Directional Stimulation in Parkinson's Disease and Essential Tremor: The Cleveland Clinic Experience.

OBJECTIVE: To assess use of directional stimulation in Parkinson's disease and essential tremor patients programmed in routine clinical care. MATERIALS AND METHODS: Patients with Parkinson's disease or essential tremor implanted at Cleveland Clinic with a directional deep brain stimulation (DBS) system from November 2017 to October 2019 were included in this retrospective case series. Omnidirectional was compared against directional stimulation using therapeutic current strength, therapeutic window percentage, and total electrical energy delivered as outcome variables. RESULTS: Fifty-seven Parkinson's disease patients (36 males) were implanted in the subthalamic nucleus (105 leads) and 33 essential tremor patients (19 males) were implanted in the ventral intermediate nucleus of the thalamus (52 leads). Seventy-four percent of patients with subthalamic stimulation (65% of leads) and 79% of patients with thalamic stimulation (79% of leads) were programmed with directional stimulation for their stable settings. Forty-six percent of subthalamic leads and 69% of thalamic leads were programmed on single segment activation. There was no correlation between the length of microelectrode trajectory through the STN and use of directional stimulation. CONCLUSIONS: Directional programming was more common than omnidirectional programming. Substantial gains in therapeutic current strength, therapeutic window, and total electrical energy were found in subthalamic and thalamic leads programmed on directional stimulation.

New Frontiers for Deep Brain Stimulation: Directionality, Sensing Technologies, Remote Programming, Robotic Stereotactic Assistance, Asleep Procedures, and Connectomics.

Over the last few years, while expanding its clinical indications from movement disorders to epilepsy and psychiatry, the field of deep brain stimulation (DBS) has seen significant innovations. Hardware developments have introduced directional leads to stimulate specific brain targets and sensing electrodes to determine optimal settings via feedback from local field potentials. In addition, variable-frequency stimulation and asynchronous high-frequency pulse trains have introduced new programming paradigms to efficiently desynchronize pathological neural circuitry and regulate dysfunctional brain networks not responsive to conventional settings. Overall, these innovations have provided clinicians with more anatomically accurate programming and closed-looped feedback to identify optimal strategies for neuromodulation. Simultaneously, software developments have simplified programming algorithms, introduced platforms for DBS remote management via telemedicine, and tools for estimating the volume of tissue activated within and outside the DBS targets. Finally, the surgical accuracy has improved thanks to intraoperative magnetic resonance or computerized tomography guidance, network-based imaging for DBS planning and targeting, and robotic-assisted surgery for ultra-accurate, millimetric lead placement. These technological and imaging advances have collectively optimized DBS outcomes and allowed "asleep" DBS procedures. Still, the short- and long-term outcomes of different implantable devices, surgical techniques, and asleep vs. awake procedures remain to be clarified. This expert review summarizes and critically discusses these recent innovations and their potential impact on the DBS field.

Current Directions in Deep Brain Stimulation for Parkinson's Disease-Directing Current to Maximize Clinical Benefit.

Several single-center studies and one large multicenter clinical trial demonstrated that directional deep brain stimulation (DBS) could optimize the volume of tissue activated (VTA) based on the individual placement of the lead in relation to the target. The ability to generate axially asymmetric fields of stimulation translates into a broader therapeutic window (TW) compared to conventional DBS. However, changing the shape and surface of stimulating electrodes (directional segmented vs. conventional ring-shaped) also demands a revision of the programming strategies employed for DBS programming. Model-based approaches have been used to predict the shape of the VTA, which can be visualized on standardized neuroimaging atlases or individual magnetic resonance imaging. While potentially useful for optimizing clinical care, these systems remain limited by factors such as patient-specific anatomical variability, postsurgical lead migrations, and inability to account for individual contact impedances and orientation of the systems of fibers surrounding the electrode. Alternative programming tools based on the functional assessment of stimulation-induced clinical benefits and side effects allow one to collect and analyze data from each electrode of the DBS system and provide an action plan of ranked alternatives for therapeutic settings based on the selection of optimal directional contacts. Overall, an increasing amount of data supports the use of directional DBS. It is conceivable that the use of directionality may reduce the need for complex programming paradigms such as bipolar configurations, frequency or pulse width modulation, or interleaving. At a minimum, stimulation through directional electrodes can be considered as another tool to improve the benefit/side effect ratio. At a maximum, directionality may become the preferred way to program because of its larger TW and lower energy consumption.

