Investigation of intraoperative accelerometer data recording for safer and improved target selection for deep brain stimulation

Background: Deep Brain Stimulation (DBS) is a well established surgical treatment for Parkinson’s Disease (PD) and Essential Tremor (ET). Electrical leads are surgically implanted in the deeply seated structures in the brain and chronically stimulated. The location of the lead with respect to the anatomy is very important for optimal treatment. Therefore, clinicians carefully plan the surgery, record electrophysiological signals from the region of interest and perform stimulation tests to identify the best location to permanently place the leads. Nevertheless, there are certain aspects of the surgery that can still be improved. Firstly, therapeutic effects of stimulation are estimated by visually evaluating changes in tremor or passively moving patient's limb to evaluate changes in rigidity. These methods are subjective and depend heavily on the experience of the evaluator. Secondly, a significant amount of patient data is collected before and during the surgery like various CT and MR images, surgical planning information, electrophysiological recordings and results of stimulation tests. These are not fully utilized at the time of choosing the position for lead placement as they are either not available or acquired on separate systems or in the form of paper notes only. Thirdly, studies have shown that the current target structures to implant the leads (Subthalamic Nucleus (STN) for PD and Ventral Intermediate Nucleus (VIM) for ET) may not be the only ones responsible for the therapeutic effects. The objective of this doctoral work is to develop new methods that help clinicians subdue the above limitations which could in the long term improve the DBS therapy. Method: After a thorough review of the existing literature, specifically customized solutions were designed for the shortcomings described above. A new method to quantitatively evaluate tremor during DBS surgery using acceleration sensor was developed. The method was then adapted to measure acceleration of passive movements and to evaluate changes in rigidity through it. Data from 30 DBS surgeries was collected by applying these methods in two clinical studies: one in Centre Hospitalier Universitaire, Clermont-Ferrand, France and another multi-center study in Universitäspital Basel and Inselspital Bern in Switzerland. To study the role of different anatomical structures in the therapeutic and adverse effects of stimulation, the data collected during the study was analysed using two methods. The first classical approach was to classify the data based on the anatomical structure in which the stimulating contact of the electrode was located. The second advanced approach was to use patient-specific Finite Element Method (FEM) simulations of the Electric Field (EF) to estimate the spatial distribution of stimulation in the structures surrounding the electrode. Such simulations of the adverse effect inducing stimulation current amplitudes are used to visualize the boundaries of safe stimulation and identify structures that could be responsible for these effects. In addition, the patient-specific simulations are also used to develop a new method called "Improvement Maps" to generate 2D and 3D visualization of intraoperative stimulation test results with the patient images and surgical planning. This visualization summarized the stimulation test results by dividing the explored area into multiple regions based on the improvement in symptoms as measured by the accelerometric methods. Results: The accelerometric method successfully measured changes in tremor and rigidity. Standard deviation, signal energy and spectral amplitude of dominant frequency correlated with changes in the symptoms. Symptom suppressing stimulation current amplitudes identified through quantitative methods were lower than those identified through the subjective methods. Comparison of anatomical targets using the accelerometric data showed that to suppress rigidity in PD patients, stimulation current needed was marginally higher for Fields of Forel (FF) and Zona Incerta (ZI) compared to STN. On the other hand, the adverse effect occurrence rate was significantly lower in ZI and FF, indicating them to be better targets compared to STN. Similarly, for ET patients, other thalamic nuclei like the Intermediolateral (InL) and Ventro-Oral (VO) as well as the Pre-Lemniscal Radiations (PLR) are as efficient in suppressing tremor as the VIM but have lower occurrence of adverse effects. Volumetric analysis of spatial distribution of stimulation agreed with these results suggesting that the structures other than the VIM could also play a role in therapeutic effects of stimulation. The visualization of the adverse effect simulations clearly show the structures which could be responsible for such effects e.g. stimulation in the internal capsula induced pyramidal effects. These findings concur with the published literature. With regard to the improvement maps, the clinicians found them intuitive and easy to use to identify the optimal position for lead placement. If the maps were available during the surgery, the clinicians' choice of lead placement would have been different. Conclusion: This doctoral work has shown that modern techniques like quantitative symptom evaluation and electric field simulations can suppress the existing drawbacks of the DBS surgery. Furthermore, these methods along with 3D visualization of data can simplify tasks for clinicians of optimizing lead placement. Better placement of the DBS lead can potentially reduce adverse effects and increase battery life of implanted pulse generator, resulting in better therapy for patients

NELFE-Dependent MYC Signature Identifies a Unique Cancer Subtype in Hepatocellular Carcinoma.

