- Functional Neurosurgery
- Movement Disorders
- Neurological Surgery
- Trigeminal Neuralgia
- Deep Brain Stimulation
Director, Stereotactic and Functional Neurosurgery (2004 - Present)
Board Certification: Neurological Surgery, American Board of Neurological Surgery (2000)
Residency:St Louis University Hospital (1995) MO
Internship:Rush University Medical College (1989) IL
Medical Education:Rush University Medical College (1988) IL
M.D., Rush Medical College, Medicine (1988)
B.A., Washington University, St. Louis, Biology (1984)
Current Research and Scholarly Interests
My research interests encompass several areas of stereotactic and functional neurosurgery, including frameless stereotactic approaches for therapy delivery to deep brain nuclei; deformable patient-specific atlases for targeting brain structures; cortical physiology and its relationship to normal and pathological movement; neural prostheses; and the development of novel neuromodulatory techniques for the treatment of movement disorders, pain, and other neurological diseases.
BrainGate2: Feasibility Study of an Intracortical Neural Interface System for Persons With Tetraplegia
The purpose of this study is to obtain preliminary device safety information and demonstrate proof of principle (feasibility of efficacy) of the ability of people with tetraplegia to control a computer cursor and other assistive devices with their thoughts.
Deep Brain Stimulation for the Treatment of Traumatic Brain Injury
This study involves the treatment of cognitive impairment secondary to moderate to severe brain injury using central thalamic deep brain stimulation. Although all patients will receive stimulation continuously through a surgically implanted pacemaker-like device, half of the patients will have the device deactivated during a blinded assessment phase. The device will be reactivated following this assessment and patients will have the option to continue stimulation in an open-label continuation.
- Independent Studies (5)
Graduate and Fellowship Programs
High performance communication by people with paralysis using an intracortical brain-computer interface.
Brain-computer interfaces (BCIs) have the potential to restore communication for people with tetraplegia and anarthria by translating neural activity into control signals for assistive communication devices. While previous pre-clinical and clinical studies have demonstrated promising proofs-of-concept (Serruya et al., 2002; Simeral et al., 2011; Bacher et al., 2015; Nuyujukian et al., 2015; Aflalo et al., 2015; Gilja et al., 2015; Jarosiewicz et al., 2015; Wolpaw et al., 1998; Hwang et al., 2012; Spüler et al., 2012; Leuthardt et al., 2004; Taylor et al., 2002; Schalk et al., 2008; Moran, 2010; Brunner et al., 2011; Wang et al., 2013; Townsend and Platsko, 2016; Vansteensel et al., 2016; Nuyujukian et al., 2016; Carmena et al., 2003; Musallam et al., 2004; Santhanam et al., 2006; Hochberg et al., 2006; Ganguly et al., 2011; O'Doherty et al., 2011; Gilja et al., 2012), the performance of human clinical BCI systems is not yet high enough to support widespread adoption by people with physical limitations of speech. Here we report a high-performance intracortical BCI (iBCI) for communication, which was tested by three clinical trial participants with paralysis. The system leveraged advances in decoder design developed in prior pre-clinical and clinical studies (Gilja et al., 2015; Kao et al., 2016; Gilja et al., 2012). For all three participants, performance exceeded previous iBCIs (Bacher et al., 2015; Jarosiewicz et al., 2015) as measured by typing rate (by a factor of 1.4-4.2) and information throughput (by a factor of 2.2-4.0). This high level of performance demonstrates the potential utility of iBCIs as powerful assistive communication devices for people with limited motor function.Clinical Trial No: NCT00912041.
View details for DOI 10.7554/eLife.18554
View details for PubMedID 28220753
View details for PubMedCentralID PMC5319839
Virtual typing by people with tetraplegia using a self-calibrating intracortical brain-computer interface.
Science translational medicine
2015; 7 (313): 313ra179-?
Brain-computer interfaces (BCIs) promise to restore independence for people with severe motor disabilities by translating decoded neural activity directly into the control of a computer. However, recorded neural signals are not stationary (that is, can change over time), degrading the quality of decoding. Requiring users to pause what they are doing whenever signals change to perform decoder recalibration routines is time-consuming and impractical for everyday use of BCIs. We demonstrate that signal nonstationarity in an intracortical BCI can be mitigated automatically in software, enabling long periods (hours to days) of self-paced point-and-click typing by people with tetraplegia, without degradation in neural control. Three key innovations were included in our approach: tracking the statistics of the neural activity during self-timed pauses in neural control, velocity bias correction during neural control, and periodically recalibrating the decoder using data acquired during typing by mapping neural activity to movement intentions that are inferred retrospectively based on the user's self-selected targets. These methods, which can be extended to a variety of neurally controlled applications, advance the potential for intracortical BCIs to help restore independent communication and assistive device control for people with paralysis.
View details for DOI 10.1126/scitranslmed.aac7328
View details for PubMedID 26560357
Clinical translation of a high-performance neural prosthesis.
2015; 21 (10): 1142-1145
Neural prostheses have the potential to improve the quality of life of individuals with paralysis by directly mapping neural activity to limb- and computer-control signals. We translated a neural prosthetic system previously developed in animal model studies for use by two individuals with amyotrophic lateral sclerosis who had intracortical microelectrode arrays placed in motor cortex. Measured more than 1 year after implant, the neural cursor-control system showed the highest published performance achieved by a person to date, more than double that of previous pilot clinical trial participants.
View details for DOI 10.1038/nm.3953
View details for PubMedID 26413781
- Assessment of brain-machine interfaces from the perspective of people with paralysis JOURNAL OF NEURAL ENGINEERING 2015; 12 (4)
Neural population dynamics in human motor cortex during movements in people with ALS
The prevailing view of motor cortex holds that motor cortical neural activity represents muscle or movement parameters. However, recent studies in non-human primates have shown that neural activity does not simply represent muscle or movement parameters; instead, its temporal structure is well-described by a dynamical system where activity during movement evolves lawfully from an initial pre-movement state. In this study, we analyze neuronal ensemble activity in motor cortex in two clinical trial participants diagnosed with Amyotrophic Lateral Sclerosis (ALS). We find that activity in human motor cortex has similar dynamical structure to that of non-human primates, indicating that human motor cortex contains a similar underlying dynamical system for movement generation.
View details for DOI 10.7554/eLife.07436
View details for Web of Science ID 000356720100001
View details for PubMedID 26099302
View details for PubMedCentralID PMC4475900
Challenges and Opportunities for Next-Generation Intracortically Based Neural Prostheses
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING
2011; 58 (7): 1891-1899
Neural prosthetic systems aim to help disabled patients by translating neural signals from the brain into control signals for guiding computer cursors, prosthetic arms, and other assistive devices. Intracortical electrode arrays measure action potentials and local field potentials from individual neurons, or small populations of neurons, in the motor cortices and can provide considerable information for controlling prostheses. Despite several compelling proof-of-concept laboratory animal experiments and an initial human clinical trial, at least three key challenges remain which, if left unaddressed, may hamper the translation of these systems into widespread clinical use. We review these challenges: achieving able-bodied levels of performance across tasks and across environments, achieving robustness across multiple decades, and restoring able-bodied quality proprioception and somatosensation. We also describe some emerging opportunities for meeting these challenges. If these challenges can be largely or fully met, intracortically based neural prostheses may achieve true clinical viability and help increasing numbers of disabled patients.
View details for DOI 10.1109/TBME.2011.2107553
View details for Web of Science ID 000291890000003
View details for PubMedID 21257365
- Novel application of virtual reality in patient engagement for deep brain stimulation: A pilot study. Brain stimulation 2018
Diffusion MRI tractography for improved transcranial MRI-guided focused ultrasound thalamotomy targeting for essential tremor.
