A literature review of magnetic resonance imaging sequence advancements in visualizing functional neurosurgery targets

OBJECTIVE: Historically, preoperative planning for functional neurosurgery has depended on the indirect localization of target brain structures using visible anatomical landmarks. However, recent technological advances in neuroimaging have permitted marked improvements in MRI-based direct target visualization, allowing for refinement of "first-pass" targeting. The authors reviewed studies relating to direct MRI visualization of the most common functional neurosurgery targets (subthalamic nucleus, globus pallidus, and thalamus) and summarize sequence specifications for the various approaches described in this literature. METHODS: The peer-reviewed literature on MRI visualization of the subthalamic nucleus, globus pallidus, and thalamus was obtained by searching MEDLINE. Publications examining direct MRI visualization of these deep brain stimulation targets were included for review. RESULTS: A variety of specialized sequences and postprocessing methods for enhanced MRI visualization are in current use. These include susceptibility-based techniques such as quantitative susceptibility mapping, which exploit the amount of tissue iron in target structures, and white matter attenuated inversion recovery, which suppresses the signal from white matter to improve the distinction between gray matter nuclei. However, evidence confirming the superiority of these sequences over indirect targeting with respect to clinical outcome is sparse. Future targeting may utilize information about functional and structural networks, necessitating the use of resting-state functional MRI and diffusion-weighted imaging. CONCLUSIONS: Specialized MRI sequences have enabled considerable improvement in the visualization of common deep brain stimulation targets. With further validation of their ability to improve clinical outcomes and advances in imaging techniques, direct visualization of targets may play an increasingly important role in preoperative planning

Autologous Peripheral Nerve Grafts to the Brain for the Treatment of Parkinson\u27s Disease

Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that aim to develop a disease-modifying therapy that slows the progression of PD. These clinical trials are evaluating the safety and feasibility of an autologous peripheral nerve graft to the substantia nigra in combination with Deep Brain Stimulation (DBS) for the treatment of PD. By grafting peripheral nerve tissue to the Substantia Nigra, the researchers aim to introduce peripheral nerve tissue, which is capable of functional regeneration after injury, to the degenerating Substantia Nigra of patients with PD. The central hypothesis of these clinical trials is that the grafted tissue will slow degeneration of the target brain region through neural repair actions of Schwann cells as well as other pro-regenerative features of the peripheral nerve tissue. This dissertation details analysis of the peripheral nerve tissue used in the above clinical trials with respect to tissue composition and gene expression, both of injury-naive human peripheral nerve as well as the post-conditioning injury nerve tissue used in the grafting procedure. RNA-seq analysis of sural nerve tissue pre and post-conditioning show significant changes in gene expression corresponding with transdifferentiation of Schwann cells from a myelinating to a repair phenotype, release of growth factors, activation of macrophages and other immune cells, and an increase in anti-apoptotic and neuroprotective gene transcripts. These results reveal in vivo gene expression changes involved in the human peripheral nerve injury repair process, which has relevance beyond this clinical trial to the fields of Schwann cell biology and peripheral nerve repair. To assess the neurobiology of the graft post-implantation we developed an animal model of the grafting procedure, termed Neuro-Avatars, which feature human graft tissue implanted into athymic nude rats. Survival and infiltration of human graft cells into the host brain were shown using immunohistochemistry of Human Nuclear Antigen. Surgical methods and outcomes from the ongoing development of this animal model are reported. To connect the results of these laboratory studies to the clinical trial we compared the severity of motor symptoms before surgery to one year post-surgery in patients who received the analyzed graft tissue. Motor symptom severity was assessed using the Unified Parkinson’s Disease Rating Scale Part III. Finally, the implications and future directions of this research is discussed. In summary, this dissertation advances the translational science cycle by using clinical trial findings and samples to answer basic science questions that will in turn guide future clinical trial design

Intraoperative anatomical navigation in asleep deep brain stimulation as a tool for the interpretation of microelectrode recordings: a prospective study

