Kristina Zeljic

A Remote and Wireless Deep Brain Stimulation Programming System.

To the Editor: The success of deep brain stimulation generally depends on a good grasp of surgical indications, precise implantation of electrodes, and the optimal adjustment of programmable parameters (1). Programming settings are modified through contact selection, pulse width, frequency, and amplitude, to achieve optimal control of clinical symptoms with minimal stimulation parameters. Hence, programming is a crucial aspect of DBS, which directly influences its therapeutic efficacy (2). DBS patients are typically required to undergo three stages of programming: intraoperative, initial postoperative, and follow-up postoperative. Intraoperative programming is intended to test the physical connectivity (impedance) of the DBS system and the clinical efficacy of DBS, thereby providing indirect evidence of accurate electrode placement (3,4). The goal of initial postoperative programming is to identify the minimal stimulation parameters needed to achieve optimal control of clinical symptoms. The purpose of followup postoperative programming is to perform appropriate adjustments to stimulation parameters according to changes in the patient’s condition, including disease progression and suboptimal symptom control due to medication adjustments. Different programming requirements exist at different programming stages. Intraoperative programming time should be minimized to reduce total operation time, while the surgical procedure should be adapted to minimize risk of infection caused by programming. For initial postoperative programming, the time needed to ascertain optimum stimulation parameters should also be minimized, and reasonable arrangement of numerous patients’ programming schedules must be organized. Finally, follow-up postoperative programming should maximize patient convenience by reducing the time and financial cost of travelling between the patient’s home and the hospital. There are a number of inadequacies in conventional programming methods. First, the programming probe must come into close contact with the implantable pulse generator (IPG) and test stimulator to complete programming. However, the probe is not sterile during intraoperative programming and must therefore be wrapped in a sterile plastic bag before it can be attached to the IPG. Furthermore, when measuring the physical connectivity of the DBS product, the surgeon must pause the surgery and make room for the attachment between the programming probe and IPG. During initial postoperative programming, only the parameters of one patient can be ascertained. In addition, the same frequency is typically used in the left and right brain for dual channel IPG. During follow-up postoperative programming, the patient must repeatedly travel between their home and the hospital, leading to increased time and expense. An ideal solution to the outlined issues lies in wireless and remote programming technology. With this technology, the need for an additional probe is eliminated, as is the need for close contact, thus significantly reducing the risk of infection. Furthermore, all patients awaiting programming can be simultaneously identified, and programming a single patient only requires switching within the patient list. Data from multiple groups can also be stored. In addition, the technology offers remote follow-up capabilities. It is therefore convenient, time-saving, and economical for patients. To address the outlined issues, we developed the SceneRay wireless and remote DBS system. This system has significant advantages across all three stages of programming compared to conventional programming methods. Patient convenience is markedly improved, while risk of infection and total treatment time are minimized, thereby leading to an overall benefit for doctors and patients alike.

Dynamic Network Communication in the Human Functional Connectome Predicts Perceptual Variability in Visual Illusion

Ubiquitous variability between individuals in visual perception is difficult to standardize and has thus essentially been ignored. Here we construct a quantitative psychophysical measure of illusory rotary motion based on the Pinna-Brelstaff figure (PBF) in 73 healthy volunteers and investigate the neural circuit mechanisms underlying perceptual variation using functional magnetic resonance imaging (fMRI). We acquired fMRI data from a subset of 42 subjects during spontaneous and 3 stimulus conditions: expanding PBF, expanding modified-PBF (illusion-free) and expanding modified-PBF with physical rotation. Brain-wide graph analysis of stimulus-evoked functional connectivity patterns yielded a functionally segregated architecture containing 3 discrete hierarchical networks, commonly shared between rest and stimulation conditions. Strikingly, communication efficiency and strength between 2 networks predominantly located in visual areas robustly predicted individual perceptual differences solely in the illusory stimulus condition. These unprecedented findings demonstrate that stimulus-dependent, not spontaneous, dynamic functional integration between distributed brain networks contributes to perceptual variability in humans.

Dissociable Changes of Frontal and Parietal Cortices in Inherent Functional Flexibility across the Human Life Span.