The MYC oncogene is dysregulated in approximately 30% of liver cancer. In an effort to exploit MYC as a therapeutic target, including in hepatocellular carcinoma (HCC), strategies have been developed on the basis of MYC amplification or gene translocation. Due to the failure of these strategies to provide accurate diagnostics and prognostic value, we have developed a Negative Elongation Factor E (NELFE)-Dependent MYC Target (NDMT) gene signature. This signature, which consists of genes regulated by MYC and NELFE, an RNA binding protein that enhances MYC-induced hepatocarcinogenesis, is predictive of NELFE/MYC-driven tumors that would otherwise not be identified by gene amplification or translocation alone. We demonstrate the utility of the NDMT gene signature to predict a unique subtype of HCC, which is associated with a poor prognosis in three independent cohorts encompassing diverse etiologies, demographics, and viral status. The application of gene signatures, such as the NDMT signature, offers patients access to personalized risk assessments, which may be utilized to direct future care

Hepatic Stellate Cells and Hepatocarcinogenesis

Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME

Ipsilateral Placement of Simultaneous Pancreas and Kidney Allografts

The current standard technique for simultaneous kidney pancreas transplantation usually involves transplanting the pancreas to the right and the kidney to the left iliac system. Here we describe a previously unreported technique where both organs are transplanted to the right iliac system through a single midline incision. Forty-nine patients underwent simultaneous ipsilateral pancreas and kidney transplantation. All pancreas grafts were drained enterically. Overall patient, pancreas, and kidney survival were 96% (47/49), 92% (45/49), and 94% (46/49) respectively. The 45 patients with functioning grafts are insulin free and off of dialysis. Mean serum creatinine at 1, 3, 6, and 12 months was 1.7Ϯ1.3, 1.2Ϯ0.3, 1.3Ϯ0.3, and 1.3Ϯ0.4 mg/dL, respectively. The placement of the pancreas and kidney transplants on the same side is safe and does not compromise patient or graft survival. This approach preserves the left iliac system for future retransplantation if necessary

A novel assistive method for rigidity evaluation during deep brain stimulation surgery using acceleration sensors

Despite the widespread use of deep brain stimulation (DBS) for movement disorders such as Parkinson's disease (PD), the exact anatomical target responsible for the therapeutic effect is still a subject of research. Intraoperative stimulation tests by experts consist of performing passive movements of the patient's arm or wrist while the amplitude of the stimulation current is increased. At each position, the amplitude that best alleviates rigidity is identified. Intrarater and interrater variations due to the subjective and semiquantitative nature of such evaluations have been reported. The aim of the present study was to evaluate the use of an acceleration sensor attached to the evaluator's wrist to assess the change in rigidity, hypothesizing that such a change will alter the speed of the passive movements. Furthermore, the combined analysis of such quantitative results with anatomy would generate a more reproducible description of the most effective stimulation sites. To test the reliability of the method, it was applied during postoperative follow-up examinations of 3 patients. To study the feasibility of intraoperative use, it was used during 9 bilateral DBS operations in patients suffering from PD. Changes in rigidity were calculated by extracting relevant outcome measures from the accelerometer data. These values were used to identify rigidity-suppressing stimulation current amplitudes, which were statistically compared with the amplitudes identified by the neurologist. Positions for the chronic DBS lead implantation that would have been chosen based on the acceleration data were compared with clinical choices. The data were also analyzed with respect to the anatomical location of the stimulating electrode. Outcome measures extracted from the accelerometer data were reproducible for the same evaluator, thus providing a reliable assessment of rigidity changes during intraoperative stimulation tests. Of the 188 stimulation sites analyzed, the number of sites where rigidity-suppressing amplitudes were found increased from 144 to 170 when the accelerometer evaluations were considered. In general, rigidity release could be observed at significantly lower amplitudes with accelerometer evaluation (mean 0.9 +/- 0.6 mA) than with subjective evaluation (mean 1.4 +/- 0.6 mA) (p > 0.001). Of 14 choices for the implant location of the DBS lead, only 2 were the same for acceleration-based and subjective evaluations. The comparison across anatomical locations showed that stimulation in the fields of Forel ameliorates rigidity at similar amplitudes as stimulation in the subthalamic nucleus, but with fewer side effects. This article describes and validates a new assistive method for assessing rigidity with acceleration sensors during intraoperative stimulation tests in DBS procedures. The initial results indicate that the proposed method may be a clinically useful aid for optimal DBS lead placement as well as a new tool in the ongoing scientific search for the optimal DBS target for PD