Publications by authors named "Philip A Starr"

148 Publications

Long-term wireless streaming of neural recordings for circuit discovery and adaptive stimulation in individuals with Parkinson's disease.

Nat Biotechnol 2021 May 3. Epub 2021 May 3.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.

Neural recordings using invasive devices in humans can elucidate the circuits underlying brain disorders, but have so far been limited to short recordings from externalized brain leads in a hospital setting or from implanted sensing devices that provide only intermittent, brief streaming of time series data. Here, we report the use of an implantable two-way neural interface for wireless, multichannel streaming of field potentials in five individuals with Parkinson's disease (PD) for up to 15 months after implantation. Bilateral four-channel motor cortex and basal ganglia field potentials streamed at home for over 2,600 h were paired with behavioral data from wearable monitors for the neural decoding of states of inadequate or excessive movement. We validated individual-specific neurophysiological biomarkers during normal daily activities and used those patterns for adaptive deep brain stimulation (DBS). This technological approach may be widely applicable to brain disorders treatable by invasive neuromodulation.
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http://dx.doi.org/10.1038/s41587-021-00897-5DOI Listing
May 2021

Are preoperative chlorhexidine gluconate showers associated with a reduction in surgical site infection following craniotomy? A retrospective cohort analysis of 3126 surgical procedures.

J Neurosurg 2021 Apr 30:1-9. Epub 2021 Apr 30.

Departments of1Neurological Surgery.

Objective: Surgical site infection (SSI) is a complication linked to increased costs and length of hospital stay. Prevention of SSI is important to reduce its burden on individual patients and the healthcare system. The authors aimed to assess the efficacy of preoperative chlorhexidine gluconate (CHG) showers on SSI rates following cranial surgery.

Methods: In November 2013, a preoperative CHG shower protocol was implemented at the authors' institution. A total of 3126 surgical procedures were analyzed, encompassing a time frame from April 2012 to April 2016. Cohorts before and after implementation of the CHG shower protocol were evaluated for differences in SSI rates.

Results: The overall SSI rate was 0.6%. No significant differences (p = 0.11) were observed between the rate of SSI of the 892 patients in the preimplementation cohort (0.2%) and that of the 2234 patients in the postimplementation cohort (0.8%). Following multivariable analysis, implementation of preoperative CHG showers was not associated with decreased SSI (adjusted OR 2.96, 95% CI 0.67-13.1; p = 0.15).

Conclusions: This is the largest study, according to sample size, to examine the association between CHG showers and SSI following craniotomy. CHG showers did not significantly alter the risk of SSI after a cranial procedure.
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http://dx.doi.org/10.3171/2020.10.JNS201255DOI Listing
April 2021

The Neurophysiology of Sleep in Parkinson's Disease.

Mov Disord 2021 Jul 7;36(7):1526-1542. Epub 2021 Apr 7.

Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

Sleep disturbances are among the most common nonmotor complications of Parkinson's disease (PD), can present in prodromal stages, and progress with advancing disease. In addition to being a symptom of neurodegeneration, sleep disturbances may also contribute to disease progression. Currently, limited options exist to modulate sleep disturbances in PD. Studying the neurophysiological changes that affect sleep in PD at the cortical and subcortical level may yield new insights into mechanisms for reversal of sleep disruption. In this article, we review cortical and subcortical recording studies of sleep in PD with a particular focus on dissecting reported electrophysiological changes. These studies show that slow-wave sleep and rapid eye movement sleep are both notably disrupted in PD. We further explore the impact of these electrophysiological changes and discuss the potential for targeting sleep via stimulation therapy to modify PD-related motor and nonmotor symptoms. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28562DOI Listing
July 2021

Image-based biophysical modeling predicts cortical potentials evoked with subthalamic deep brain stimulation.

Brain Stimul 2021 May-Jun;14(3):549-563. Epub 2021 Mar 20.

Department of Neurology, Emory University, USA. Electronic address:

Background: Subthalamic deep brain stimulation (DBS) is an effective surgical treatment for Parkinson's disease and continues to advance technologically with an enormous parameter space. As such, in-silico DBS modeling systems have become common tools for research and development, but their underlying methods have yet to be standardized and validated.

Objective: Evaluate the accuracy of patient-specific estimates of neural pathway activations in the subthalamic region against intracranial, cortical evoked potential (EP) recordings.

Methods: Pathway activations were modeled in eleven patients using the latest advances in connectomic modeling of subthalamic DBS, focusing on the hyperdirect pathway (HDP) and corticospinal/bulbar tract (CSBT) for their relevance in human research studies. Correlations between pathway activations and respective EP amplitudes were quantified.

Results: Good model performance required accurate lead localization and image fusions, as well as appropriate selection of fiber diameter in the biophysical model. While optimal model parameters varied across patients, good performance could be achieved using a global set of parameters that explained 60% and 73% of electrophysiologic activations of CSBT and HDP, respectively. Moreover, restricted models fit to only EP amplitudes of eight standard (monopolar and bipolar) electrode configurations were able to extrapolate variation in EP amplitudes across other directional electrode configurations and stimulation parameters, with no significant reduction in model performance across the cohort.

Conclusions: Our findings demonstrate that connectomic models of DBS with sufficient anatomical and electrical details can predict recruitment dynamics of white matter. These results will help to define connectomic modeling standards for preoperative surgical targeting and postoperative patient programming applications.
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http://dx.doi.org/10.1016/j.brs.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164987PMC
March 2021

CT and MRI Image Fusion Error: An Analysis of Co-Registration Error Using Commercially Available Deep Brain Stimulation Surgical Planning Software.

Stereotact Funct Neurosurg 2021 3;99(3):196-202. Epub 2021 Feb 3.