2018; 19: 572–80
Purpose: To evaluate the use of diffusion magnetic resonance imaging (MRI) tractography for neurosurgical guidance of transcranial MRI-guided focused ultrasound (tcMRgFUS) thalamotomy for essential tremor (ET).Materials and methods: Eight patients with medication-refractory ET were treated with tcMRgFUS targeting the ventral intermediate nucleus (Vim) of the thalamus contralateral to their dominant hand. Diffusion and structural MRI data and clinical evaluations were acquired pre-treatment and post-treatment. To identify the optimal target location, tractography was performed on pre-treatment diffusion MRI data between the treated thalamus and the hand-knob region of the ipsilateral motor cortex, the entire ipsilateral motor cortex and the contralateral dentate nucleus. The tractography-identified locations were compared to the lesion location delineated on 1 year post-treatment T2-weighted MR image. Their overlap was correlated with the clinical outcomes measured by the percentage change of the Clinical Rating Scale for Tremor scores acquired pre-treatment, as well as 1 month, 3 months, 6 months and 1 year post-treatment.Results: The probabilistic tractography was consistent from subject-to-subject and followed the expected anatomy of the thalamocortical radiation and the dentatothalamic tract. Higher overlap between the tractography-identified location and the tcMRgFUS treatment-induced lesion highly correlated with better treatment outcome (r = -0.929, -0.75, -0.643, p = 0.00675, 0.0663, 0.139 for the tractography between the treated thalamus and the hand-knob region of the ipsilateral motor cortex, the entire ipsilateral motor cortex and the contralateral dentate nucleus, respectively, at 1 year post-treatment). The correlation for the tractography between the treated thalamus and the hand-knob region of the ipsilateral motor cortex is the highest for all time points (r = -0.719, -0.976, -0.707, -0.929, p = 0.0519, 0.000397, 0.0595, 0.00675 at 1 month, 3 months, 6 months and 1 year post-treatment, respectively).Conclusion: Our data support the use of diffusion tractography as a complementary approach to current targeting methods for tcMRgFUS thalamotomy.
View details for DOI 10.1016/j.nicl.2018.05.010
View details for PubMedID 29984165
A prospective trial of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: Results at the 2-year follow-up.
Annals of neurology
2018; 83 (1): 107–14
Magnetic resonance guided focused ultrasound (MRgFUS) has recently been investigated as a new treatment modality for essential tremor (ET), but the durability of the procedure has not yet been evaluated. This study reports results at a 2- year follow-up after MRgFUS thalamotomy for ET.A total of 76 patients with moderate-to-severe ET, who had not responded to at least two trials of medical therapy, were enrolled in the original randomized study of unilateral thalamotomy and evaluated using the clinical rating scale for tremor. Sixty-seven of the patients continued in the open-label extension phase of the study with monitoring for 2 years. Nine patients were excluded by 2 years, for example, because of alternative therapy such as deep brain stimulation (n = 3) or inadequate thermal lesioning (n = 1). However, all patients in each follow-up period were analyzed.Mean hand tremor score at baseline (19.8 ± 4.9; 76 patients) improved by 55% at 6 months (8.6 ± 4.5; 75 patients). The improvement in tremor score from baseline was durable at 1 year (53%; 8.9 ± 4.8; 70 patients) and at 2 years (56%; 8.8 ± 5.0; 67 patients). Similarly, the disability score at baseline (16.4 ± 4.5; 76 patients) improved by 64% at 6 months (5.4 ± 4.7; 75 patients). This improvement was also sustained at 1 year (5.4 ± 5.3; 70 patients) and at 2 years (6.5 ± 5.0; 67 patients). Paresthesias and gait disturbances were the most common adverse effects at 1 year-each observed in 10 patients with an additional 5 patients experiencing neurological adverse effects. None of the adverse events worsened over the period of follow-up, and 2 of these resolved. There were no new delayed complications at 2 years.Tremor suppression after MRgFUS thalamotomy for ET is stably maintained at 2 years. Latent or delayed complications do not develop after treatment. Ann Neurol 2018;83:107-114.
View details for DOI 10.1002/ana.25126
View details for PubMedID 29265546
Rapid calibration of an intracortical brain-computer interface for people with tetraplegia.
Journal of neural engineering
2018; 15 (2): 026007
Brain-computer interfaces (BCIs) can enable individuals with tetraplegia to communicate and control external devices. Though much progress has been made in improving the speed and robustness of neural control provided by intracortical BCIs, little research has been devoted to minimizing the amount of time spent on decoder calibration.We investigated the amount of time users needed to calibrate decoders and achieve performance saturation using two markedly different decoding algorithms: the steady-state Kalman filter, and a novel technique using Gaussian process regression (GP-DKF).Three people with tetraplegia gained rapid closed-loop neural cursor control and peak, plateaued decoder performance within 3 min of initializing calibration. We also show that a BCI-naïve user (T5) was able to rapidly attain closed-loop neural cursor control with the GP-DKF using self-selected movement imagery on his first-ever day of closed-loop BCI use, acquiring a target 37 s after initiating calibration.These results demonstrate the potential for an intracortical BCI to be used immediately after deployment by people with paralysis, without the need for user learning or extensive system calibration.
View details for DOI 10.1088/1741-2552/aa9ee7
View details for PubMedID 29363625
gene therapy trial for Parkinson's disease.
2017; 2 (7)
BACKGROUND. We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson's disease (PD) patients. METHODS. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2-GAD delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and (18)F-fluorodeoxyglucose (FDG) PET imaging. RESULTS. Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2-GAD group compared with the sham group continued at 12 months [time effect: F(4,138) = 11.55, P < 0.001; group effect: F(1,35) = 5.45, P < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2-GAD group (P = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines (P < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2-GAD group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2-GAD group (P < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. CONCLUSION. These findings show that clinical benefits after gene therapy with STN AAV2-GAD in PD patients persist at 12 months. TRIAL REGISTRATION. ClinicalTrials.gov NCT00643890. FUNDING. Neurologix Inc.
View details for DOI 10.1172/jci.insight.90133
View details for PubMedID 28405611
Awake versus asleep deep brain stimulation for Parkinson's disease: a critical comparison and meta-analysis.
Journal of neurology, neurosurgery, and psychiatry
No definitive comparative studies of the efficacy of 'awake' deep brain stimulation (DBS) for Parkinson's disease (PD) under local or general anaesthesia exist, and there remains significant debate within the field regarding differences in outcomes between these two techniques.We conducted a literature review and meta-analysis of all published DBS for PD studies (n=2563) on PubMed from January 2004 to November 2015. Inclusion criteria included patient number >15, report of precision and/or clinical outcomes data, and at least 6 months of follow-up. There were 145 studies, 16 of which were under general anaesthesia. Data were pooled using an inverse-variance weighted, random effects meta-analytic model for observational data.There was no significant difference in mean target error between local and general anaesthesia, but there was a significantly less mean number of DBS lead passes with general anaesthesia (p=0.006). There were also significant decreases in DBS complications, with fewer intracerebral haemorrhages and infections with general anaesthesia (p<0.001). There were no significant differences in Unified Parkinson's Disease Rating Scale (UPDRS) Section II scores off medication, UPDRS III scores off and on medication or levodopa equivalent doses between the two techniques. Awake DBS cohorts had a significantly greater decrease in treatment-related side effects as measured by the UPDRS IV off medication score (78.4% awake vs 59.7% asleep, p=0.022).Our meta-analysis demonstrates that while DBS under general anaesthesia may lead to lower complication rates overall, awake DBS may lead to less treatment-induced side effects. Nevertheless, there were no significant differences in clinical motor outcomes between the two techniques. Thus, DBS under general anaesthesia can be considered at experienced centres in patients who are not candidates for traditional awake DBS or prefer the asleep alternative.