Multi-modal imaging with specialized sequences improves accuracy of the automated subcortical grey matter segmentation.

The basal ganglia and limbic system, particularly the thalamus, putamen, internal and external globus pallidus, substantia nigra, and sub-thalamic nucleus, comprise a clinically relevant signal network for Parkinson's disease. In order to manually trace these structures, a combination of high-resolution and specialized sequences at 7 T are used, but it is not feasible to routinely scan clinical patients in those scanners. Targeted imaging sequences at 3 T have been presented to enhance contrast in a select group of these structures. In this work, we show that a series of atlases generated at 7 T can be used to accurately segment these structures at 3 T using a combination of standard and optimized imaging sequences, though no one approach provided the best result across all structures. In the thalamus and putamen, a median Dice Similarity Coefficient (DSC) over 0.88 and a mean surface distance <1.0 mm were achieved using a combination of T1 and an optimized inversion recovery imaging sequences. In the internal and external globus pallidus a DSC over 0.75 and a mean surface distance <1.2 mm were achieved using a combination of T1 and inversion recovery imaging sequences. In the substantia nigra and sub-thalamic nucleus a DSC of over 0.6 and a mean surface distance of <1.0 mm were achieved using the inversion recovery imaging sequence. On average, using T1 and optimized inversion recovery together significantly improved segmentation results than over individual modality (p < 0.05 Wilcoxon sign-rank test).

Confined Thalamic Deep Brain Stimulation in Refractory Essential Tremor.

BACKGROUND: Thalamic ventral intermediate nucleus (VIM) deep brain stimulation (DBS) is an effective therapy for medication-refractory essential tremor (ET). However, 13-40% of patients with an initially robust tremor efficacy lose this benefit over time despite reprogramming attempts. At our institution, a cohort of ET patients with VIM DBS underwent implantation of a second anterior (ventralis oralis anterior; VOA) DBS lead to permit "confined stimulation." We sought to assess whether confined stimulation conferred additional tremor capture compared to VIM or VOA stimulation alone. METHODS: Seven patients participated in a protocol-based programming session during which a video-recorded Fahn-Tolosa-Marin Part A (FTM-A) tremor rating scale was used in the following 4 DBS states: off stimulation, VIM stimulation alone, VOA stimulation alone, and dual lead (confined) stimulation. RESULTS: The average (SD) baseline FTM-A off score was 17.6 (4.0). VIM stimulation alone lowered the average FTM-A total score to 6.9 (4.0). Confined stimulation further attenuated the tremor, reducing the total score to 5.7 (2.8). CONCLUSIONS: Confined thalamic DBS can provide additional symptomatic benefits in patients with unsatisfactory tremor control from VIM or VOA stimulation alone.

Stereotactic EEG via multiple single-path omnidirectional trajectories within a single platform: institutional experience with a novel technique.

OBJECTIVEStereotactic electroencephalography (SEEG) is being used with increasing frequency to interrogate subcortical, cortical, and multifocal epileptic foci. The authors describe a novel technique for SEEG in patients with suspected epileptic foci refractory to medical management.METHODSIn the authors' technique, standard epilepsy evaluation and neuroimaging are used to create a hypothesis-driven SEEG plan, which informs the 3D printing of a novel single-path, multiple-trajectory, omnidirectional platform. Following skull-anchor platform fixation, electrodes are sequentially inserted according to the preoperative plan. The authors describe their surgical experience and technique based on a review of all cases, adult and pediatric, in which patients underwent invasive epilepsy monitoring via SEEG during an 18-month period at Vanderbilt University Medical Center. Platform and anatomical variables influencing localization error were evaluated using multivariate linear regression.RESULTSUsing this novel technology, 137 electrodes were inserted in 15 patients with focal epilepsy with favorable recording results and no clinical complications. The mean entry point localization error was 1.42 mm (SD 0.98 mm), and the mean target point localization error was 3.36 mm (SD 2.68 mm). Platform distance, electrode trajectory angle, and intracranial distance, but not skull thickness, were independently associated with localization error.CONCLUSIONSThe multiple-trajectory, single-path, omnidirectional platform offers satisfactory accuracy and favorable clinical results, while avoiding cumbersome frames and prohibitive up-front costs associated with other SEEG technologies.