Department of Neurological Surgery, University of California, San Francisco, California, USA.

Introduction: During deep brain stimulation (DBS) surgery, computed tomography (CT) and magnetic resonance imaging (MRI) scans need to be co-registered or fused. Image fusion is associated with the error that can distort the location of anatomical structures. Co-registration in DBS surgery is usually performed automatically by proprietary software; the amount of error during this process is not well understood. Here, our goal is to quantify the error during automated image co-registration with FrameLink™, a commonly used software for DBS planning and clinical research.

Methods: This is a single-center retrospective study at a quaternary care referral center, comparing CT and MR imaging co-registration for a consecutive series of patients over a 12-month period. We collected CT images and MRI scans for 22 patients with Parkinson's disease requiring placement of DBS. Anatomical landmarks were located on CT images and MRI scans using a novel image analysis algorithm that included a method for capturing the potential error inherent in the image standardization step of the analysis. The distance between the anatomical landmarks was measured, and the error was found by averaging the distances across all patients.

Results: The average error during co-registration was 1.25 mm. This error was significantly larger than the error resulting from image standardization (0.19 mm) and was worse in the anterior-posterior direction.

Conclusions: The image fusion errors found in this analysis were nontrivial. Although the estimated error may be inflated, it is sig-nificant enough that users must be aware of this potential inaccuracy, and developers of proprietary software should provide details about the magnitude and direction of co-registration errors.
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http://dx.doi.org/10.1159/000511114DOI Listing
February 2021

A Qualitative Analysis of Ethical Perspectives on Recruitment and Consent for Human Intracranial Electrophysiology Studies.

AJOB Neurosci 2021 01;12(1):57-67

University of California.

Intracranial electrophysiological research methods, including those applying electrodes on the cortical surface or in deep structures, have become increasingly important in human neuroscience. They also pose novel ethical concerns, as human studies require the participation of neurological patients undergoing surgery for conditions such as epilepsy and Parkinson's disease. Research participants in this setting may be vulnerable to conflicts of interest, therapeutic misconception, and other threats to valid recruitment and consent. We conducted semi-structured interviews with investigators from NIH-funded studies involving recording or stimulation inside the human skull. We elicited perspectives on study recruitment and consent procedures, and analyzed transcripts using a modified grounded theory approach. We interviewed 26 investigators from 19 separate intracranial electrophysiology studies, who described two study types: opportunity studies ( = 15) and experimental trials ( = 4). Respondents described significant heterogeneity in recruitment and consent procedures, even among studies employing similar techniques. In some studies, clinician-investigators were specifically barred from obtaining consent, while in other studies clinician-investigators were specifically required to obtain consent; regulatory guidance was inconsistent. Respondents also described various models for subject selection, the timing of consent, and continuing consent for temporally extended studies. Respondents expressed ethical concerns about participants' vulnerability and the communication of research-related risks. We found a lack of consensus among investigators regarding recruitment and consent methods in human intracranial electrophysiology. This likely reflects the novelty and complexity of such studies and indicates a need for further discussion and development of best practices in this research domain.
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http://dx.doi.org/10.1080/21507740.2020.1866098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168380PMC
January 2021

Thalamic deep brain stimulation for acquired dystonia in children and young adults: a phase 1 clinical trial.

J Neurosurg Pediatr 2020 Nov 27:1-10. Epub 2020 Nov 27.

1Department of Neurology, Weill Institute for Neurosciences, and.

Objective: The aim of this study was to evaluate the feasibility and preliminary efficacy and safety of combined bilateral ventralis oralis posterior/ventralis intermedius (Vop/Vim) deep brain stimulation (DBS) for the treatment of acquired dystonia in children and young adults. Pallidal DBS is efficacious for severe, medication-refractory isolated dystonia, providing 50%-60% long-term improvement. Unfortunately, pallidal stimulation response rates in acquired dystonia are modest and unpredictable, with frequent nonresponders. Acquired dystonia, most commonly caused by cerebral palsy, is more common than isolated dystonia in pediatric populations and is more recalcitrant to standard treatments. Given the limitations of pallidal DBS in acquired dystonia, there is a need to explore alternative brain targets. Preliminary evidence has suggested that thalamic stimulation may be efficacious for acquired dystonia.

Methods: Four participants, 3 with perinatal brain injuries and 1 with postencephalitic symptomatic dystonia, underwent bilateral Vop/Vim DBS and bimonthly evaluations for 12 months. The primary efficacy outcome was the change in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Barry-Albright Dystonia Scale (BADS) scores between the baseline and 12-month assessments. Video documentation was used for blinded ratings. Secondary outcomes included evaluation of spasticity (Modified Ashworth Scale score), quality of life (Pediatric Quality of Life Inventory [PedsQL] and modified Unified Parkinson's Disease Rating Scale Part II [UPDRS-II] scores), and neuropsychological assessments. Adverse events were monitored for safety.

Results: All participants tolerated the procedure well, and there were no safety concerns or serious adverse events. There was an average improvement of 21.5% in the BFMDRS motor subscale score, but the improvement was only 1.6% according to the BADS score. Following blinded video review, dystonia severity ratings were even more modest. Secondary outcomes, however, were more encouraging, with the BFMDRS disability subscale score improving by 15.7%, the PedsQL total score by 27%, and the modified UPDRS-II score by 19.3%. Neuropsychological assessment findings were unchanged 1 year after surgery.