View details for DOI 10.1136/jnnp-2016-314500
View details for PubMedID 28250028
Feedback control policies employed by people using intracortical brain-computer interfaces
JOURNAL OF NEURAL ENGINEERING
2017; 14 (1)
When using an intracortical BCI (iBCI), users modulate their neural population activity to move an effector towards a target, stop accurately, and correct for movement errors. We call the rules that govern this modulation a 'feedback control policy'. A better understanding of these policies may inform the design of higher-performing neural decoders.We studied how three participants in the BrainGate2 pilot clinical trial used an iBCI to control a cursor in a 2D target acquisition task. Participants used a velocity decoder with exponential smoothing dynamics. Through offline analyses, we characterized the users' feedback control policies by modeling their neural activity as a function of cursor state and target position. We also tested whether users could adapt their policy to different decoder dynamics by varying the gain (speed scaling) and temporal smoothing parameters of the iBCI.We demonstrate that control policy assumptions made in previous studies do not fully describe the policies of our participants. To account for these discrepancies, we propose a new model that captures (1) how the user's neural population activity gradually declines as the cursor approaches the target from afar, then decreases more sharply as the cursor comes into contact with the target, (2) how the user makes constant feedback corrections even when the cursor is on top of the target, and (3) how the user actively accounts for the cursor's current velocity to avoid overshooting the target. Further, we show that users can adapt their control policy to decoder dynamics by attenuating neural modulation when the cursor gain is high and by damping the cursor velocity more strongly when the smoothing dynamics are high.Our control policy model may help to build better decoders, understand how neural activity varies during active iBCI control, and produce better simulations of closed-loop iBCI movements.
View details for DOI 10.1088/1741-2560/14/1/016001
View details for Web of Science ID 000390362600001
View details for PubMedID 27900953
View details for PubMedCentralID PMC5239755
Subthalamic oscillations and phase amplitude coupling are greater in the more affected hemisphere in Parkinson's disease.
2017; 128 (1): 128-137
Determine the incidence of resting state oscillations in alpha/beta, high frequency (HFO) bands, and their phase amplitude coupling (PAC) in a large cohort in Parkinson's disease (PD).Intra-operative local field potentials (LFPs) from subthalamic nucleus (STN) were recorded from 100 PD subjects, data from 74 subjects were included in the analysis.Alpha/beta oscillations were evident in >99%, HFO in 87% and PAC in 98% of cases. Alpha/beta oscillations (P<0.01) and PAC were stronger in the more affected (MA) hemisphere (P=0.03). Alpha/beta oscillations were primarily found in 13-20Hz (low beta). Beta and HFO frequencies with the greatest coupling, were positively correlated (P=0.001). Tremor attenuated alpha (P=0.002) and beta band oscillations (P<0.001).STN alpha/beta band oscillations and PAC were evident in ⩾98% cases and were greater in MA hemisphere. Resting tremor attenuated underlying alpha/beta band oscillations.Beta band LFP power may be used to drive adaptive deep brain stimulation (aDBS), augmented by a kinematic classifier in tremor dominant PD.
View details for DOI 10.1016/j.clinph.2016.10.095
View details for PubMedID 27889627
Signal-independent noise in intracortical brain-computer interfaces causes movement time properties inconsistent with Fitts' law.
Journal of neural engineering
2017; 14 (2): 026010
Do movements made with an intracortical BCI (iBCI) have the same movement time properties as able-bodied movements? Able-bodied movement times typically obey Fitts' law: [Formula: see text] (where MT is movement time, D is target distance, R is target radius, and [Formula: see text] are parameters). Fitts' law expresses two properties of natural movement that would be ideal for iBCIs to restore: (1) that movement times are insensitive to the absolute scale of the task (since movement time depends only on the ratio [Formula: see text]) and (2) that movements have a large dynamic range of accuracy (since movement time is logarithmically proportional to [Formula: see text]).Two participants in the BrainGate2 pilot clinical trial made cortically controlled cursor movements with a linear velocity decoder and acquired targets by dwelling on them. We investigated whether the movement times were well described by Fitts' law.We found that movement times were better described by the equation [Formula: see text], which captures how movement time increases sharply as the target radius becomes smaller, independently of distance. In contrast to able-bodied movements, the iBCI movements we studied had a low dynamic range of accuracy (absence of logarithmic proportionality) and were sensitive to the absolute scale of the task (small targets had long movement times regardless of the [Formula: see text] ratio). We argue that this relationship emerges due to noise in the decoder output whose magnitude is largely independent of the user's motor command (signal-independent noise). Signal-independent noise creates a baseline level of variability that cannot be decreased by trying to move slowly or hold still, making targets below a certain size very hard to acquire with a standard decoder.The results give new insight into how iBCI movements currently differ from able-bodied movements and suggest that restoring a Fitts' law-like relationship to iBCI movements may require non-linear decoding strategies.
View details for DOI 10.1088/1741-2552/aa5990
View details for PubMedID 28177925
Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial.
The lancet. Psychiatry
2017; 4 (11): 839–49
Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted.Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162.Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery.This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy.Abbott (previously St Jude Medical).
View details for DOI 10.1016/S2215-0366(17)30371-1
View details for PubMedID 28988904
- The neurosurgical origins of image-guided surgery CURRENT PROBLEMS IN SURGERY 2015; 52 (12): 476-520
- Beta Oscillations in Freely Moving Parkinson's Subjects Are Attenuated During Deep Brain Stimulation MOVEMENT DISORDERS 2015; 30 (13): 1750-1758
Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial
ANNALS OF NEUROLOGY
2015; 78 (2): 248-257
A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra.We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 × 10(11) vector genomes) and putamen (1.0 × 10(12) vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-month evaluation in the motor subscore of the Unified Parkinson's Disease Rating Scale in the practically defined off state.Fifty-one patients were enrolled in the trial. There was no significant difference between groups in the primary endpoint (change from baseline: AAV2-neurturin, -7.0 ± 9.92; sham, -5.2 ± 10.01; p = 0.515) or in most secondary endpoints. Two subjects had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin.AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin. Ann Neurol 2015;78:248-257.
View details for DOI 10.1002/ana.24436
View details for Web of Science ID 000358501600009
Transcranial MRI-Guided Focused Ultrasound: A Review of the Technologic and Neurologic Applications
AMERICAN JOURNAL OF ROENTGENOLOGY
2015; 205 (1): 150-159
This article reviews the physical principles of MRI-guided focused ultra-sound and discusses current and potential applications of this exciting technology.MRI-guided focused ultrasound is a new minimally invasive method of targeted tissue thermal ablation that may be of use to treat central neuropathic pain, essential tremor, Parkinson tremor, and brain tumors. The system has also been used to temporarily disrupt the blood-brain barrier to allow targeted drug delivery to brain tumors.
View details for DOI 10.2214/AJR.14.13632
View details for Web of Science ID 000356781000041
View details for PubMedID 26102394
Sixty Hertz Neurostimulation Amplifies Subthalamic Neural Synchrony in Parkinson's Disease
2015; 10 (3)
High frequency subthalamic nucleus (STN) deep brain stimulation (DBS) improves the cardinal motor signs of Parkinson's disease (PD) and attenuates STN alpha/beta band neural synchrony in a voltage-dependent manner. While there is a growing interest in the behavioral effects of lower frequency (60 Hz) DBS, little is known about its effect on STN neural synchrony. Here we demonstrate for the first time that during intra-operative 60 Hz STN DBS, one or more bands of resting state neural synchrony were amplified in the STN in PD. We recorded intra-operative STN resting state local field potentials (LFPs) from twenty-eight STNs in seventeen PD subjects after placement of the DBS lead (model 3389, Medtronic, Inc.) before and during three randomized neurostimulation sets (130 Hz/1.35V, 130 Hz/2V, 60 Hz/2V). During 130 Hz/2V DBS, baseline (no DBS) STN alpha (8 - 12 Hz) and beta (13 - 35 Hz) band power decreased (N=14, P < 0.001 for both), whereas during 60 Hz/2V DBS, alpha band and peak frequency power increased (P = 0.012, P = 0.007, respectively). The effect of 60 Hz/2V DBS opposed that of power-equivalent (130 Hz/1.35V) DBS (alpha: P < 0.001, beta: P = 0.006). These results show that intra-operative 60 Hz STN DBS amplified whereas 130 Hz STN DBS attenuated resting state neural synchrony in PD; the effects were frequency-specific. We demonstrate that neurostimulation may be useful as a tool to selectively modulate resting state resonant bands of neural synchrony and to investigate its influence on motor and non-motor behaviors in PD and other neuropsychiatric diseases.