Multi-Modal and Targeted Imaging Improves Automated Mid-Brain Segmentation.

The basal ganglia and limbic system, particularly the thalamus, putamen, internal and external globus pallidus, substantia nigra, and sub-thalamic nucleus, comprise a clinically relevant signal network for Parkinson's disease. In order to manually trace these structures, a combination of high-resolution and specialized sequences at 7T are used, but it is not feasible to scan clinical patients in those scanners. Targeted imaging sequences at 3T such as F-GATIR, and other optimized inversion recovery sequences, have been presented which enhance contrast in a select group of these structures. In this work, we show that a series of atlases generated at 7T can be used to accurately segment these structures at 3T using a combination of standard and optimized imaging sequences, though no one approach provided the best result across all structures. In the thalamus and putamen, a median Dice coefficient over 0.88 and a mean surface distance less than 1.0mm was achieved using a combination of T1 and an optimized inversion recovery imaging sequences. In the internal and external globus pallidus a Dice over 0.75 and a mean surface distance less than 1.2mm was achieved using a combination of T1 and F-GATIR imaging sequences. In the substantia nigra and sub-thalamic nucleus a Dice coefficient of over 0.6 and a mean surface distance of less than 1.0mm was achieved using the optimized inversion recovery imaging sequence. On average, using T1 and optimized inversion recovery together produced significantly improved segmentation results than any individual modality (p<0.05 wilcox sign-rank test).

Subthalamic Nucleus Deep Brain Stimulation Alters Prefrontal Correlates of Emotion Induction.

OBJECTIVES: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor symptoms in advanced Parkinson's disease. STN DBS may also affect emotion, possibly by impacting a parallel limbic cortico-striatal circuit. The objective of this study was to investigate changes in prefrontal cortical activity related to DBS during an emotion induction task. MATERIALS AND METHODS: We used near infrared spectroscopy to monitor prefrontal cortex hemodynamic changes during an emotion induction task. Seven DBS patients were tested sequentially in the stimulation-on and stimulation-off states while on dopaminergic medication. Patients watched a series of positive, negative, and neutral videos. The general linear model was used to compare prefrontal oxygenated hemoglobin concentration between DBS states. RESULTS: Deep brain stimulation was correlated with prefrontal oxygenated hemoglobin changes relative to the stimulation off state in response to both positive and negative videos. These changes were specific to emotional stimuli and were not seen during neutral stimuli. CONCLUSIONS: These results suggest that STN stimulation influences the prefrontal cortical representation of positive and negative emotion induction.

Variations in Thalamic Anatomy Affect Targeting in Deep Brain Stimulation for Epilepsy.

BACKGROUND: Thalamic size and shape vary significantly across patients - with changes specific to the anterior thalamus occurring with age and in the setting of chronic epilepsy. Such ambiguity raises concerns regarding electrode position and potential implications for seizure outcomes. METHODS: MRIs from 6 patients from a single center underwent quantitative analysis. In addition to direct measurements from postimplantation MRIs, the CRAnialVault Explorer suite was used to normalize electrode position to a common reference system. Relationships between thalamic dimensions, electrode location, and seizure outcome were analyzed. RESULTS: Although this study group was too small to sufficiently power statistical analysis, general trends were identified. There was a trend towards smaller thalamic volumes in nonresponders. Electrode locations demonstrated more variation after normalization. There was a trend towards a more lateral, posterior, and inferior electrode position in nonresponders. CONCLUSIONS: Variations in thalamic shape and volume necessitate direct targeting. Given that changes occur to thalamic anatomy with age and in the setting of epilepsy, improved methods for visualizing and targeting the anterior nucleus are necessary. Pronounced thalamic atrophy may preclude proper electrode placement and serve as a poor prognostic indicator. A greater understanding of thalamic anatomy and connectivity is necessary to optimize deep brain stimulation for epilepsy.

The Impact of Pallidal and Subthalamic Deep Brain Stimulation on Urologic Function in Parkinson's Disease.