Conclusions: Bilateral thalamic neuromodulation by DBS for severe, medication-refractory acquired dystonia was well tolerated. Primary and secondary outcomes showed highly variable treatment effect sizes comparable to those of pallidal stimulation in this population. As previously described, improvements in quality of life and disability were not reflected in dystonia severity scales, suggesting a need for the development of scales specifically for acquired dystonia.Clinical trial registration no.: NCT03078816 (clinicaltrials.gov).
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http://dx.doi.org/10.3171/2020.7.PEDS20348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155109PMC
November 2020

NeuroDAC: An open-source arbitrary biosignal waveform generator.

J Neural Eng 2020 Nov 5. Epub 2020 Nov 5.

School of Engineering, Brown University, Providence, Rhode Island, UNITED STATES.

Objective: Researchers are developing biomedical devices with embedded closed-loop algorithms for providing advanced adaptive therapies. As these devices become more capable and algorithms become more complex, tasked with integrating and interpreting multi-channel, multi-modal electrophysiological signals, there is a need for flexible bench-top testing and prototyping. We present a methodology for leveraging off-the- shelf audio equipment to construct a biosignal waveform generator capable of streaming pre-recorded biosignals from a host computer. By re-playing known, well-characterized, but physiologically relevant real-world biosignals into a device under test, researchers can evaluate their systems without the need for expensive in vivo experiments.

Approach: An open-source design based on the proposed methodology is described and validated, the NeuroDAC. NeuroDAC allows for 8 independent channels of biosignal playback using a simple, custom designed attenuation and buffering circuit. Applications can communicate with the device over a USB interface using standard audio drivers. On-board analog amplitude adjustment is used to maximize the dynamic range for a given signal and can be independently tuned for each channel.

Main Results: Low noise component selection yields a no-signal noise floor of just 5.35 ± 0.063 μVrms. NeuroDAC's frequency response is characterized with a high pass -3 dB rolloff at 0.57 Hz, and is capable of accurately reproducing a wide assortment of biosignals ranging from EMG, EEG, and ECG to extracellularly recorded neural activity. We also present an application example using the device to test embedded algorithms on a closed-loop neural modulation device, the Medtronic RC+S.

Significance: By making the design of NeuroDAC open-source we aim to present an accessible tool for rapidly prototyping new biomedical devices and algorithms than can be easily modified based on individual testing needs. ClinicalTrials.gov Identifiers: NCT04281134, NCT03437928, NCT03582891.
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http://dx.doi.org/10.1088/1741-2552/abc7f0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096859PMC
November 2020

Developing Collaborative Platforms to Advance Neurotechnology and Its Translation.

Neuron 2020 10;108(2):286-301

Department of Engineering Science, University of Oxford, Oxford OX3 7DQ, UK; MRC Brain Network Dynamics Unit, University of Oxford, Oxford OX3 7DQ, UK. Electronic address:

Neurotechnological devices are failing to deliver on their therapeutic promise because of the time it takes to translate them from bench to clinic. In this Perspective, we reflect on lessons learned from medical device successes and failures and consider how such lessons might shape a strategic vision for translating neurotechnologies in the future. We articulate how the intentional design and deployment of "scientific platforms," from the technology stack of hardware and software through the supporting ecosystem, could catalyze a new wave of innovation, discovery, and therapy. We also identify specific actions that could promote future neurotechnology roadmaps and industrial-academic-government collaborative activities. We believe that community-supported neurotechnology platforms will prove to be transformational in accelerating ideas from bench to bedside, maximizing scientific discovery and improving patient care.
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http://dx.doi.org/10.1016/j.neuron.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610607PMC
October 2020

A Deep Brain Stimulation Trial Period for Treating Chronic Pain.

J Clin Med 2020 Sep 29;9(10). Epub 2020 Sep 29.

Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA.

Early studies of deep brain stimulation (DBS) for various neurological disorders involved a temporary trial period where implanted electrodes were externalized, in which the electrical contacts exiting the patient's brain are connected to external stimulation equipment, so that stimulation efficacy could be determined before permanent implant. As the optimal brain target sites for various diseases (i.e., Parkinson's disease, essential tremor) became better established, such trial periods have fallen out of favor. However, deep brain stimulation trial periods are experiencing a modern resurgence for at least two reasons: (1) studies of newer indications such as depression or chronic pain aim to identify new targets and (2) a growing interest in adaptive DBS tools necessitates neurophysiological recordings, which are often done in the peri-surgical period. In this review, we consider the possible approaches, benefits, and risks of such inpatient trial periods with a specific focus on developing new DBS therapies for chronic pain.
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http://dx.doi.org/10.3390/jcm9103155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600449PMC
September 2020

Eight cylindrical contact lead recordings in the subthalamic region localize beta oscillations source to the dorsal STN.

Neurobiol Dis 2020 12 23;146:105090. Epub 2020 Sep 23.

Philip Starr Laboratory, Department of Neurosurgery, University of California, San Francisco, California, USA.

Background: In Parkinson's disease (PD) patients, the subthalamic nucleus (STN) has prominent oscillatory activity in the beta band, which may be related to the motor symptoms severity. Local field potential (LFP) studies using standard four-contact deep brain stimulation (DBS) leads indicate that the source of beta activity in the STN region is the dorsolateral segment of the nucleus. However, these leads have few contacts outside of the STN, making the source localization of beta activity around the STN region uncertain.

Objective: This study aimed to investigate the electrophysiological characteristics of the STN and the surrounding area in PD to better locate the source of these oscillations and their clinical relevance.

Methods: Eight PD patients were bilaterally implanted in the STN with the eight ring-contact DBS lead (Boston Scientific Corporation). LFPs were recorded intra-operatively from each DBS contact in the off medication state at rest. Each contact location was normalized relative to the STN borders based on microelectrode recordings. For each recording, power spectral density was computed, averaged over multiple frequency bands and phase reversal analysis was used to localize the source of oscillatory activity. Beta burst, high-frequency activity (HFA), and phase-amplitude coupling (PAC) were also computed. Neurophysiological signatures were correlated with hemibody symptoms severity and clinical outcomes.