View details for DOI 10.1371/journal.pone.0121067
View details for Web of Science ID 000351880000129
View details for PubMedID 25807463
Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy.
2015; 84 (10): 1017-1025
To report long-term efficacy and safety results of the SANTE trial investigating deep brain stimulation of the anterior nucleus of the thalamus (ANT) for treatment of localization-related epilepsy.This long-term follow-up is a continuation of a previously reported trial of 5- vs 0-V ANT stimulation. Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators' discretion. Seizure frequency was determined using daily seizure diaries.The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001).Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population.This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years.
View details for DOI 10.1212/WNL.0000000000001334
View details for PubMedID 25663221
Lack of efficacy of motor cortex stimulation for the treatment of neuropathic pain in 14 patients.
2014; 17 (4): 303-311
Motor cortex stimulation has been reported as an effective treatment for medically resistant neuropathic pain. The goal of this study is to review the efficacy of this treatment in a series of 14 patients.The records of a consecutive series of 14 patients undergoing MCS for neuropathic pain at Stanford University Hospital and Clinics between 2002 and 2010 were retrospectively analyzed. The primary outcome measure was a visual analogue scale, which patients completed prior to surgery and following each programming session. The motor cortex was localized using 1) MR image guidance, 2) intraoperative somatosensory evoked potentials and motor response to stimulation, and 3) postoperative imaging. All patients underwent extensive stimulator programming.Five patients exhibited a transient improvement of >50%. Of these, only two patients maintained >50% improvement to their last clinic visit. One of these patients died of unrelated causes, and the other complained of variable response at home. The median time from best to final VAS was 50 days. Average postoperative follow-up was 55.5 weeks. Postoperative imaging demonstrated appropriate lead placement in 12 patients. The other two patients did not undergo postoperative imaging.In our cohort of 14 patients with neuropathic pain, motor cortex stimulation failed to produce acceptable long-term benefit. Possible reasons for this failure are discussed in the context of a small retrospective study.
View details for DOI 10.1111/ner.12181
View details for PubMedID 24773411
194 High Performance Computer Cursor Control Using Neuronal Ensemble Recordings From the Motor Cortex of a Person With ALS.
2013; 60: 184-?
Chronically implanted brain-computer interface systems have been demonstrated in several human research participants, with encouraging early results. A major aim of the current project is to provide improved speed and accuracy of computer cursor control for people with paralysis.A 50-year-old woman with Amyotrophic Lateral Sclerosis (ALS) and weakness of all 4 limbs (but with some retained upper extremity function) underwent implantation of an array of 100 silicon microelectrodes into the 'hand knob' area of the precentral gyrus as part of a multi-site pilot clinical trial (Braingate2, IDE). Beginning 1 month following implantation, twice-weekly recording sessions were carried out in the participant's home. A circular cursor and several targets were displayed on a computer monitor. The participant performed a 'center-out' cursor task by moving her finger on a trackpad to acquire the targets while neural activity was recorded. This neural activity was correlated with finger movement to produce a velocity-based Kalman filter, which was in turn used to derive on-screen cursor movement from neural activity. Under neural control, the participant acquired 1 of either 4 or 8 peripheral targets, placed between 150 and 225 pixels from a central target. Each block consisted of 160 consecutive trials. Targets were acquired by touching the target with the neurally controlled cursor, with or without a required dwell time. All targets had a diameter of 100 pixels: Accuracy and acquisition time varied across 36 blocks, with more recent sessions tending toward higher performance. Best performance in the 8 target task with 250 msec dwell was 92% accuracy, with average acquisition time of 1.89 ± 1.09 seconds.Our research participant was able to acquire targets using neural control with high speed and accuracy. Optimizations are being explored to increase performance further, with the eventual goal of providing cursor control approaching that achievable by able-bodied computer users.
View details for DOI 10.1227/01.neu.0000432784.58847.74
View details for PubMedID 23839461
- Hand posture classification using electrocorticography signals in the gamma band over human sensorimotor brain areas JOURNAL OF NEURAL ENGINEERING 2013; 10 (2)
Deep brain stimulation surgical techniques.
Handbook of clinical neurology
2013; 116: 27-37
Stereotactic techniques for placement of deep brain stimulation (DBS) electrodes have undergone continuous refinement since the introduction of human stereotaxis in the 1940s. Volumetric imaging techniques, including magnetic resonance imaging and computed tomography, have replaced ventriculography, and increasingly sophisticated computer systems now allow highly refined targeting of subcortical structures. This chapter reviews the underlying principles of stereotactic surgery, including imaging, targeting, and registration, and describes the surgical approach to DBS placement using both framed and frameless techniques.
View details for DOI 10.1016/B978-0-444-53497-2.00003-6
View details for PubMedID 24112882
High frequency deep brain stimulation attenuates subthalamic and cortical rhythms in Parkinson's disease
FRONTIERS IN HUMAN NEUROSCIENCE
Parkinson's disease (PD) is marked by excessive synchronous activity in the beta (8-35 Hz) band throughout the cortico-basal ganglia network. The optimal location of high frequency deep brain stimulation (HF DBS) within the subthalamic nucleus (STN) region and the location of maximal beta hypersynchrony are currently matters of debate. Additionally, the effect of STN HF DBS on neural synchrony in functionally connected regions of motor cortex is unknown and is of great interest. Scalp EEG studies demonstrated that stimulation of the STN can activate motor cortex antidromically, but the spatial specificity of this effect has not been examined. The present study examined the effect of STN HF DBS on neural synchrony within the cortico-basal ganglia network in patients with PD. We measured local field potentials dorsal to and within the STN of PD patients, and additionally in the motor cortex in a subset of these patients. We used diffusion tensor imaging (DTI) to guide the placement of subdural cortical surface electrodes over the DTI-identified origin of the hyperdirect pathway (HDP) between motor cortex and the STN. The results demonstrated that local beta power was attenuated during HF DBS both dorsal to and within the STN. The degree of attenuation was monotonic with increased DBS voltages in both locations, but this voltage-dependent effect was greater in the central STN than dorsal to the STN (p < 0.05). Cortical signals over the estimated origin of the HDP also demonstrated attenuation of beta hypersynchrony during DBS dorsal to or within STN, whereas signals from non-specific regions of motor cortex were not attenuated. The spatially-specific suppression of beta synchrony in the motor cortex support the hypothesis that DBS may treat Parkinsonism by reducing excessive synchrony in the functionally connected sensorimotor network.
View details for DOI 10.3389/fnhum.2012.00155
View details for Web of Science ID 000304862500001
View details for PubMedID 22675296
- Does Ganglionectomy Still Have a Role in the Era of Neuromodulation? WORLD NEUROSURGERY 2012; 77 (2): 280-282
EMERGING HORIZONS IN NEUROMODULATION: NEW FRONTIERS IN BRAIN AND SPINE STIMULATION
2012; 107: 185-205
The recent development of optogenetics, a revolutionary research tool in neuroscience, portends an evolution of current clinical neuromodulation tools. A form of gene therapy, optogenetics makes possible highly precise spatial and temporal control of specific neuronal populations. This technique has already provided several new insights relevant to clinical neuroscience, from the physiological substrate of functional magnetic resonance imaging to the mechanism of deep brain stimulation in Parkinson's disease. The increased precision of optogenetic techniques also raises the possibility of eventual human use. Translational efforts have begun in primates, with success reported from multiple labs in rhesus macaques. These developments will remain of ongoing interest to neurologists and neurosurgeons.
View details for DOI 10.1016/B978-0-12-404706-8.00010-3
View details for Web of Science ID 000314132800009
View details for PubMedID 23206683
"Connectomic surgery": diffusion tensor imaging (DTI) tractography as a targeting modality for surgical modulation of neural networks.