• Introduction: Microelectrode Recording (MER) is still regarded as a fundamental feature of Deep Brain Stimulation (DBS). In awake DBS, MERs are better characterized due to lack of sedation. During asleep DBS, general anesthesia interferes with MERs. Therefore, basing intraoperative lead localization in asleep DBS on extracellular recordings alone, requires huge expertise by the surgeon, who risks sub-optimal final electrode placement. This study aims to investigate whether anatomical navigation during asleep DBS surgery is a reliable and useful additional tool. The intraoperative association of anatomical (imaging studies and 3D reconstructions) and electrophysiological (microelectrode recordings) information would in fact permit a facilitated surgical procedure. • Methods/Materials: Patients enrolled in this study undergo asleep DBS in the Pediatric and Functional Neurosurgery Department of Padova. During surgery, intraoperative MERs are integrated with deterministic anatomical imaging of the structures crossed by the trajectory, obtained using a dedicated software. This allows to visualize exact anatomical relationships of each point along the trajectory of the lead with the 3D reconstructed areas of interest. For Subthalamic Nucleus (STN) DBS these areas include the thalamus, the zona incerta, the STN and the substantia nigra, whereas for Globus Pallidus Internus (GPi) DBS these include the striatum, GPe, GPi, and the optic tract. To investigate whether this feature of anatomical navigation is a reliable and helpful additional factor in the decision-making for the placement of the definitive electrode, we compare the intraoperatively planned electrode placement with the postoperatively reconstructed electrode position. • Results: Preliminary results show that the mean distance between the intraoperatively planned target and the postoperatively reconstructed target is <1 mm and the mean trajectory deviation <1°. There is a significant increase in target deviation between the first performed trajectory and the second one. This is coherent with the hypothesis that there’s an increase of brain shift as the procedure goes on due to intraoperative liquor loss. • Discussion: The study suggests that intraoperative anatomical navigation in DBS, using the dedicated software may be adequate for facilitated precise electrode placement, as there is no relevant difference between the intraoperatively planned electrode placement and the postoperatively reconstructed electrode position. • Conclusion: Preliminary results suggest that the anatomical navigation is a useful and reliable tool to significantly facilitate the interpretation of intraoperative MERs.• Introduction: Microelectrode Recording (MER) is still regarded as a fundamental feature of Deep Brain Stimulation (DBS). In awake DBS, MERs are better characterized due to lack of sedation. During asleep DBS, general anesthesia interferes with MERs. Therefore, basing intraoperative lead localization in asleep DBS on extracellular recordings alone, requires huge expertise by the surgeon, who risks sub-optimal final electrode placement. This study aims to investigate whether anatomical navigation during asleep DBS surgery is a reliable and useful additional tool. The intraoperative association of anatomical (imaging studies and 3D reconstructions) and electrophysiological (microelectrode recordings) information would in fact permit a facilitated surgical procedure. • Methods/Materials: Patients enrolled in this study undergo asleep DBS in the Pediatric and Functional Neurosurgery Department of Padova. During surgery, intraoperative MERs are integrated with deterministic anatomical imaging of the structures crossed by the trajectory, obtained using a dedicated software. This allows to visualize exact anatomical relationships of each point along the trajectory of the lead with the 3D reconstructed areas of interest. For Subthalamic Nucleus (STN) DBS these areas include the thalamus, the zona incerta, the STN and the substantia nigra, whereas for Globus Pallidus Internus (GPi) DBS these include the striatum, GPe, GPi, and the optic tract. To investigate whether this feature of anatomical navigation is a reliable and helpful additional factor in the decision-making for the placement of the definitive electrode, we compare the intraoperatively planned electrode placement with the postoperatively reconstructed electrode position. • Results: Preliminary results show that the mean distance between the intraoperatively planned target and the postoperatively reconstructed target is <1 mm and the mean trajectory deviation <1°. There is a significant increase in target deviation between the first performed trajectory and the second one. This is coherent with the hypothesis that there’s an increase of brain shift as the procedure goes on due to intraoperative liquor loss. • Discussion: The study suggests that intraoperative anatomical navigation in DBS, using the dedicated software may be adequate for facilitated precise electrode placement, as there is no relevant difference between the intraoperatively planned electrode placement and the postoperatively reconstructed electrode position. • Conclusion: Preliminary results suggest that the anatomical navigation is a useful and reliable tool to significantly facilitate the interpretation of intraoperative MERs