Results: Beta band power and phase reversal localized the beta oscillator to the dorsal STN and correlated with pre-operative off medication hemibody bradykinesia and rigidity score. The contact along the electrode with the largest beta oscillatory power co-localized with the independently chosen optimized contact used for long-term chronic DBS. Lastly, beta bursting, HFA, and Beta-HFA PAC co-localized with the beta oscillator at the dorsal STN, and Beta-HFA PAC correlated with DBS effect.

Conclusions: Our findings support the hypothesis that the primary source of beta oscillations is located in dorsal STN, and argue against the alternative hypothesis that beta activity in the STN region arises from volume conduction from other sources. We demonstrate intrinsic STN beta-HFA PAC as an independent marker of DBS effect.
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http://dx.doi.org/10.1016/j.nbd.2020.105090DOI Listing
December 2020

Studies of deep brain stimulation in Parkinson's disease.

Lancet Neurol 2020 10 16;19(10):807-808. Epub 2020 Sep 16.

Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA.

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http://dx.doi.org/10.1016/S1474-4422(20)30323-9DOI Listing
October 2020

Intraoperative Stereotactic Frame Registration Using a Three-Dimensional Imaging System with and without Preoperative Computed Tomography for Image Fusion.

Stereotact Funct Neurosurg 2020 20;98(5):313-318. Epub 2020 Aug 20.

Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA,

Background: The O-arm O2 imaging system (OAO2) is an intraoperative cone beam 3D tomogram imaging tool with a wide enough field of view to perform intraoperative fiducial registration with standard stereotactic frames. However, the OAO2 3D images (cone beam CT) provide limited tissue contrast, which may reduce the accuracy of fusion to a preoperative targeting MRI for planning awake deep brain stimulation (DBS) surgeries. Therefore, most users obtain a preoperative CT scan to use as the reference exam for computational fusion with the preoperative targeting MRI and the intraoperative OAO2 cone beam CT.

Objective: In this study, we retrospectively analyzed the discrepancy between stereotactic coordinates of deep brain targets on MRI derived from intraoperative OAO2 fiducial registration with and without the use of preoperative CT as the reference for image fusion.

Methods: Preoperative stereotactic CT/MRI and intraoperative OAO2 cone beam CT were retrospectively evaluated for 27 consecutive DBS patients, using two commercial surgical planning software packages (BrainLab Elements and Medtronic Stealth 8). The anterior commissure, posterior commissure, and left subthalamic nucleus were identified on preoperative MRI. Each patient had intraoperative fiducial registration using the OAO2 with a Leksell headframe. For each subject, the reference scan for image fusion was set as either the preoperative CT or the preoperative MRI (volumetric T1 with contrast). Computed stereotactic coordinates for each target were then compared.

Results: For 8 of 27 subjects, a discrepancy greater than 1.0 mm for at least one designated target was observed utilizing the Medtronic Stealth S8 planning station when a preoperative CT scan was not used. An additional 5 (5/27) had a discrepancy greater than 2 mm. The most common discrepancy was in the z axis. No coordinate discrepancies greater than 1 mm were observed utilizing BrainLab Elements.

Conclusions: Caution is advised in fusing intraoperative OAO2 images directly to preoperative MRI without a preoperative CT as the reference exam for image fusion, as the specific fusion algorithm employed may unpredictably affect targeting accuracy.
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http://dx.doi.org/10.1159/000509312DOI Listing
May 2021

Phenomenology and Management of Subthalamic Stimulation-Induced Dyskinesia in Patients With Isolated Dystonia.

Mov Disord Clin Pract 2020 Jul 22;7(5):548-551. Epub 2020 Apr 22.

Department of Neurology University of California San Francisco, San Francisco, California, USA; Movement Disorders and Neuromodulation Center San Francisco, California USA.

Background: The pallidum has been the preferred DBS target for dystonia, but recent studies have shown equal or greater improvement in patients implanted in the STN. Transient stimulation-induced dyskinesia (SID) is frequently observed when stimulating this novel target, and there are no previously published video case reports of this phenomenon.

Cases: We describe in detail the SID phenomenology experienced by 4 patients who had been implanted with STN DBS for isolated dystonia.

Conclusions: SID can occur in focal, segmental, axial, or generalized distribution, can resemble levodopa-induced dyskinesia choreiform or dystonic movements observed in Parkinson's disease, and is generally transient and resolves with customized DBS programming. Providers should be aware that SID can occur after STN DBS when treating isolated dystonia and not assume movements are the result of worsening or spread of the underlying dystonia.
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http://dx.doi.org/10.1002/mdc3.12946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328432PMC
July 2020

Subthalamic nucleus deep brain stimulation with a multiple independent constant current-controlled device in Parkinson's disease (INTREPID): a multicentre, double-blind, randomised, sham-controlled study.

Lancet Neurol 2020 06 26;19(6):491-501. Epub 2020 May 26.

Department of Neurosurgery, University of Kansas Medical Center, Kansas City, KS, USA.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus is an established therapeutic option for managing motor symptoms of Parkinson's disease. We conducted a double-blind, sham-controlled, randomised controlled trial to assess subthalamic nucleus DBS, with a novel multiple independent contact current-controlled (MICC) device, in patients with Parkinson's disease.