Frontiers in integrative neuroscience
2012; 6: 15-?
Deep brain stimulation (DBS) is being used to treat a growing number of neurological disorders. Until recently, DBS has been thought to act mainly by suppressing local neuronal activity, essentially producing a functional lesion. Numerous studies are now demonstrating that DBS has widespread network effects mediated by white matter pathways. The new science of connectomics aims to map the connectivity between brain regions in health and disease. Targeting DBS specifically to pathways which exhibit pathological connectivity could greatly expand the possibilities for treating brain diseases. This brief review examines the current state of brain imaging for visualization of these networks and describes how DBS might be used to restore normal connectivity in pathological states.
View details for DOI 10.3389/fnint.2012.00015
View details for PubMedID 22536176
Maximal subthalamic beta hypersynchrony of the local field potential in Parkinson's disease is located in the central region of the nucleus
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
2011; 82 (12): 1387-1389
A pathological marker of Parkinson's disease is the existence of abnormal synchrony of neuronal activity within the beta frequency range (13-35 Hz) in the subthalamic nucleus (STN). Recent studies examining the topography of this rhythm have located beta hypersynchrony in the most dorsal part of the STN. In contrast, this study of the topography of the local field potential beta oscillations in 18 STNs with a 1 mm spatial resolution revealed that the point of maximal beta hypersynchrony was located at 53 ± 24% of the trajectory span from the dorsal to the ventral borders of the STN (corresponding to a 3.0 ± 1.6 mm depth for a 5.9 ± 0.75 mm STN span). This suggests that maximal beta hypersynchrony is located in the central region of the nucleus and that further investigation should be done before using STN spectral profiles as an indicator for guiding placement of deep brain stimulation leads.
View details for DOI 10.1136/jnnp.2010.223107
View details for Web of Science ID 000296766100018
View details for PubMedID 21205981
Incidence and Avoidance of Neurologic Complications with Paddle Type Spinal Cord Stimulation Leads
2011; 14 (5): 412-422
While reference is frequently made to the risk of spinal cord or nerve root injury with the surgical implantation of paddle type spinal cord stimulation (SCS) electrodes, data are lacking on the frequency, causes, and prevention of these complications. To determine the incidence and frequency of neurologic complications, we performed 1) a comprehensive analysis of the literature to determine the incidence of complications that have caused or could lead to neurologic injury; 2) an analysis of the US Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) data base; and 3) an investigation of manufacturers' data on surgically implanted paddle electrodes. We then convened an expert panel of neurosurgeons experienced in the surgical implantation of paddle electrodes to provide recommendations to minimize the risk of neurologic injury. The scientific literature describes the breadth of neurologic complications that can result from SCS electrode implantation but does not provide interpretable data with respect to the incidence and frequency of these complications. The MAUDE data base is not constructed to be sensitive or specific enough to provide these critical data. Primary data show a risk of neurologic injury from implantation of paddle electrodes below 0.6%. Preoperative, intraoperative, and postoperative measures to further minimize this risk are described. This investigation, the first comprehensive evaluation of the incidence and frequency of neurologic injury as a result of SCS paddle electrode implantation, suggests that neurologic injury is a rare, but serious, complication of SCS. The incidence of these complications should be decreased by the adoption of approaches that improve procedural safety and by careful patient follow-up and complication management. Physicians should be aware of these approaches and take every precaution to reduce the risk of neurologic injury. Physicians also should report any adverse event leading to injury or death and work together to improve access to these data.
View details for DOI 10.1111/j.1525-1403.2011.00395.x
View details for Web of Science ID 000295522000005
View details for PubMedID 21967534
Human Subthalamic Neuron Spiking Exhibits Subtle Responses to Sedatives
2011; 115 (2): 254-264
During deep brain stimulation implant surgery, microelectrode recordings are used to map the location of targeted neurons. The effects produced by propofol or remifentanil on discharge activity of subthalamic neurons were studied intraoperatively to determine whether they alter neuronal activity.Microelectrode recordings from 11 neurons, each from individual patients, were discriminated and analyzed before and after administration of either propofol or remifentanil. Subthalamic neurons in rat brain slices were recorded in patch-clamp to investigate cellular level effects.Neurons discharged at 42 ± 9 spikes/s (mean ± SD) and showed a common pattern of inhibition that lasted 4.3 ms. Unique discharge profiles were evident for each neuron, seen using joint-interval analysis. Propofol (intravenous bolus 0.3 mg/kg) produced sedation, with minor effects on discharge activity (less than 2.0% change in frequency). A prolongation of recurrent inhibition was evident from joint-interval analysis, and propofol's effect peaked within 2 min, with recovery evident at 10 min. Subthalamic neurons recorded in rat brain slices exhibited inhibitory synaptic currents that were prolonged by propofol (155%) but appeared to lack tonic inhibitory currents. Propofol did not alter membrane potential, membrane resistance, current-evoked discharge, or holding current during voltage clamp. Remifentanil (0.05 mg/kg) had little effect on overall subthalamic neuron discharge activity and did not prolong recurrent inhibition.These results help to characterize the circuit properties and feedback inhibition of subthalamic neurons and demonstrate that both propofol and remifentanil produce only minor alterations of subthalamic neuron discharge activity that should not interfere with deep brain stimulation implant surgery.
View details for Web of Science ID 000293168800006
View details for PubMedID 21701380
Long-Term Outcomes of Spinal Cord Stimulation With Paddle Leads in the Treatment of Complex Regional Pain Syndrome and Failed Back Surgery Syndrome
2011; 14 (4): 312-318
Spinal cord stimulation (SCS) is frequently used to treat chronic, intractable back, and leg pain. Implantation can be accomplished with percutaneous leads or paddle leads. Although there is an extensive literature on SCS, the long-term efficacy, particularly with paddle leads, remains poorly defined. Outcome measure choice is important when defining therapeutic efficacy for chronic pain. Numerical rating scales such as the NRS-11 remain the most common outcome measure in the literature, although they may not accurately correlate with quality of life improvements and overall satisfaction.We reviewed the medical records of patients with failed back surgery syndrome (FBSS) or complex regional pain syndrome (CRPS) implanted with SCS systems using paddle leads between 1997 and 2008 at the Cleveland Clinic with a minimum six-month follow-up. Patients were contacted to fill out a questionnaire evaluating outcomes with the NRS-11 as well as overall satisfaction.A total of 35 eligible patients chose to participate. More than 50% of the patients with CRPS reported greater than 50% pain relief at a mean follow-up of 4.4 years. Approximately 30% of the FBSS patients reported a 50% or greater improvement at a mean follow-up of 3.8 years. However, 77.8% of patients with CRPS and 70.6% of patients with FBSS indicated that they would undergo SCS surgery again for the same outcome.Patients with CRPS and FBSS have a high degree of satisfaction, indexed as willingness to undergo the same procedure again for the same outcome at a mean follow-up of approximately four years. The percentage of satisfaction with the SCS system is disproportionally greater than the percentage of patients reporting 50% pain relief, particularly among patients with FBSS. This suggests that the visual analog scale may not be the optimal measure to evaluate long-term outcomes in this patient population.