Striatal dopamine transporter availability and individual clinical course within the 1-year follow-up of deep brain stimulation of the subthalamic nucleus in patients with Parkinson’s disease

Objective: Degeneration of dopaminergic neurons in the substantia nigra projecting to the striatum is responsible for the motor symptoms in Parkinson’s disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established procedure to alleviate these symptoms in advanced PD. Yet the mechanism of action, especially the effects of STN-DBS on the availability of striatal dopamine transporter (DAT) as a marker of nigrostriatal nerve cell function, remains largely unknown. The aim of our study was therefore to evaluate whether 1) DAT availability changes within one year of STN-DBS and whether 2) the clinical outcome is predictable by DAT availability before surgical procedure (pre-op). Methods: Twenty-seven PD patients (age: 62.7 ± 8.9 years (y); duration of illness: 13.0 ± 4.9y; PD subtypes: akinetic-rigid n=11, equivalence n=13, tremor-dominant n=3) underwent [123I]FP-CIT single-photon emission computed tomography (SPECT) pre-op and one year after STN-DBS (post-op). DAT availability (specific-to-unspecific binding ratio, SBR) was assessed by volume of interest (VOI) analysis of the caudate nucleus and the putamen ipsilateral and contralateral to the clinically more affected side. Results: 1) Unified Parkinson’s Disease Rating Scale (UPDRS) III (pre-op on: on medication; pre-op off: off medication; post-op on/on: on medication/on stimulation; post-op on/off: on medication/off stimulation) improved significantly (pre-op on: 25.6 ± 12.3, pre-op off: 42.3 ± 15.2, post-op on/off: 41.4 ± 13.2; post-op on/on: 16.1 ± 9.4; pre-op on vs. post-op on/on: p = 0.006) while L-dopa equivalent daily dose (LEDD) was reduced (pre-op 957 ± 440 mg, post-op 313 ± 189 mg; p < 0.001). SBR did not differ significantly before and one year after DBS, regardless of PD subtypes. 2) Pre-op DAT availability was not related to the change in UPDRS III but the change in DAT availability was significantly correlated with the change in UPDRS III (contralateral head of the caudate VOI: p=0.014, contralateral putamen VOI: p=0.018). Conclusion Overall, DAT availability did not change significantly after one-year of STN-DBS. However, on an individual base, the improvement in UPDRS III was associated with an increase of DAT availability while DAT availability before STN-DBS surgery did not predict the clinical outcome. Whether a subtype-specific pattern of pre-op DAT availability can become a reliable predictor for successful STN-DBS has to be evaluated in larger study cohorts.:Introduction 2 1.1 Parkinson’s Disease Pathophysiology 2 1.2 Parkinson’s Disease Clinical Manifestation 4 1.2.1 Parkinson’s Disease Diagnosis 5 1.2.1.1 Unified Parkinson’s Disease Rating Scale 5 1.2.1.2 Imaging 6 1.2.2 Parkinson’s Disease Subtypes 6 1.3 Parkinson’s Disease Therapy 7 1.3.1 Pharmacologic Therapy 7 1.3.2 Surgical Therapy – Deep Brain Stimulation 9 1.3.2.1 Patient Selection 9 1.3.2.2 Operative Technique 9 1.3.2.3 Efficacy 10 1.3.2.4 Complications 11 1.3.2.5 Mechanism of action 11 2 Publication 15 3 Summary of Work 23 3.1 Background 23 3.2 DAT availability changes after STN-DBS 24 3.3 Pre-op DAT availability predicts the clinical outcome 25 3.4 DBS has a neuroprotective effect 25 3.5 Limitations and future direction 26 3.6 Conclusion 26 4 References 27 5 Attachments 35 5.1 Index of Abbreviations 35 5.2 List of figures 36 5.3 Academic Contribution 37 5.4 Declaration of the independent writing of this thesis 39 5.5 Declaration of Submission 40 5.6 Curriculum Vitae 41 5.7 Acknowledgements 4