Methods: This trial took place at 23 implanting centres in the USA. Key inclusion criteria were age between 22 and 75 years, a diagnosis of idiopathic Parkinson's disease with over 5 years of motor symptoms, and stable use of anti-parkinsonian medications for 28 days before consent. Patients who passed screening criteria were implanted with the DBS device bilaterally in the subthalamic nucleus. Patients were randomly assigned in a 3:1 ratio to receive either active therapeutic stimulation settings (active group) or subtherapeutic stimulation settings (control group) for the 3-month blinded period. Randomisation took place with a computer-generated data capture system using a pre-generated randomisation table, stratified by site with random permuted blocks. During the 3-month blinded period, both patients and the assessors were masked to the treatment group while the unmasked programmer was responsible for programming and optimisation of device settings. The primary outcome was the difference in mean change from baseline visit to 3 months post-randomisation between the active and control groups in the mean number of waking hours per day with good symptom control and no troublesome dyskinesias, with no increase in anti-parkinsonian medications. Upon completion of the blinded phase, all patients received active treatment in the open-label period for up to 5 years. Primary and secondary outcomes were analysed by intention to treat. All patients who provided informed consent were included in the safety analysis. The open-label phase is ongoing with no new enrolment, and current findings are based on the prespecified interim analysis of the first 160 randomly assigned patients. The study is registered with ClinicalTrials.gov, NCT01839396.

Findings: Between May 17, 2013, and Nov 30, 2017, 313 patients were enrolled across 23 sites. Of these 313 patients, 196 (63%) received the DBS implant and 191 (61%) were randomly assigned. Of the 160 patients included in the interim analysis, 121 (76%) were randomly assigned to the active group and 39 (24%) to the control group. The difference in mean change from the baseline visit (post-implant) to 3 months post-randomisation in increased ON time without troublesome dyskinesias between the active and control groups was 3·03 h (SD 4·52, 95% CI 1·3-4·7; p<0·0001). 26 serious adverse events in 20 (13%) patients occurred during the 3-month blinded period. Of these, 18 events were reported in the active group and 8 in the control group. One death was reported among the 196 patients before randomisation, which was unrelated to the procedure, device, or stimulation.

Interpretation: This double-blind, sham-controlled, randomised controlled trial provides class I evidence of the safety and clinical efficacy of subthalamic nucleus DBS with a novel MICC device for the treatment of motor symptoms of Parkinson's disease. Future trials are needed to investigate potential benefits of producing a more defined current field using MICC technology, and its effect on clinical outcomes.

Funding: Boston Scientific.
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http://dx.doi.org/10.1016/S1474-4422(20)30108-3DOI Listing
June 2020

Simultaneous cortical and subcortical recordings in humans with movement disorders: Acute and chronic paradigms.

Neuroimage 2020 08 6;217:116904. Epub 2020 May 6.

Department of Neurological Surgery, University of California, 505 Parnassus Avenue, San Francisco, CA, 94143, USA.

Invasive basal ganglia recordings in humans have significantly advanced our understanding of the neurophysiology of movement disorders. A recent technical advance has been the addition of electrocorticography to basal ganglia recording, for evaluating distributed motor networks. Here we review the rationale, results, and ethics of this multisite recording technique in movement disorders, as well as its application in chronic recording paradigms utilizing implantable neural interfaces that include a sensing function.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116904DOI Listing
August 2020

Smart neuromodulation in movement disorders.

Handb Clin Neurol 2020 ;168:153-161

Department of Neurosurgery, University of California, San Francisco, San Francisco, CA, United States.

Deep brain stimulation (DBS) is a technique for invasive subcortical neuromodulation using a totally implantable permanent device. DBS is an effective therapy for movement disorders and is under investigation for the treatment of many other conditions including Tourette syndrome, epilepsy, and depression. Traditional DBS is limited by labor-intensive manual programming, high current requirements, and lack of responsiveness to fluctuations in the patient's signs and symptoms. The field is moving toward adaptive closed loop systems with stimulation modulated by peripheral or intracranial sensors, a technique often described as "smart neuromodulation." Advances in the understanding of brain rhythms associated with specific neurologic symptoms and the introduction of novel bidirectional neural interfaces are facilitating investigative studies of closed loop stimulation in movement disorders. These studies suggest the potential for greater efficacy with fewer adverse effects. It may be possible to generalize the hardware platforms and control strategies developed to other brain disorders.
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http://dx.doi.org/10.1016/B978-0-444-63934-9.00012-3DOI Listing
December 2020

Prefrontal-Subthalamic Hyperdirect Pathway Modulates Movement Inhibition in Humans.

Neuron 2020 05 9;106(4):579-588.e3. Epub 2020 Mar 9.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

The ability to dynamically change motor outputs, such as stopping an initiated response, is an important aspect of human behavior. A hyperdirect pathway between the inferior frontal gyrus and subthalamic nucleus is hypothesized to mediate movement inhibition, but there is limited evidence for this in humans. We recorded high spatial and temporal resolution field potentials from both the inferior frontal gyrus and subthalamic nucleus in 21 subjects. Cortical potentials evoked by subthalamic stimulation revealed short latency events indicative of monosynaptic connectivity between the inferior frontal gyrus and ventral subthalamic nucleus. During a stop signal task, stopping-related potentials in the cortex preceded stopping-related activity in the subthalamic nucleus, and synchronization between these task-evoked potentials predicted the stop signal reaction time. Thus, we show that a prefrontal-subthalamic hyperdirect pathway is present in humans and mediates rapid stopping. These findings may inform therapies to treat disorders featuring perturbed movement inhibition.
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http://dx.doi.org/10.1016/j.neuron.2020.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274135PMC
May 2020

Defining research priorities in dystonia.

Neurology 2020 03 25;94(12):526-537. Epub 2020 Feb 25.