Extensive evidence suggests that frontoparietal regions can dynamically update their pattern of functional connectivity, supporting cognitive control and adaptive implementation of task demands. However, it is largely unknown whether this flexibly functional reconfiguration is intrinsic and occurs even in the absence of overt tasks. Based on recent advances in dynamics of resting-state functional resonance imaging (fMRI), we propose a probabilistic framework in which dynamic reconfiguration of intrinsic functional connectivity between each brain region and others can be represented as a probability distribution. A complexity measurement (i.e., entropy) was used to quantify functional flexibility, which characterizes heterogeneous connectivity between a particular region and others over time. Following this framework, we identified both functionally flexible and specialized regions over the human life span (112 healthy subjects from 13 to 76 years old). Across brainwide regions, we found regions showing high flexibility mainly in the higher-order association cortex, such as the lateral prefrontal cortex (LPFC), lateral parietal cortex, and lateral temporal lobules. In contrast, visual, auditory, and sensory areas exhibited low flexibility. Furthermore, we observed that flexibility of the right LPFC improved during maturation and reduced due to normal aging, with the opposite occurring for the left lateral parietal cortex. Our findings reveal dissociable changes of frontal and parietal cortices over the life span in terms of inherent functional flexibility. This study not only provides a new framework to quantify the spatiotemporal behavior of spontaneous brain activity, but also sheds light on the organizational principle behind changes in brain function across the human life span. SIGNIFICANCE STATEMENT Recent neuroscientific research has demonstrated that the human capability of adaptive task control is primarily the result of the flexible operation of frontal brain networks. However, it remains unclear whether this flexibly functional reconfiguration is intrinsic and occurs in the absence of an overt task. In this study, we propose a probabilistic framework to quantify the functional flexibility of each brain region using resting-state fMRI. We identify regions showing high flexibility mainly in the higher-order association cortex. In contrast, primary and unimodal visual and sensory areas show low flexibility. On the other hand, our findings reveal dissociable changes of frontal and parietal cortices in terms of inherent functional flexibility over the life span.

Remotely Programmed Deep Brain Stimulation of the Bilateral Subthalamic Nucleus for the Treatment of Primary Parkinson Disease: A Randomized Controlled Trial Investigating the Safety and Efficacy of a Novel Deep Brain Stimulation System.

Background: Deep brain stimulation (DBS) is the most commonly performed surgery for the debilitating symptoms of Parkinson disease (PD). However, DBS systems remain largely unaffordable to patients in developing countries, warranting the development of a safe, economically viable, and functionally comparable alternative. Objective: To investigate the efficacy and safety of wirelessly programmed DBS of bilateral subthalamic nucleus (STN) in patients with primary PD. Methods: Sixty-four patients with primary PD were randomly divided into test and control groups (1:1), where DBS was initiated at either 1 month or 3 months, respectively, after surgery. Safety and efficacy of the treatment were compared between on- and off-medication states 3 months after surgery. Outcome measures included analysis of Unified Parkinsons Disease Rating Scale (UPDRS) scores, duration of “on” periods, and daily equivalent doses of levodopa. All patients were followed up both 6 and 12 months after surgery. Results: Three months after surgery, significant decrease in the UPDRS motor scores were observed for the test group in the off-medication state (25.08 ± 1.00) versus the control group (4.20 ± 1.99). Conclusions: Bilateral wireless programming STN-DBS is safe and effective for patients with primary PD in whom medical management has failed to restore motor function.

Effects of Anterior Capsulotomy on Decision Making in Patients with Refractory Obsessive–Compulsive Disorder

Despite various lines of evidence implicating impaired decision-making ability in individuals with obsessive–compulsive disorder (OCD), neuropsychological investigation has generated inconsistent findings. Although the cortico-striato-thalamo-cortical (CSTC) circuitry has been suggested, the involvement of the cortex has not yet been fully demonstrated. Moreover, it is unknown whether surgical intervention on the CSTC circuitry results in a predicted improvement of decision-making ability of OCD. Here we present a study of decision making based on the Iowa Gambling Task (IGT) to investigate decision making in a large sample of individuals with treatment-resistant OCD with and without anterior capsulotomy (AC). Task performance was evaluated in healthy subjects, individuals with OCD that had not undergone surgery, and postsurgical OCD patients with AC. The latter group was further divided into a short-term postsurgical group and a long-term postsurgical group. We found that the OCD patients without surgery performed significantly worse than the healthy controls on the IGT. There were no significant differences in decision-making between the presurgical OCD patients and those at the short-term postsurgical follow-up. Decision-making ability of the long-term postsurgical OCD patients was improved to the level comparable to that of healthy controls. All clinical symptoms (OCD, depression, and anxiety) assessed by psychiatric rating scales were significantly alleviated post-surgically, but exhibited no correlation with their IGT task performance. Our findings provide strong evidence that OCD is linked to impairments in decision-making ability; that impaired CSTC circuitry function is directly involved in the manifestation of OCD; and that AC related improvements in cognitive functions are caused by long-term plasticity in the brain circuitry.

