Prefrontal Cortical Modulation of Motor and Non-Motor Functions in Parkinson's Disease

The prefrontal cortex is involved in various cognitive and affective functions. In neuropsychiatric conditions in which these functions are perturbed, such as Parkinson’s disease, prefrontal activity is not well characterized, in part due to methodological constraints that limit the ability to assess neural activity with high spatial and temporal resolution in humans. We utilized high resolution invasive neurophysiology in Parkinson’s patients undergoing awake, deep brain stimulation surgery to study the prefrontal cortex in Parkinson’s disease. In Chapter 1, we introduce Parkinson’s disease and circuit models of disease informed by invasive recordings. Next, we discuss two studies in which we used invasive recordings to characterize prefrontal activity during movement inhibition and during emotional face processing. In Chapter 2, we introduce evidence of a prefrontal hyperdirect pathway in humans, and we characterize its topography. We found broad prefrontal innervation, with a preferential localization of fast fibers in the inferior frontal cortex. We also show inferior frontal-subthalamic co-modulation during movement inhibition, providing evidence for human hyperdirect involvement in stopping. Finally, we discuss an exploratory study of prefrontal activity during emotional face processing, where we found that Parkinson’s disease is characterized by prefrontal hyperactivity (Chapter 3). These two studies expand our understanding of the prefrontal mechanisms of cognitive and affective functions in Parkinson’s disease

Lead-OR: A multimodal platform for deep brain stimulation surgery

Background: Deep brain stimulation (DBS) electrode implant trajectories are stereotactically defined using preoperative neuroimaging. To validate the correct trajectory, microelectrode recordings (MERs) or local field potential recordings can be used to extend neuroanatomical information (defined by MRI) with neurophysiological activity patterns recorded from micro- and macroelectrodes probing the surgical target site. Currently, these two sources of information (imaging vs. electrophysiology) are analyzed separately, while means to fuse both data streams have not been introduced. Methods: Here, we present a tool that integrates resources from stereotactic planning, neuroimaging, MER, and high-resolution atlas data to create a real-time visualization of the implant trajectory. We validate the tool based on a retrospective cohort of DBS patients (N = 52) offline and present single-use cases of the real-time platform. Results: We establish an open-source software tool for multimodal data visualization and analysis during DBS surgery. We show a general correspondence between features derived from neuroimaging and electrophysiological recordings and present examples that demonstrate the functionality of the tool. Conclusions: This novel software platform for multimodal data visualization and analysis bears translational potential to improve accuracy of DBS surgery. The toolbox is made openly available and is extendable to integrate with additional software packages

Creation of Computerized 3D MRI-Integrated Atlases of the Human Basal Ganglia and Thalamus

Functional brain imaging and neurosurgery in subcortical areas often requires visualization of brain nuclei beyond the resolution of current magnetic resonance imaging (MRI) methods. We present techniques used to create: (1) a lower resolution 3D atlas, based on the Schaltenbrand and Wahren print atlas, which was integrated into a stereotactic neurosurgery planning and visualization platform (VIPER); and (2) a higher resolution 3D atlas derived from a single set of manually segmented histological slices containing nuclei of the basal ganglia, thalamus, basal forebrain, and medial temporal lobe. Both atlases were integrated to a canonical MRI (Colin27) from a young male participant by manually identifying homologous landmarks. The lower resolution atlas was then warped to fit the MRI based on the identified landmarks. A pseudo-MRI representation of the high-resolution atlas was created, and a non-linear transformation was calculated in order to match the atlas to the template MRI. The atlas can then be warped to match the anatomy of Parkinson's disease surgical candidates by using 3D automated non-linear deformation methods. By way of functional validation of the atlas, the location of the sensory thalamus was correlated with stereotactic intraoperative physiological data. The position of subthalamic electrode positions in patients with Parkinson's disease was also evaluated in the atlas-integrated MRI space. Finally, probabilistic maps of subthalamic stimulation electrodes were developed, in order to allow group analysis of the location of contacts associated with the best motor outcomes. We have therefore developed, and are continuing to validate, a high-resolution computerized MRI-integrated 3D histological atlas, which is useful in functional neurosurgery, and for functional and anatomical studies of the human basal ganglia, thalamus, and basal forebrain

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

Caracterización beta, gamma y de oscilaciones de alta frecuencia para localización de diana en procedimientos de Estimulación Cerebral Profunda