From the Division of Clinical Research (C.L.), National Institute of Neurological Disorders and Stroke, National Institutes of Health; Harvard Medical School (L.O., N.S.), Massachusetts General Hospital, Boston, MA; University of Alabama, Birmingham (D.S.), Birmingham, AL; Medical Neurology Branch (M.H.), NINDS, NIH, Bethesda, MD; Division of Neuroscience (B.-A.S., C.S.-F.), NINDS, NIH, Bethesda, MD; Department of Neurology (B.D.B.), University of Colorado Denver, Aurora, CO; Duke University School of Medicine, Durham, NC; RUCDR/Infinite Biologics (J.C.M.), Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ; Washington University School of Medicine (J.S.P.), St Louis, MO; Department of Neurology (S.E.P.R.), University of New Mexico Health Sciences Center, Albuquerque, NM; Department of Neurology (R.S.-P.), Icahn School of Medicine at Mount Sinai, New York, NY; Coriell Institute for Medical Research (L.S.), Camden, NJ; Department of Neuroscience (R.S.), Baylor College of Medicine, Houston, TX; Harvard Medical School (K.S.), Department of Otolaryngology, Head and Neck Surgery, Massachusetts Eye and Ear Institute, Boston, MA; Department of Neurological Surgery (P.A.S.), University of California San Francisco, San Francisco, CA; Division of Extramural Activities (A.T.), NINDS, NIH, Rockville, MD; and Department of Neurology (J.V.), University of Minnesota, Minneapolis, MN.

Objective: Dystonia is a complex movement disorder. Research progress has been difficult, particularly in developing widely effective therapies. This is a review of the current state of knowledge, research gaps, and proposed research priorities.

Methods: The NIH convened leaders in the field for a 2-day workshop. The participants addressed the natural history of the disease, the underlying etiology, the pathophysiology, relevant research technologies, research resources, and therapeutic approaches and attempted to prioritize dystonia research recommendations.

Results: The heterogeneity of dystonia poses challenges to research and therapy development. Much can be learned from specific genetic subtypes, and the disorder can be conceptualized along clinical, etiology, and pathophysiology axes. Advances in research technology and pooled resources can accelerate progress. Although etiologically based therapies would be optimal, a focus on circuit abnormalities can provide a convergent common target for symptomatic therapies across dystonia subtypes. The discussions have been integrated into a comprehensive review of all aspects of dystonia.

Conclusion: Overall research priorities include the generation and integration of high-quality phenotypic and genotypic data, reproducing key features in cellular and animal models, both of basic cellular mechanisms and phenotypes, leveraging new research technologies, and targeting circuit-level dysfunction with therapeutic interventions. Collaboration is necessary both for collection of large data sets and integration of different research methods.
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http://dx.doi.org/10.1212/WNL.0000000000009140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274927PMC
March 2020

Cerebellar Deep Brain Stimulation for Acquired Hemidystonia.

Mov Disord Clin Pract 2020 Feb 8;7(2):188-193. Epub 2020 Jan 8.

Movement Disorders and Neuromodulation Center, Department of Neurology University of California San Francisco San Francisco California USA.

Background: The cerebellum's role in dystonia is increasingly recognized. Dystonia can be a disabling and refractory condition; deep brain stimulation can help many patients, but it is traditionally less effective in acquired dystonia. New surgical targets would be instrumental in providing treatment options and understanding dystonia further.

Objective: To evaluate the efficacy of deep brain stimulation of the cerebellum in acquired dystonia.

Methods: We report our management of a 37-year-old woman with severe left arm and leg dystonia, a complication of an ischemic stroke in childhood. She had already had 2 thalamotomies with only transient benefit. These procedures, in addition to her initial stroke that had damaged the basal ganglia, left traditional deep brain stimulation targets unavailable.

Results: After implantation of bilateral deep cerebellar nuclei, dystonia improved with a 40% reduction in severity on scales and subjective reports of improved posturing, gait, and pain. This improvement has been maintained for almost 2 years after implantation.

Conclusion: Cerebellar stimulation has potential for therapeutic benefit in acquired dystonia and should be further explored.
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http://dx.doi.org/10.1002/mdc3.12876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011833PMC
February 2020

Beta Oscillations in Working Memory, Executive Control of Movement and Thought, and Sensorimotor Function.

J Neurosci 2019 10;39(42):8231-8238

Department of Psychology, University of California San Diego La Jolla, CA 92093

Beta oscillations (∼13 to 30 Hz) have been observed during many perceptual, cognitive, and motor processes in a plethora of brain recording studies. Although the function of beta oscillations (hereafter "beta" for short) is unlikely to be explained by any single monolithic description, we here discuss several convergent findings. In prefrontal cortex (PFC), increased beta appears at the end of a trial when working memory information needs to be erased. A similar "clear-out" function might apply during the stopping of action and the stopping of long-term memory retrieval (stopping thoughts), where increased prefrontal beta is also observed. A different apparent role for beta in PFC occurs during the delay period of working memory tasks: it might serve to maintain the current contents and/or to prevent interference from distraction. We confront the challenge of relating these observations to the large literature on beta recorded from sensorimotor cortex. Potentially, the clear-out of working memory in PFC has its counterpart in the postmovement clear-out of the motor plan in sensorimotor cortex. However, recent studies support alternative interpretations. In addition, we flag emerging research on different frequencies of beta and the relationship between beta and single-neuron spiking. We also discuss where beta might be generated: basal ganglia, cortex, or both. We end by considering the clinical implications for adaptive deep-brain stimulation.
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http://dx.doi.org/10.1523/JNEUROSCI.1163-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794925PMC
October 2019

Proceedings of the Sixth Deep Brain Stimulation Think Tank Modulation of Brain Networks and Application of Advanced Neuroimaging, Neurophysiology, and Optogenetics.