3D FUNCTIONAL MODELING OF DBS EFFICACY AND DEVELOPMENT OF ANALYTICAL TOOLS TO EXPLORE FUNCTIONAL STN

Introduction: Exploring the brain for optimal locations for deep brain stimulation (DBS) therapy is a challenging task, which can be facilitated by analysis of DBS efficacy in a large number of patients with Parkinson’s disease (PD). The Unified Parkinson\u27s Disease Rating Scale (UPDRS) scores indicate the DBS efficacy of the corresponding stimulation location in a particular patient. The spatial distribution of these clinical scores can be used to construct a functional model which closely models the expected efficacy of stimulation in the region. Designs and Methods: In this study, different interpolation techniques were investigated that can appropriately model the DBS efficacy for Parkinson’s disease patients. These techniques are linear triangulation based interpolation, ‘roving window’ interpolation and ‘Monopolar inverse weighted distance’ (MIDW) interpolation. The MIDW interpolation technique is developed on the basis of electric field geometry of the monopolar DBS stimulation electrodes, based on the DBS model of monopolar cathodic stimulation of brain tissues. Each of these models was evaluated for their predictability, interpolation accuracy, as well as other benefits and limitations. The bootstrapping based optimization method was proposed to minimize the observational and patient variability in the collected database. A simulation study was performed to validate that the statistically optimized interpolated models were capable to produce reliable efficacy contour plots and reduced false effect due to outliers. Some additional visualization and analysis tools including a graphic user interface (GUI) were also developed for better understanding of the scenario. Results: The interpolation performance of the MIDW interpolation, the linear triangulation method and Roving window method was evaluated as interpolation error as 0.0903, 0.1219 and0.3006 respectively. Degree of prediction for the above methods was found to be 0.0822, 0.2986 and 0.0367 respectively. The simulation study demonstrate that the mean improvement in outlier handling and increased reliability after bootstrapping based optimization (performed on Linear triangulation interpolation method) is 6.192% and 12.8775% respectively. The different interpolation techniques used to model monopolar and bipolar stimulation data is found to be useful to study the corresponding efficacy distribution. A user friendly GUI (PDRP_GUI) and other utility tools are developed. Conclusion: Our investigation demonstrated that the MIDW and linear triangulation methods provided better degree of prediction, whereas the MIDW interpolation with appropriate configuration provided better interpolation accuracy. The simulation study suggests that the bootstrapping-based optimization can be used as an efficient tool to reduce outlier effects and increase interpolated reliability of the functional model of DBS efficacy. Additionally, the differential interpolation techniques used for monopolar and bipolar stimulation modeling facilitate study of overall DBS efficacy using the entire dataset

Imaging the subthalamic nucleus in Parkinson’s disease

This thesis is comprised of a set of work that aims to visualize and quantify the anatomy, structural variability, and connectivity of the subthalamic nucleus (STN) with optimized neuroimaging methods. The study populations include both healthy cohorts and individuals living with Parkinson's disease (PD). PD was chosen specifically due to the involvement of the STN in the pathophysiology of the disease. Optimized neuroimaging methods were primarily obtained using ultra-high field (UHF) magnetic resonance imaging (MRI). An additional component of this thesis was to determine to what extent UHF-MRI can be used in a clinical setting, specifically for pre-operative planning of deep brain stimulation (DBS) of the STN for patients with advanced PD. The thesis collectively demonstrates that i, MRI research, and clinical applications must account for the different anatomical and structural changes that occur in the STN with both age and PD. ii, Anatomical connections involved in preparatory motor control, response inhibition, and decision-making may be compromised in PD. iii. The accuracy of visualizing and quantifying the STN strongly depends on the type of MR contrast and voxel size. iv, MRI at a field strength of 3 Tesla (T) can under certain circumstances be optimized to produce results similar to that of 7 T at the expense of increased acquisition time

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