View details for DOI 10.1111/j.1525-1403.2011.00372.x
View details for Web of Science ID 000293562500007
View details for PubMedID 21992424
- OPTOGENETICS: BACKGROUND AND CONCEPTS FOR NEUROSURGERY NEUROSURGERY 2011; 69 (1): 1-3
Spinal Cord Stimulation Versus Re-operation in Patients With Failed Back Surgery Syndrome: An International Multicenter Randomized Controlled Trial (EVIDENCE Study)
2011; 14 (4): 330-335
This paper presents the protocol of the EVIDENCE study, a multicenter multinational randomized controlled trial to assess the effectiveness and cost-effectiveness of spinal cord stimulation (SCS) with rechargeable pulse generator versus re-operation through 36-month follow-up in patients with failed back surgery syndrome.Study subjects have neuropathic radicular leg pain exceeding or equaling any low back pain and meet specified entry criteria. One-to-one randomization is stratified by site and by one or more prior lumbosacral operations. The sample size of 132 subjects may be adjusted to between 100 and 200 subjects using a standard adaptive design statistical method with pre-defined rules. Crossover treatment is possible. Co-primary endpoints are proportion of subjects reporting ≥ 50% leg pain relief without crossover at 6 and at 24 months after SCS screening trial or re-operation. Insufficient pain relief constitutes failure of randomized treatment, as does crossover. Secondary endpoints include cost-effectiveness; relief of leg, back, and overall pain; change in disability and quality of life; and rate of crossover. We are collecting data on subject global impression of change, patient satisfaction with treatment, employment status, pain/paresthesia overlap, SCS programming, and adverse events.As the first multicenter randomized controlled trial of SCS versus re-operation and the first to use only rechargeable SCS pulse generators, the EVIDENCE study will provide up-to-date evidence on the treatment of failed back surgery syndrome.
View details for DOI 10.1111/j.1525-1403.2011.00371.x
View details for Web of Science ID 000293562500019
View details for PubMedID 21992427
AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial
2011; 10 (4): 309-319
Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson's disease.Patients aged 30-75 years who had progressive levodopa-responsive Parkinson's disease and an overnight off-medication unified Parkinson's disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890.Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD group vs two in the sham group) and nausea (six vs two).The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinson's disease and shows the promise for gene therapy for neurological disorders.Neurologix.
View details for DOI 10.1016/S1474-4422(11)70039-4
View details for Web of Science ID 000289185000014
View details for PubMedID 21419704
- Deep Brain Stimulation in "On"-State Parkinson Hyperpyrexia NEUROLOGY 2011; 76 (7): S69-S71
Deep Brain Stimulation for Parkinson Disease An Expert Consensus and Review of Key Issues
ARCHIVES OF NEUROLOGY
2011; 68 (2): 165-171
To provide recommendations to patients, physicians, and other health care providers on several issues involving deep brain stimulation (DBS) for Parkinson disease (PD).An international consortium of experts organized, reviewed the literature, and attended the workshop. Topics were introduced at the workshop, followed by group discussion.A draft of a consensus statement was presented and further edited after plenary debate. The final statements were agreed on by all members.(1) Patients with PD without significant active cognitive or psychiatric problems who have medically intractable motor fluctuations, intractable tremor, or intolerance of medication adverse effects are good candidates for DBS. (2) Deep brain stimulation surgery is best performed by an experienced neurosurgeon with expertise in stereotactic neurosurgery who is working as part of a interprofessional team. (3) Surgical complication rates are extremely variable, with infection being the most commonly reported complication of DBS. (4) Deep brain stimulation programming is best accomplished by a highly trained clinician and can take 3 to 6 months to obtain optimal results. (5) Deep brain stimulation improves levodopa-responsive symptoms, dyskinesia, and tremor; benefits seem to be long-lasting in many motor domains. (6) Subthalamic nuclei DBS may be complicated by increased depression, apathy, impulsivity, worsened verbal fluency, and executive dysfunction in a subset of patients. (7) Both globus pallidus pars interna and subthalamic nuclei DBS have been shown to be effective in addressing the motor symptoms of PD. (8) Ablative therapy is still an effective alternative and should be considered in a select group of appropriate patients.
View details for DOI 10.1001/archneurol.2010.260
View details for Web of Science ID 000287330300003
View details for PubMedID 20937936
Probabilistic analysis of activation volumes generated during deep brain stimulation
2011; 54 (3): 2096-2104
Deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson's disease (PD) and shows great promise for the treatment of several other disorders. However, while the clinical analysis of DBS has received great attention, a relative paucity of quantitative techniques exists to define the optimal surgical target and most effective stimulation protocol for a given disorder. In this study we describe a methodology that represents an evolutionary addition to the concept of a probabilistic brain atlas, which we call a probabilistic stimulation atlas (PSA). We outline steps to combine quantitative clinical outcome measures with advanced computational models of DBS to identify regions where stimulation-induced activation could provide the best therapeutic improvement on a per-symptom basis. While this methodology is relevant to any form of DBS, we present example results from subthalamic nucleus (STN) DBS for PD. We constructed patient-specific computer models of the volume of tissue activated (VTA) for 163 different stimulation parameter settings which were tested in six patients. We then assigned clinical outcome scores to each VTA and compiled all of the VTAs into a PSA to identify stimulation-induced activation targets that maximized therapeutic response with minimal side effects. The results suggest that selection of both electrode placement and clinical stimulation parameter settings could be tailored to the patient's primary symptoms using patient-specific models and PSAs.
View details for DOI 10.1016/j.neuroimage.2010.10.059
View details for Web of Science ID 000286302000033
View details for PubMedID 20974269
A Socioeconomic Survey of Spinal Cord Stimulation (SCS) Surgery
2010; 13 (4): 265-269
We evaluated trends in inpatient spinal cord stimulation (SCS) for the 14-year period from 1993 to 2006.We utilized the Nationwide Inpatient Sample data base from the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality.A total of 57,486 patients underwent inpatient placement of SCS systems from 1993 to 2006. Length of stay steadily decreased from 4.0 days in 1993 to 2.1 days in 2006. Average cost increased from $15,342 in 1993 to nearly $58,088 in 2006. The National Bill for SCS surgery in 2006 alone totaled nearly $215MM. Medicare accounted for 35% of payers, while private insurance accounted for 41% of claims.Given the expense of these systems, it is important to assess not only the efficacy of novel neuromodulatory interventions, but also their cost. Future studies should be designed with these important outcome measures in mind.
View details for DOI 10.1111/j.1525-1403.2010.00292.x
View details for Web of Science ID 000282640100004
View details for PubMedID 21992880
Clinical Motor Outcome of Bilateral Subthalamic Nucleus Deep-Brain Stimulation for Parkinson's Disease Using Image-Guided Frameless Stereotaxy
2010; 67 (4): 1088-1093
Image-guided neuronavigation has largely replaced stereotactic frames when precise, real-time anatomic localization is required during neurosurgical procedures. However, some procedures, including placement of deep-brain stimulation (DBS) leads for the treatment of movement disorders, are still performed using frame-based stereotaxy. Despite the demonstration of comparable accuracy between frame-based and "frameless" image-guided approaches, the clinical efficacy of frameless DBS placement has never been reported.To analyze the outcomes of subthalamic nucleus (STN) DBS using the frameless technique for the treatment of Parkinson's disease (PD).Of 31 subjects (20 men) with PD for 10 ± 4 years, 28 had bilateral STN DBS and 3 had unilateral STN DBS. The Unified Parkinson's Disease Rating Scale (UPDRS) motor scale (III) and total medication doses were assessed before surgery on and off medication and off medication/ON DBS (off/ON) after 6 to 12 months of STN DBS.There was a 58% improvement from bilateral STN DBS in the UPDRS III (40 ± 16 preoperatively off, 17 ± 11 off/ON) 9.6 ± 1.9 months after surgery (P < .001). This compared favorably with the published outcomes using the frame-based technique. All motor subscores improved significantly (P < .01). The mean reduction in medication was 50%. No intraoperative complications occurred, but one subject with hypertension died of a delayed hemorrhage postoperatively. Two subjects developed postoperative infections that required lead removal and antibiotics.Bilateral STN DBS for PD performed by an experienced team using a frameless approach results in outcomes comparable to those reported with the use of the frame-based technique.