Front Neurosci 2019 12;13:936. Epub 2019 Sep 12.

Department of Neurology, Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States.

The annual deep brain stimulation (DBS) Think Tank aims to create an opportunity for a multidisciplinary discussion in the field of neuromodulation to examine developments, opportunities and challenges in the field. The proceedings of the Sixth Annual Think Tank recapitulate progress in applications of neurotechnology, neurophysiology, and emerging techniques for the treatment of a range of psychiatric and neurological conditions including Parkinson's disease, essential tremor, Tourette syndrome, epilepsy, cognitive disorders, and addiction. Each section of this overview provides insight about the understanding of neuromodulation for specific disease and discusses current challenges and future directions. This year's report addresses key issues in implementing advanced neurophysiological techniques, evolving use of novel modulation techniques to deliver DBS, ans improved neuroimaging techniques. The proceedings also offer insights into the new era of brain network neuromodulation and connectomic DBS to define and target dysfunctional brain networks. The proceedings also focused on innovations in applications and understanding of adaptive DBS (closed-loop systems), the use and applications of optogenetics in the field of neurostimulation and the need to develop databases for DBS indications. Finally, updates on neuroethical, legal, social, and policy issues relevant to DBS research are discussed.
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http://dx.doi.org/10.3389/fnins.2019.00936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751331PMC
September 2019

Washout of chronic therapeutic deep brain stimulation increases cortical phase-amplitude coupling.

Parkinsonism Relat Disord 2019 09 27;66:269-271. Epub 2019 Aug 27.

Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA; Parkinson's Disease Research, Education and Clinical Center at the San Francisco Veteran's Affairs Medical Center, San Francisco, CA, USA; Graduate Program in Neuroscience, University of California, San Francisco, CA, USA. Electronic address:

Invasive human brain recordings have shown that acute therapeutic deep brain stimulation (DBS) reduces cortical synchronization, measured by coupling of beta phase to gamma amplitude. Here we show by noninvasive scalp electroencephalography that withdrawal of chronic DBS elevates phase-amplitude coupling, in proportion to the worsening of contralateral rigidity.
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http://dx.doi.org/10.1016/j.parkreldis.2019.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376959PMC
September 2019

Altered Prefrontal Theta and Gamma Activity during an Emotional Face Processing Task in Parkinson Disease.

J Cogn Neurosci 2019 11 19;31(11):1768-1776. Epub 2019 Jul 19.

University of California San Francisco.

Patients with Parkinson disease (PD) often experience nonmotor symptoms including cognitive deficits, depression, and anxiety. Cognitive and affective processes are thought to be mediated by prefrontal cortico-basal ganglia circuitry. However, the topography and neurophysiology of prefrontal cortical activity during complex tasks are not well characterized. We used high-resolution electrocorticography in pFC of patients with PD and essential tremor, during implantation of deep brain stimulator leads in the awake state, to understand disease-specific changes in prefrontal activity during an emotional face processing task. We found that patients with PD had less task-related theta-alpha power and greater task-related gamma power in the dorsolateral pFC, inferior frontal cortex, and lateral OFC. These findings support a model of prefrontal neurophysiological changes in the dopamine-depleted state, in which focal areas of hyperactivity in prefrontal cortical regions may compensate for impaired long-range interactions mediated by low-frequency rhythms. These distinct neurophysiological changes suggest that nonmotor circuits undergo characteristic changes in PD.
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http://dx.doi.org/10.1162/jocn_a_01450DOI Listing
November 2019

Patient Experience with Rechargeable Implantable Pulse Generator Deep Brain Stimulation for Movement Disorders.

Stereotact Funct Neurosurg 2019 9;97(2):113-119. Epub 2019 Jul 9.

Department of Neurology, University of California San Francisco, San Francisco, California, USA.

Background/aims: Nonrechargeable deep brain stimulation implantable pulse generators (IPGs) for movement disorders require surgical replacement every few years due to battery depletion. Rechargeable IPGs reduce frequency of replacement surgeries and inherent risks of complications but require frequent recharging. Here, we evaluate patient experience with rechargeable IPGs and define predictive characteristics for higher satisfaction.

Methods: We contacted all patients implanted with rechargeable IPGs at a single center in a survey-based study. We analyzed patient satisfaction with respect to age, diagnosis, target, charging duration, and body mass index. We tabulated hardware-related adverse events.

Results: Dystonia patients had significantly higher satisfaction than Parkinson's disease patients in recharging, display, programmer, and training domains. Common positive responses were "fewer surgeries" and "small size." Common negative responses were "difficulty finding the right position to recharge" and "need to recharge every day." Hardware-related adverse events occurred in 21 of 59 participants.

Conclusion: Patient experience with rechargeable IPGs was largely positive; however, frustrations with recharging and adverse events were common. Dystonia diagnosis was most predictive of high satisfaction across multiple categories, potentially related to expected long disease duration with need for numerous IPG replacements.
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http://dx.doi.org/10.1159/000500993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689445PMC
February 2020

Effect of levodopa on electroencephalographic biomarkers of the parkinsonian state.

J Neurophysiol 2019 07 8;122(1):290-299. Epub 2019 May 8.

Department of Neurological Surgery, University of California , San Francisco, California.