OBJECTIVE: Deep Brain Stimulation (DBS) is an established adjunctive surgical intervention for treating Parkinson's disease (PD) motor symptoms. Both surgical targets, the globus pallidus interna (GPi) and subthalamic nucleus (STN), appear equally beneficial when treating motor symptoms but effects on nonmotor symptoms are not clear. Lower urinary tract symptoms (LUTS) are a common PD complaint. Given prior data in STN-DBS, we aimed to further explore potential benefits in LUTS in both targets. METHODS: We performed a prospective, nonblinded clinical trial evaluating LUTS in PD patients in both targets pre and post DBS using validated urologic surveys. Participants were already slated for DBS and target selection predetermined before study entry. LUTS was evaluated using: the American Urological Association (AUA-SI), Quality of Life score (QOL), Overactive Bladder 8 Questionnaire (OAB-q), and Sexual Health Inventory for Men (SHIM). RESULTS: Of 33 participants, 20 underwent STN DBS and 13 had GPi DBS. Patients demonstrated moderate baseline LUTS. The urologic QOL score significantly improved post DBS (3.24 ± 1.77vs. 2.52 ± 1.30; p = 0.03). Analyzed by target, only the STN showed significant change in QOL (3.20 ± 1.61 vs 2.25 ± 1.33; p = 0.04). There were no other significant differences in urologic scores post DBS noted in either target. CONCLUSION: In PD patients with moderate LUTS, there were notable improvements in QOL for LUTS post DBS in the total sample and STN target. There may be differences in DBS effects on LUTS between targets but this will require further larger, blinded studies.

On the Fallacy of Quantitative Segmentation for T1-Weighted MRI.

T1-weighted magnetic resonance imaging (MRI) generates contrasts with primary sensitivity to local T1 properties (with lesser T2 and PD contributions). The observed signal intensity is determined by these local properties and the sequence parameters of the acquisition. In common practice, a range of acceptable parameters is used to ensure "similar" contrast across scanners used for any particular study (e.g., the ADNI standard MPRAGE). However, different studies may use different ranges of parameters and report the derived data as simply "T1-weighted". Physics and imaging authors pay strong heed to the specifics of the imaging sequences, but image processing authors have historically been more lax. Herein, we consider three T1-weighted sequences acquired the same underlying protocol (MPRAGE) and vendor (Philips), but "normal study-to-study variation" in parameters. We show that the gray matter/white matter/cerebrospinal fluid contrast is subtly but systemically different between these images and yields systemically different measurements of brain volume. The problem derives from the visually apparent boundary shifts, which would also be seen by a human rater. We present and evaluate two solutions to produce consistent segmentation results across imaging protocols. First, we propose to acquire multiple sequences on a subset of the data and use the multi-modal imaging as atlases to segment target images any of the available sequences. Second (if additional imaging is not available), we propose to synthesize atlases of the target imaging sequence and use the synthesized atlases in place of atlas imaging data. Both approaches significantly improve consistency of target labeling.

Fully automated targeting using nonrigid image registration matches accuracy and exceeds precision of best manual approaches to subthalamic deep brain stimulation targeting in Parkinson disease.

BACKGROUND: Finding the optimal location for the implantation of the electrode in deep brain stimulation (DBS) surgery is crucial for maximizing the therapeutic benefit to the patient. Such targeting is challenging for several reasons, including anatomic variability between patients as well as the lack of consensus about the location of the optimal target. OBJECTIVE: To compare the performance of popular manual targeting methods against a fully automatic nonrigid image registration-based approach. METHODS: In 71 Parkinson disease subthalamic nucleus (STN)-DBS implantations, an experienced functional neurosurgeon selected the target manually using 3 different approaches: indirect targeting using standard stereotactic coordinates, direct targeting based on the patient magnetic resonance imaging, and indirect targeting relative to the red nucleus. Targets were also automatically predicted by using a leave-one-out approach to populate the CranialVault atlas with the use of nonrigid image registration. The different targeting methods were compared against the location of the final active contact, determined through iterative clinical programming in each individual patient. RESULTS: Targeting by using standard stereotactic coordinates corresponding to the center of the motor territory of the STN had the largest targeting error (3.69 mm), followed by direct targeting (3.44 mm), average stereotactic coordinates of active contacts from this study (3.02 mm), red nucleus-based targeting (2.75 mm), and nonrigid image registration-based automatic predictions using the CranialVault atlas (2.70 mm). The CranialVault atlas method had statistically smaller variance than all manual approaches. CONCLUSION: Fully automatic targeting based on nonrigid image registration with the use of the CranialVault atlas is as accurate and more precise than popular manual methods for STN-DBS.