View details for DOI 10.1227/NEU.0b013e3181ecc887
View details for Web of Science ID 000282197900060
View details for PubMedID 20881573
alpha-Synuclein Suppression by Targeted Small Interfering RNA in the Primate Substantia Nigra
2010; 5 (8)
The protein alpha-synuclein is involved in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Its toxic potential appears to be enhanced by increased protein expression, providing a compelling rationale for therapeutic strategies aimed at reducing neuronal alpha-synuclein burden. Here, feasibility and safety of alpha-synuclein suppression were evaluated by treating monkeys with small interfering RNA (siRNA) directed against alpha-synuclein. The siRNA molecule was chemically modified to prevent degradation by exo- and endonucleases and directly infused into the left substantia nigra. Results compared levels of alpha-synuclein mRNA and protein in the infused (left) vs. untreated (right) hemisphere and revealed a significant 40-50% suppression of alpha-synuclein expression. These findings could not be attributable to non-specific effects of siRNA infusion since treatment of a separate set of animals with luciferase-targeting siRNA produced no changes in alpha-synuclein. Infusion with alpha-synuclein siRNA, while lowering alpha-synuclein expression, had no overt adverse consequences. In particular, it did not cause tissue inflammation and did not change (i) the number and phenotype of nigral dopaminergic neurons, and (ii) the concentrations of striatal dopamine and its metabolites. The data represent the first evidence of successful anti-alpha-synuclein intervention in the primate substantia nigra and support further development of RNA interference-based therapeutics.
View details for DOI 10.1371/journal.pone.0012122
View details for Web of Science ID 000280849100030
View details for PubMedID 20711464
Socioeconomic Trends in Deep Brain Stimulation (DBS) Surgery
2010; 13 (3): 182-186
Objective: We evaluated trends in deep brain stimulation (DBS) for the 14-year period from 1993 to 2006. Materials and Methods: We utilized the Nationwide Inpatient Sample data base from the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. Results: A total of 34,792 patients underwent DBS surgery from 1993 to 2006. There were 756 DBS cases performed in 1993 compared with 4200 DBS procedures performed in 2006. Significant increases in nationwide DBS volume coincided with regulatory approval for new indications-Parkinson's disease and dystonia, respectively. Cost of DBS surgery increased from $38,840 in 1993 to $69,329 in 2006. The majority of cases were done in metropolitan areas (97%) at large academic centers (91%) at a national bill of $291 MM. Conclusions: Future studies will need to include the socioeconomic impact of the technology on disease status, patient access, and costs as it expands to novel indications.
View details for DOI 10.1111/j.1525-1403.2010.00278.x
View details for Web of Science ID 000279764700011
View details for PubMedID 21992830
Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy
2010; 51 (5): 899-908
We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy.Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation.One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and "most severe" seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events.Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.
View details for DOI 10.1111/j.1528-1167.2010.02536.x
View details for Web of Science ID 000277000900024
View details for PubMedID 20331461
Intracranial Neurostimulation for Pain Control: A Review
2010; 13 (2): 157-165
Intracranial neurostimulation for pain relief is most frequently delivered by stimulating the motor cortex, the sensory thalamus, or the periaqueductal and periventricular gray matter. The stimulation of these sites through MCS (motor cortex stimulation) and DBS (deep brain stimulation) has proven effective for treating a number of neuropathic and nociceptive pain states that are not responsive or amenable to other therapies or types of neurostimulation. Prospective randomized clinical trials to confirm the efficacy of these intracranial therapies have not been published. Intracranial neurostimulation is somewhat different than other forms of neurostimulation in that its current primary application is for the treatment of medically intractable movement disorders. However, the increasing use of intracranial neurostimulation for the treatment of chronic pain, especially for pain not responsive to other neuromodulation techniques, reflects the efficacy and relative safety of these intracranial procedures. First employed in 1954, intracranial neurostimulation represents one of the earliest uses of neurostimulation to treat chronic pain that is refractory to medical therapy. Currently, 2 kinds of intracranial neurostimulation are commonly used to control pain: motor cortex stimulation and deep brain stimulation. MCS has shown particular promise in the treatment of trigeminal neuropathic pain and central pain syndromes such as thalamic pain syndrome. DBS may be employed for a number of nociceptive and neuropathic pain states, including cluster headaches, chronic low back pain, failed back surgery syndrome, peripheral neuropathic pain, facial deafferentation pain, and pain that is secondary to brachial plexus avulsion. The unique lack of stimulation-induced perceptual experience with MCS makes MCS uniquely suited for blinded studies of its effectiveness. This article will review the scientific rationale, indications, surgical techniques, and outcomes of intracranial neuromodulation procedures for the treatment of chronic pain.
View details for Web of Science ID 000276581600006
View details for PubMedID 20309382
Recurrent Seizures Related to Motor Cortex Stimulator Programming
2010; 13 (1): 37-42
Objective. Motor cortex stimulation (MCS) is increasingly being utilized for the treatment of intractable pain. While the risks of MCS are relatively low, focal or generalized seizures may be produced during programming of MCS systems. Occasionally, patients may experience seizures hours after programming. In order to understand this phenomenon better, we undertook a retrospective analysis of five patients in whom seizures limited the efficacy of MCS. Methods. A retrospective chart review was performed in five patients who underwent MCS between 2002 and 2006 and who had persistent seizures that limited programming. Results. The initial seizure during programming in these patients occurred at amplitudes of between 4.8 and 6.6 V. Four patients experienced generalized tonic-clonic seizures and one patient experienced focal seizures. Subsequent seizures occurred at amplitudes of between 4.4 and 5.5 V, with a tendency for seizure thresholds to progressively decrease. All five patients experienced at least one seizure occurring many minutes to hours after programming, with no side-effects initially observed once the final settings had been programmed. Four out of five patients were programmed with frequencies documented at between 70 and 90 Hz; documentation on frequency was unavailable for the remaining patient. One patient never achieved adequate pain relief and had the MCS system explanted. Conclusions. Despite the overall safety of MCS for the treatment of chronic pain, seizures during and after programming are a serious risk that should be anticipated. In this group of patients, seizures were associated only with stimulus rates between 70 and 90 Hz. No patient developed chronic epilepsy from the stimulation.
View details for DOI 10.1111/j.1525-1403.2009.00256.x
View details for Web of Science ID 000273318200016
View details for PubMedID 21992763
Bilateral symmetry and coherence of subthalamic nuclei beta band activity in Parkinson's disease
2010; 221 (1): 260-266
Abnormal synchronization of neuronal activity in the basal ganglia has been associated with the dysfunction of sensorimotor circuits in Parkinson's disease (PD). In particular, oscillations at frequencies within the beta range (13-35 Hz) are specifically modulated by dopaminergic medication and are correlated with the clinical state of the subjects. While these oscillations have been shown to be coherent ipsilaterally within the basal ganglia and between the basal ganglia nuclei and the ipsilateral motor cortex in PD, the bilateral extent of their coherence has never been characterized. Here we demonstrate for the first time that the beta band oscillations recorded in the local field potential of the subthalamic nuclei (STN), while appearing different across subjects, are occurring at the same frequencies bilaterally (p<0.001) and are coherent between the two STNs of individual PD subjects (11/12 cases, p<0.05). These findings suggest the existence of a bilateral network controlling the beta band activity in the basal ganglia in PD.
View details for DOI 10.1016/j.expneurol.2009.11.012
View details for Web of Science ID 000273827500030
View details for PubMedID 19944098
NANS Training Requirements for Spinal Cord Stimulation Devices: Selection, Implantation, and Follow-up
2009; 12 (3): 171-174
View details for Web of Science ID 000267540300001
2009; 64 (5): 796-804
Modulation of the nervous system by electrical or chemical means (neuromodulation) is becoming increasingly sophisticated, with application to a growing number of neurological diseases. However, both chemical and electrical neuromodulation are limited in their specificity. Electrical stimulation, for example, indiscriminately activates different neuronal populations within the electrical field, leading to side effects that can limit efficacy. The delivery of genes that encode proteins capable of conveying light sensitivity to neurons has provided a tool that may overcome some of the limitations of traditional neuromodulation techniques. Activation or inhibition of specific neuronal populations with different wavelengths of light opens up possibilities for modulating neural circuits with previously unimagined levels of precision. We briefly review this new technology, illustrating its advantages and potential applications.