The objective of this study was to evaluate proposed electroencephalographic (EEG) biomarkers of Parkinson's disease (PD) and test their correlation with motor impairment in a new, well-characterized cohort of PD patients and controls. Sixty-four-channel EEG was recorded from 14 patients with rigid-akinetic PD with minimal tremor and from 14 age-matched healthy controls at rest and during voluntary movement. Patients were tested off and on medication during a single session. Recordings were analyzed for phase-amplitude coupling over sensorimotor cortex and for pairwise coherence from all electrode pairs in the recording montage (distributed coherence). Phase-amplitude coupling and distributed coherence were found to be elevated Off compared with On levodopa, and their reduction was correlated with motor improvement. In the Off medication state, phase-amplitude coupling was greater in sensorimotor contacts contralateral to the most affected body part and reduced by voluntary movement. We conclude that phase-amplitude coupling and distributed coherence are cortical biomarkers of the parkinsonian state that are detectable noninvasively and may be useful as objective aids for management of dopaminergic therapy. Several analytic methods may be used for noninvasive measurement of abnormal brain synchronization in PD. Calculation of phase-amplitude coupling requires only a single electrode over motor cortex. Several EEG biomarkers of the parkinsonian state have been proposed that are related to abnormal cortical synchronization. We report several new findings in this study: correlations of EEG markers of synchronization with specific motor signs of Parkinson's disease (PD), and demonstration that one of the EEG markers, phase-amplitude coupling, is more elevated over the more clinically affected brain hemisphere. These findings underscore the potential utility of scalp EEG for objective, noninvasive monitoring of medication state in PD.
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http://dx.doi.org/10.1152/jn.00141.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689788PMC
July 2019

Pallidal thermolesion unleashes gamma oscillations in the motor cortex in Parkinson's disease.

Mov Disord 2019 06 13;34(6):903-911. Epub 2019 Mar 13.

Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.

Background: In Parkinson's disease, the emergence of motor dysfunction is thought to be related to an imbalance between "antikinetic" and "prokinetic" patterns of oscillatory activity in the motor network. Invasive recordings from the basal ganglia and cortex in surgical patients have suggested that levodopa and therapeutic deep brain stimulation can suppress antikinetic beta band (13-30 Hz) rhythms while promoting prokinetic gamma band (60-90 Hz) rhythms. Surgical ablation of the globus pallidus internus is one of the oldest effective therapies for Parkinson's disease and produces remarkably immediate relief of rigidity and bradykinesia, but its effects on oscillatory activity in the motor network have not been studied.

Objectives: We characterize the effects of pallidotomy on cortical oscillatory activity in Parkinson's patients.

Methods: Using a temporary 6-contact lead placed over the sensorimotor cortex in the subdural space, we recorded acute changes in cortical oscillatory activities in 3 Parkinson's disease patients undergoing pallidotomy and compared the results to that of 3 essential tremor patients undergoing thalamotomy.

Results: In all 3 Parkinson's disease patients, we observed the emergence of a ~70-80 Hz narrowband oscillation with effective thermolesion of the pallidum. This gamma oscillatory activity was spatially localized over the primary motor cortex, was minimally affected by voluntary movements, and was not found in the motor cortex of essential tremor patients undergoing thalamotomy.

Conclusions: Our finding suggests that acute lesioning of the pallidum promotes cortical gamma band oscillations. This may represent an important mechanism for alleviating bradykinesia in Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27658DOI Listing
June 2019

Long-Term Outcomes of Bilateral Pallidal Deep Brain Stimulation for X-Linked Dystonia and Parkinsonism.

Stereotact Funct Neurosurg 2018 27;96(5):320-326. Epub 2018 Nov 27.

Movement Disorder and Neuromodulation Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA,

Background: X-linked dystonia parkinsonism (XDP) causes adult-onset progressive dystonia and parkinsonism, which may not respond to pharmacotherapy.

Objective: Previous case reports have reported beneficial effects from bilateral pallidal (GPi) deep brain stimulation (DBS). Here, we report the long-term clinical outcomes of 3 patients treated at our center.

Methods: All patients presented with medication refractory dystonia and parkinsonism. They were followed prospectively. Clinical evaluations included the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Unified Parkinson's Disease Rating Scale (UPDRS). Adverse events were recorded.

Results: The average length of follow-up was 45.7 months. No serious adverse events occurred. All patients experienced an immediate and sustained improvement in dystonia. Mean percentage improvement in motor subscores of BFMDRS was 63.5% at the last follow-up visit. Parkinsonism was less responsive to neuromodulation, with a mean improvement in UPDRS-III of 39.5%. Standard pallidal stimulation parameters were used. Freezing of gait developed after DBS therapy in 2 patients, stimulation-induced in one and due to disease progression in the other.

Conclusion: Bilateral pallidal DBS resulted in significant and sustained improvement in dystonia and moderate improvement in parkinsonism. Pallidal DBS represents an important treatment option for XPD for the management of motor symptoms.
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http://dx.doi.org/10.1159/000492823DOI Listing
May 2019

Totally Implantable Bidirectional Neural Prostheses: A Flexible Platform for Innovation in Neuromodulation.

Authors:
Philip A Starr

Front Neurosci 2018 7;12:619. Epub 2018 Sep 7.

Professor of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States.

Implantable neural prostheses are in widespread use for treating a variety of brain disorders. Until recently, most implantable brain devices have been unidirectional, either delivering neurostimulation without brain sensing, or sensing brain activity to drive external effectors without a stimulation component. Further, many neural interfaces that incorporate a sensing function have relied on hardwired connections, such that subjects are tethered to external computers and cannot move freely. A new generation of neural prostheses has become available, that are both bidirectional (stimulate as well as record brain activity) and totally implantable (no externalized connections). These devices provide an opportunity for discovering the circuit basis for neuropsychiatric disorders, and to prototype personalized neuromodulation therapies that selectively interrupt neural activity underlying specific signs and symptoms.
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http://dx.doi.org/10.3389/fnins.2018.00619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137308PMC
September 2018