CranialCloud: a cloud-based architecture to support trans-institutional collaborative efforts in neurodegenerative disorders.

PURPOSE: Neurological diseases have a devastating impact on millions of individuals and their families. These diseases will continue to constitute a significant research focus for this century. The search for effective treatments and cures requires multiple teams of experts in clinical neurosciences, neuroradiology, engineering, and industry. Hence, the need to communicate a large amount of information with accuracy and precision is more necessary than ever for this specialty. METHODS: In this paper, we present a distributed system that supports this vision, which we call the CranialVault Cloud (CranialCloud). It consists in a network of nodes, each with the capability to store and process data, that share the same spatial normalization processes, thus guaranteeing a common reference space. We detail and justify design choices, the architecture and functionality of individual nodes, the way these nodes interact, and how the distributed system can be used to support inter-institutional research. RESULTS: We discuss the current state of the system that gathers data for more than 1,600 patients and how we envision it to grow. CONCLUSION: We contend that the fastest way to find and develop promising treatments and cures is to permit teams of researchers to aggregate data, spatially normalize these data, and share them. The CranialVault system is a system that supports this vision.

Successful subthalamic nucleus deep brain stimulation therapy after significant lead displacement from a subdural hematoma.

A 57-year-old man with a 21 year history of Parkinson's disease underwent bilateral subthalamic nucleus deep brain stimulation (DBS) placement. One week postoperatively he developed an acute left subdural hematoma from a fall with significant displacement of the DBS leads. It was promptly evacuated, the patient slowly recovered neurologically, and the leads again moved near to the original position. Six months of stimulation therapy attained 50% reduction in symptoms. This case report demonstrates the movement of DBS leads due to brain shift and their ability to come back to previous location once the brain shift is corrected.

The optimal pallidal target in deep brain stimulation for dystonia: a study using a functional atlas based on nonlinear image registration.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus internus is established as efficacious for dystonia, yet the optimal target within this structure is not well defined. Published evidence suggests that spatial normalization provides a better estimate of DBS lead location than traditional methods based on standard stereotactic coordinates. METHODS: We retrospectively reviewed our pallidal implanted dystonia population. Patient imaging scans were morphed into an MRI atlas using a nonlinear image registration algorithm. Active contact locations were projected onto the atlas and clusters analyzed for the degree of variance in two groups: (1) good and poor responders and (2) cervical (CD) and generalized dystonia (GD). RESULTS: The average active contact location between CD and GD good responders was distinct but not significantly different. The mean active contact for CD poor responders was significantly different from CD responders and GD poor responders in the dorsoventral direction. CONCLUSIONS: A normalized imaging space is arguably more accurate in visualizing postoperative leads. Despite some separation between groups, this data suggests there was not an optimal pallidal target for common dystonia patients. Degrees of variance overlapped due to a large degree of individual target variation. Patient selection may ultimately be the key to maximizing patient outcomes.

Use of efficacy probability maps for the post-operative programming of deep brain stimulation in essential tremor.

INTRODUCTION: Post-operative programming of deep brain stimulation for movement disorders can be both time consuming and difficult, which can delay the optimal symptom control for the patient. Probabilistic maps of stimulation response could improve programming efficiency and optimization. METHODS: The clinically selected contacts of patients who had undergone ventral intermediate nucleus deep brain stimulation for the treatment of essential tremor at our institution were compared against contacts selected based on a probability map of symptom reduction built by populating data from a number of patients using non-rigid image registration. A subgroup of patients whose clinical contacts did not match the map-based selections prospectively underwent a tremor rating scale evaluation to compare the symptom relief achieved by the two options. Both the patient and video reviewer were blinded to the selection. RESULTS: 54% of the map-based and clinical contacts were an exact match retrospectively and were within one contact 83% of the time. In 5 of the 8 mismatched leads that were evaluated prospectively in a double blind fashion, the map-based contact showed equivalent or better tremor improvement than the clinically active contact. CONCLUSIONS: This study suggests that probability maps of stimulation responses can assist in selecting the clinically optimal contact and increase the efficiency of programming.