The safety issues and hardware-related complications of deep brain stimulation therapy: a single-center retrospective analysis of 478 patients with Parkinson’s disease

Introduction Deep brain stimulation (DBS) is a well-established therapy for the treatment of advanced Parkinson’s disease (PD) in patients experiencing motor fluctuations and medication-refractory tremor. Despite the relative tolerability and safety of this procedure, associated complications and unnatural deaths are still unavoidable. Methods In this study, hardware-related complications and the causes of unnatural death were retrospectively analyzed in 478 patients with PD who were treated with DBS. Results The results showed a 3-year survival rate of 98.6% and a 5-year survival rate of 96.4% for patients with PD who underwent DBS treatment at the study center. Pneumonia was the cause of death with the highest frequency. Prophylactic antibiotics and steroids or antihistamine drugs were adopted to reduce the risk of infection. Twenty-two patients (4.6%) experienced hardware-related complications. Conclusion Deaths of PD patients who receive DBS are typically unrelated to the disease itself or complications associated with the surgery. Pneumonia, malignant tumors, asphyxia, and multiple-organ failure are the common causes of death. Swallowing-related problems may be the most important clinical symptom in late-stage PD, as they cannot be stabilized or improved by DBS alone, and are potentially lethal. Although prophylactic antibiotics and steroids or antihistamine drugs may reduce the risk of infection, it is imperative to identify high-risk patients for whom a therapeutic approach not requiring an implantable device is more suitable, for example, pallidotomy and potentially transcranial ultrasound.

Failure in Cognitive Suppression of Negative Affect in Adolescents with Generalized Anxiety Disorder

Hyperactivity of limbic (e.g., amygdalar) responses to negative stimuli has been implicated in the pathophysiology of generalized anxiety disorder (GAD). Evidence has also suggested that even a simple cognitive task involving emotionally salient stimuli can modulate limbic and prefrontal neural activation. However, whether neural modulation of emotional stimulus processing in a cognitive task is defective in adolescents with GAD has not yet been investigated. In this study, 20 adolescents with GAD and 14 comparable healthy controls underwent event-related functional magnetic resonance imaging (fMRI) coupled with an emotional valence evaluation task. During the evaluation of negative versus neutral stimuli, we found significant activation of the right inferior frontal gyrus (IFG) in healthy controls, while the bilateral amygdala was activated in GAD patients. Between-group analyses showed dramatically reduced task-activation of the right IFG in GAD patients, and the magnitude of IFG activity negatively correlated with symptom severity. Psychophysiological interaction analysis further revealed significantly decreased functional interaction between right IFG and anterior cingulate cortex and ventromedial prefrontal cortex in GAD patients compared with healthy controls. Taken together, our findings show failure to suppress negative affect by recruiting a cognitive distraction in adolescents with GAD, providing new insights into the pathophysiology of GAD.

Divergent Structural Responses to Pharmacological Interventions in Orbitofronto-Striato-Thalamic and Premotor Circuits in Obsessive-Compulsive Disorder

Prior efforts to dissect etiological and pharmacological modulations in brain morphology in obsessive-compulsive disorder (OCD) are often undermined by methodological and sampling constraints, yielding conflicting conclusions and no reliable neuromarkers. Here we evaluated alteration of regional gray matter volume including effect size (Cohens d value) in 95 drug-naïve patients (age range: 18–55) compared to 95 healthy subjects (age: 18–63), then examined pharmacological effects in 65 medicated (age: 18–57) and 73 medication-free patients (age: 18–61). Robustness of statistical outcomes and effect sizes was rigorously tested with Monte Carlo cross-validation. Relative to controls, both drug-naïve and medication-free patients exhibited comparable volumetric increases mainly in the left thalamus (d = 0.90, 0.82, respectively), left ventral striatum (d = 0.88, 0.67), bilateral medial orbitofrontal cortex (d = 0.86, 0.71; 0.90, 0.73), and left inferior temporal gyrus (d = 0.83, 0.66), and decreased volumes in left premotor/presupplementary motor areas (d = − 0.83, − 0.71). Interestingly, abnormalities in the thalamus and medial orbitofrontal cortex were present in medicated patients whereas entirely absent in premotor and ventral striatum. It suggests that pharmacotherapy elicited divergent responses in orbitofronto-striato-thalamic and premotor circuits, which warrants the design of longitudinal studies investigating the potential of these neuromarkers in stratified treatments of OCD.

Discriminative Structured Feature Engineering for Macroscale Brain Connectomes

Neuroimaging techniques can measure structural and functional brain connectivity with unprecedented detail in vivo. This so-called brain connectome can be represented as high dimensional matrices corresponding to edge weights in graphs. After measuring the matrices of two cohorts (i.e., patients and healthy controls), one is often required to formulate computational network models for effective feature engineering to draw discriminative distinctions between the cohorts, as well as estimate the associated statistical significance. We designed a novel method to reveal the intrinsic features of functional matrices of discriminative power for group comparison. More specifically, by encouraging co-selection of edges connected to the same node, we preserved the discriminative edges to maximum extent. To reduce the false positive rate of the extracted discriminative edges, an optimization procedure was developed to evaluate the significance of these edges and remove trivial ones. We validated the proposed method using both synthetic data and real benchmarks, and compared it to l1 regularized logistic regression, univariate t-test and stability selection. The experimental results clearly showed that the proposed approach outperformed the three competing methods under various settings. In addition to increasing the F-measure of feature selection, our approach captured the endogenous, discriminative connectivity patterns consistent with recent findings in biomedical literature. This data-driven method paves a new avenue of enquiry into the inherent nature of network models for functional brain connectomes.