Deep Brain Stimulation (DBS) has been successfully used to treat patients with Parkinson’s Disease. DBS employs an electrode that regulates the oscillatory activity of the basal ganglia, such as the subthalamic nucleus (STN). A critical point during the surgical implantation of such electrode is the precise localization of the target. This is done using presurgical images, stereotactic frames, and microelectrode recordings (MER). The latter allows neurophysiologists to visualize the electrical activity of different structures along the surgical track, each of them with well-defined variations in the frequency pattern; however, this is far from an automatic or semi-automatic method to help these specialists make decisions concerning the surgical target. To pave the way to automation, we analyzed three frequency bands in MER signals acquired from 11 patients undergoing DBS: beta (13-40 Hz), gamma (40-200 Hz), and high-frequency oscillations (HFO – 201-400 Hz). In this study, we propose and assess five indexes in order to detect the STN: variations in autoregressive parameters and their derivative along the surgical track, the energy of each band calculated using the Yule-Walker power spectral density, the high-to-low (H/L) ratio, and its derivative. We found that the derivative of one parameter of the beta band and the H/L ratio of the HFO/gamma bands produced errors in STN targeting like those reported in the literature produced by image-based methods (<2 mm). Although the indexes introduced here are simple to compute and could be applied in real time, further studies must be conducted to be able to generalize their results.La estimulación cerebral profunda (DBS por sus siglas en inglés) ha sido usada exitosamente en el tratamiento de pacientes con enfermedad de Párkinson. La DBS tiene un electrodo que regula la actividad oscilatoria de los ganglios basales involucrados, como el núcleo subtalámico (STN). Un aspecto crítico en el implante de dicho electrodo es la localización precisa de la diana quirúrgica. Esta se realiza mediante imágenes pre-quirúrgicas, marcos estereotácticos y registros de micro-electrodos (MER). Este último permite visualizar la actividad eléctrica de diferentes estructuras a través del recorrido quirúrgico, cada una de ellas con un patrón de variaciones bien definidas en frecuencia; sin embargo, esto dista de ser un método automático o semi-automático que ayude al neurofisiólogo a tomar decisiones en cuanto a la diana quirúrgica. Con el ánimo de contribuir a la automatización, analizamos tres bandas de frecuencias de señales MER adquiridas en 11 pacientes sometidos a DBS: beta (13-40 Hz), gamma (40-200 Hz) y oscilaciones de alta frecuencia (HFO – 201-400 Hz). Se propusieron y evaluaron 5 índices para detectar el STN: variaciones de parámetros auto-regresivos y su derivada a lo largo del recorrido quirúrgico, la energía de cada banda a partir de la densidad espectral de potencia mediante el método de Yule-Walker, la relación de frecuencias altas a bajas y su derivada. Encontramos que la derivada de un parámetro de la banda beta y la relación alta-bajas de las bandas HFO/gamma alcanzaron errores en la localización del STN, similares a los reportados en la literatura (<2mm). Aunque los índices propuestos son sencillos de calcular y de fácil implementación en tiempo real, se deben seguir explorando para incrementar la capacidad de generalización de los resultados obtenidos

Methodological considerations for neuroimaging in deep brain stimulation of the subthalamic nucleus in Parkinson’s disease patients

Deep brain stimulation (DBS) of the subthalamic nucleus is a neurosurgical intervention for Parkinson’s disease patients who no longer appropriately respond to drug treatments. A small fraction of patients will fail to respond to DBS, develop psychiatric and cognitive side-effects, or incur surgery-related complications such as infections and hemorrhagic events. In these cases, DBS may require recalibration, reimplantation, or removal. These negative responses to treatment can partly be attributed to suboptimal pre-operative planning procedures via direct targeting through low-field and low-resolution magnetic resonance imaging (MRI). One solution for increasing the success and efficacy of DBS is to optimize preoperative planning procedures via sophisticated neuroimaging techniques such as high-resolution MRI and higher field strengths to improve visualization of DBS targets and vasculature. We discuss targeting approaches, MRI acquisition, parameters, and post-acquisition analyses. Additionally, we highlight a number of approaches including the use of ultra-high field (UHF) MRI to overcome limitations of standard settings. There is a trade-off between spatial resolution, motion artifacts, and acquisition time, which could potentially be dissolved through the use of UHF-MRI. Image registration, correction, and post-processing techniques may require combined expertise of traditional radiologists, clinicians, and fundamental researchers. The optimization of pre-operative planning with MRI can therefore be best achieved through direct collaboration between researchers and clinicians