Multisurgeon, multisite validation of a trajectory planning algorithm for deep brain stimulation procedures.

Deep brain stimulation, which is used to treat various neurological disorders, involves implanting a permanent electrode into precise targets deep in the brain. Reaching these targets safely is difficult because surgeons have to plan trajectories that avoid critical structures and reach targets within specific angles. A number of systems have been proposed to assist surgeons in this task. These typically involve formulating constraints as cost terms, weighting them by surgical importance, and searching for optimal trajectories, in which constraints and their weights reflect local practice. Assessing the performance of such systems is challenging because of the lack of ground truth and clear consensus on an optimal approach among surgeons. Due to difficulties in coordinating inter-institution evaluation studies, these have been performed so far at the sites at which the systems are developed. Whether or not a scheme developed at one site can also be used at another is thus unknown. In this paper, we conduct a study that involves four surgeons at three institutions to determine whether or not constraints and their associated weights can be used across institutions. Through a series of experiments, we show that a single set of weights performs well for all surgeons in our group. Out of 60 trajectories, our trajectories were accepted by a majority of neurosurgeons in 95% of the cases and the average acceptance rate was 90%. This study suggests, albeit on a limited number of surgeons, that the same system can be used to provide assistance across multiple sites and surgeons.

Neurologist consistency in interpreting information provided by an interactive visualization software for deep brain stimulation postoperative programming assistance.

INTRODUCTION: Postoperative programming in deep brain stimulation (DBS) therapy for movement disorders can be challenging and time consuming. Providing the neurologist with tools to visualize the electrode location relative to the patient's anatomy along with models of tissue activation and statistical data can therefore be very helpful. In this study, we evaluate the consistency between neurologists in interpreting and using such information provided by our DBS programming assistance software. METHODS: Five neurologists experienced in DBS programming were each given a dataset of 29 leads implanted in 17 patients. For each patient, probabilistic maps of stimulation response, anatomical images, models of tissue activation volumes, and electrode positions were presented inside a software framework called CRAnialVault Explorer (CRAVE) developed in house. Consistency between neurologists in optimal contact selection using the software was measured. RESULTS: With only the efficacy map, the average consistency among the five neurologists with respect to the mode and mean of their selections was 97% and 95%, respectively, while these numbers were 93% and 89%, respectively, when both efficacy and an adverse effect map were used simultaneously. Fleiss' kappa statistic also showed very strong agreement among the neurologists (0.87 when using one map and 0.72 when using two maps). CONCLUSION: Our five neurologists demonstrated high consistency in interpreting information provided by the CRAVE interactive visualization software for DBS postoperative programming assistance. Three of our five neurologists had no prior experience with the software, which suggests that the software has a short learning curve and contact selection is not dependent on familiarity with the program tools.

Effect of data normalization on the creation of neuro-probabilistic atlases.

In the past 15 years, rapid improvements in imaging technology and methodology have had a tremendous impact on how we study the human brain. During deep brain stimulation surgeries, detailed anatomical images can be combined with physiological data obtained by microelectrode recordings and microstimulations to address questions relating to the location of specific motor or sensorial functions. The main advantage of techniques such as microelectrode recordings and microstimulations over brain imaging is their ability to localize patient physiological activity with a high degree of spatial resolution. Aggregating data acquired from large populations permits to build what are commonly referred to as statistical atlases. Data points from statistical atlases can be combined to produce probabilistic maps. A crucial step in this process is the intersubject spatial normalization that is required to relate a position in one subject's brain to a position in another subject's brain. In this paper, we study the impact of spatial normalization techniques on building statistical atlases. We find that the Talairach or anterior-posterior commissure coordinate system commonly used in the medical literature produces atlases that are more dispersed than those obtained with normalization methods that rely on nonlinear volumetric image registration. We also find that the maps produced using nonlinear techniques correlate with their expected anatomic positions.