuration are simulated using the intensity from native white matter as reference. Models are made of homogeneous native and coagulated gray, thalamus, and white matter as well as blood. Dual layer models, including models with a layer of cerebrospinal fluid between the fibers and the brain tissue, are also made. Simulated I780 was 0.16 for gray matter, 0.67 for coagulate gray matter, 0.36 for thalamus, 0.39 for coagulated thalamus, unity for white matter, 0.70 for coagulated white matter, and 0.24 for blood. Thalamic matter is also found to reflect more light than gray matter and less than white matter in clinical studies. In conclusion, the reflected light intensity can be used to differentiate between gray and white matter during navigation. Furthermore, coagulation of light gray tissue, such as the thalamus, might be difficult to detect using I780, but coagulation in darker gray tissue should result in a rapid increase of I780.

Combined diffuse light reflectance and electrical impedance measurements as a navigation aid in deep brain surgery.

AIM: The aim of this study is to assess reflected light intensity combined with impedance as a navigation aid during stereotactic neurosurgery. METHODS: During creation of 21 trajectories for stereotactic implantation of deep brain stimulation electrodes in the globus pallidus internus or subthalamus (zona incerta or subthalamic nucleus), impedance at 512 kHz and reflected light intensity at 780 nm were measured continuously and simultaneously with a radio frequency electrode containing optical fibres. The signals were compared with the anatomy, determined from pre- and post-operative MRI and CT. The measurements were performed within minutes, and signal analysis was done post-operatively. RESULTS: Reflected light intensity was low from the cortex, lateral ventricle, caudate nucleus and putamen; intermediate from the globus pallidus and thalamus; while it was high from the subcortical white matter, internal capsule and subthalamus. The electrical impedance was less consistent, but generally low in the cortex, intermediate in the subcortical white matter, putamen, globus pallidus and thalamus, and high in the internal capsule and subthalamus. CONCLUSION: Reflected light intensity and electrical impedance give complementary information about passed tissue, and the combination seems promising as a navigation aid during stereotactic neurosurgery.

Impact of cysts during radiofrequency lesioning in deep brain structures--a simulation and in vitro study.

Radiofrequency lesioning of nuclei in the thalamus or the basal ganglia can be used to reduce symptoms caused by e.g. movement disorders such as Parkinson's disease. Enlarged cavities containing cerebrospinal fluid (CSF) are commonly present in the basal ganglia and tend to increase in size and number with age. Since the cavities have different electrical and thermal properties compared with brain tissue, it is likely that they can affect the lesioning process and thereby the treatment outcome. Computer simulations using the finite element method and in vitro experiments have been used to investigate the impact of cysts on lesions' size and shape. Simulations of the electric current and temperature distributions as well as convective movements have been conducted for various sizes, shapes and locations of the cysts as well as different target temperatures. Circulation of the CSF caused by the heating was found to spread heat effectively and the higher electric conductivity of the CSF increased heating of the cyst. These two effects were together able to greatly alter the resulting lesion size and shape when the cyst was in contact with the electrode tip. Similar results were obtained for the experiments.

Radio-frequency lesioning in brain tissue with coagulation-dependent thermal conductivity: modelling, simulation and analysis of parameter influence and interaction.

Radio-frequency brain lesioning is a method for reducing e.g. symptoms of movement disorders. A small electrode is used to thermally coagulate malfunctioning tissue. Influence on lesion size from thermal and electric conductivity of the tissue, microvascular perfusion and preset electrode temperature was investigated using a finite-element model. Perfusion was modelled as an increased thermal conductivity in non-coagulated tissue. The parameters were analysed using a 2(4)-factorial design (n=16) and quadratic regression analysis (n=47). Increased thermal conductivity of the tissue increased lesion volume, while increased perfusion decreased it since coagulation creates a thermally insulating layer due to the cessation of blood perfusion. These effects were strengthened with increased preset temperature. The electric conductivity had negligible effect. Simulations were found realistic compared to in vivo experimental lesions.

The effect of cystic cavities on deep brain stimulation in the basal ganglia: a simulation-based study.

Although the therapeutic effect of deep brain stimulation (DBS) is well recognized, a fundamental understanding of the mechanisms responsible is still not known. In this study finite element method (FEM) modelling and simulation was used in order to study relative changes of the electrical field extension surrounding a monopolar DBS electrode positioned in grey matter. Due to the frequently appearing cystic cavities in the DBS-target globus pallidus internus, a nucleus of grey matter with and without a cerebrospinal fluid filled cystic cavity was modelled. The position, size and shape of the cyst were altered in relation to the electrode. The simulations demonstrated an electrical field around the active element with decreasing values in the radial direction. A stepwise change was present at the edge between grey and white matters. The cyst increased the radial extension and changed the shape of the electrical field substantially. The position, size and shape of the cyst were the main influencing factors. We suggest that cystic cavities in the DBS-target may result in closely related unexpected structures or neural fibre bundles being stimulated and could be one of the reasons for suboptimal clinical effects or stimulation-induced side effects.

Comparison between a detailed and a simplified finite element model of radio-frequency lesioning in the brain.

A detailed and a simplified model of a lesioning electrode was made using the finite element method. 15 simulations of the lesioning procedure were performed for each model and the resulting lesion volumes were compared in order to investigate if the simplified model is adequate. The simplified model resulted in a very slight overestimation of the volume compared to the detailed model. It was thus concluded that the simplified model is adequate for simulations.