View details for DOI 10.1227/01.NEU.0000339171.87593.6A
View details for Web of Science ID 000265661100014
View details for PubMedID 19404144
Optical Deconstruction of Parkinsonian Neural Circuitry
2009; 324 (5925): 354-359
Deep brain stimulation (DBS) is a therapeutic option for intractable neurological and psychiatric disorders, including Parkinson's disease and major depression. Because of the heterogeneity of brain tissues where electrodes are placed, it has been challenging to elucidate the relevant target cell types or underlying mechanisms of DBS. We used optogenetics and solid-state optics to systematically drive or inhibit an array of distinct circuit elements in freely moving parkinsonian rodents and found that therapeutic effects within the subthalamic nucleus can be accounted for by direct selective stimulation of afferent axons projecting to this region. In addition to providing insight into DBS mechanisms, these results demonstrate an optical approach for dissection of disease circuitry and define the technological toolbox needed for systematic deconstruction of disease circuits by selectively controlling individual components.
View details for DOI 10.1126/science.1167093
View details for Web of Science ID 000265221600033
View details for PubMedID 19299587
The STN beta-band profile in Parkinson's disease is stationary and shows prolonged attenuation after deep brain stimulation
2009; 215 (1): 20-28
Producing accurate movements may rely on the functional independence of sensorimotor circuits within basal ganglia nuclei. In parkinsonism there is abnormal synchrony of electrical activity within these circuits that results in a loss of independence across motor channels. Local field potential (LFP) recordings reflect the summation of local electrical fields and an increase in LFP power reflects increased synchrony in local neuronal networks. We recorded LFPs from the subthalamic nucleus (STN) deep brain stimulation (DBS) lead in the operating room in 22 cases from 16 subjects with Parkinson's disease (PD) who were off medication. There was elevated LFP power at beta frequencies (13-35 Hz) at rest. The LFP spectral profile was consistent across several periods of rest that were separated by movement and/or DBS, and appeared to be a relatively stationary phenomenon. The spectral profile and frequencies of the beta-band peak(s) varied among subjects but were similar between the right and left STNs within certain individuals. These results suggest that the LFP spectrum at rest may characterize a "signature" rhythm for an individual with PD. Beta-band power was attenuated after intra-operative STN DBS (p<0.05). The attenuation lasted for 10 s after short periods (30 s) and for up to 50 s after longer periods (5 min) of DBS. The finding that longer periods of DBS attenuated beta power for a longer time suggests that there may be long-acting functional changes to networks in the STN in PD after chronic DBS.
View details for DOI 10.1016/j.expneurol.2008.09.008
View details for Web of Science ID 000262462300003
View details for PubMedID 18929561
- Advanced Neurotechnologies for Chronic Neural Interfaces: New Horizons and Clinical Opportunities JOURNAL OF NEUROSCIENCE 2008; 28 (46): 11830-11838
Spinal cord stimulation has comparable efficacy in common pain etiologies
2008; 11 (3): 171-181
Objectives. The probability of success with spinal cord stimulation (SCS) depends largely on appropriate patient selection. Here, we have assessed the predictive value of pain etiology as it relates to pain relief with SCS as part of a prospective multicenter clinical trial. Methods. Sixty-five subjects with chronic and intractable pain tested an epidural SCS system. Subjects reported pain ratings (visual analog scale) with stimulation off and stimulation on at scheduled follow-up visits for up to 18 months after activation of the system. Visual analog scale scores were averaged and stratified by dominant pain etiologies, comprising failed back surgery syndrome, complex regional pain syndrome, and a subgroup of subjects with miscellaneous other pain etiologies. Results. More than 70% of subjects in each subgroup had successful outcomes during the temporary trial period and similar percentages of subjects from each etiology subgroup subsequently went on to permanent implantation. After permanent implantation, all subgroups reported more than 50% pain relief, on average, at each follow-up time point. No predictive value of pain etiology was observed. Conclusions. Spinal cord stimulation is an effective therapy for neuropathic pain arising from a variety of causes. Failed back surgery syndrome, complex regional pain syndrome, and pain of other etiologies responded equally well to SCS.
View details for Web of Science ID 000257673600004
Peripheral nerve stimulation for chronic pain
CURRENT PAIN AND HEADACHE REPORTS
2008; 12 (1): 28-31
Electrical stimulation has been used since ancient times to treat painful conditions. Electrotherapy for pain was largely consigned to the realm of quackery until the introduction of the Gate Control Theory by Melzack and Wall in 1965 provided a rationale for direct stimulation of peripheral nerves. Since that time, peripheral nerve stimulation has been applied to the treatment of painful conditions throughout the body, beginning with the major nerves of the extremities and culminating today in precise subcutaneous field stimulation targeted to specific areas of neuropathic pain. This article reviews the history, development, and current areas of interest in peripheral nerve stimulation for the treatment of neuropathic pain.
View details for Web of Science ID 000254517700004
View details for PubMedID 18417020
Fluoroscopic Registration and Localization for Image-Guided Cranial Neurosurgical Procedures: A Feasibility Study
STEREOTACTIC AND FUNCTIONAL NEUROSURGERY
2008; 86 (5): 271-277
Frameless image-guided neurosurgical techniques can achieve high degrees of accuracy when skull-implanted fiducials are used for registration. However, fiducial placement is invasive and uncomfortable for patients. Development of a noninvasive registration method for accurate image-guided functional neurosurgery such as deep brain stimulator placement would therefore be highly desirable. We performed an initial series of experiments using a commercially available fluoroscopic registration package to assess the feasibility of this approach for image-guided functional neurosurgery. We also evaluated the accuracy of landmark placement in the fluoroscopic images using the navigational capability of the software.A fluoroscopic target was created by etching a hexagonal pattern of 1-mm diameter holes on a copper-clad board (0.0254-mm copper cladding on fiberglass). The target was then mounted in a plastic phantom skull, oriented in a mid-sagittal plane. Five implantable fiducial markers were screwed into the phantom in positions which approximated those commonly used clinically. 1.25-mm CT slices were obtained, uploaded to a Stealthstation neuronavigational system and were displayed using the Fluoromerge software package. Lateral and AP images were generated with 2 approximately orthogonal views of the phantom. Registration was carried out both fluoroscopically and using the implanted fiducials. Targets were localized using both methods and the localization errors recorded.Localization error was less than 1 mm using fiducial-based registration, and between 0.8 and 2.9 mm using fluoroscopic registration. Error varied depending on location within the volume of the phantom.Initial experiments show that fluoroscopic registration is feasible for the performance of frameless functional neurosurgical procedures, although accuracy is still insufficient. Intraoperative verification of lead location was also shown to be feasible in one case.
View details for DOI 10.1159/000147635
View details for Web of Science ID 000259875800001
View details for PubMedID 18663338
- Achieving Optimal Accuracy in Frameless Functional Neurosurgical Procedures STEREOTACTIC AND FUNCTIONAL NEUROSURGERY 2008; 86 (5): 332-333
- Spinal cord stimulation has comparable efficacy in common pain etiologies Neuromodulation 2008; 11: 171-181
Intracranial hypotension from intrathecal baclofen pump insertion
STEREOTACTIC AND FUNCTIONAL NEUROSURGERY
2008; 86 (2): 75-79
Intracranial hypotension is a syndrome of low cerebrospinal fluid pressure with a variable clinical presentation ranging from postural headaches to coma. A number of neuroradiologic techniques are now available to aid in the diagnosis of this syndrome (CT, MRI, radioisotope cisternography and CT myelography), each showing specific radiographic abnormalities. In this report, we present a case of intracranial hypotension secondary to baclofen pump placement. We review the major clinical findings, neuroimaging abnormalities, key diagnostic features as well as treatment options.
View details for DOI 10.1159/000112427
View details for Web of Science ID 000253247300002
View details for PubMedID 18073519
A new spinal cord stimulation system effectively relieves chronic, intractable pain: A multicenter prospective clinical study
2007; 10 (3): 262-278
Objectives. A prospective, open label, multicenter clinical trial confirmed the functionality of a new spinal cord stimulation (SCS) system for the treatment of chronic, intractable pain of the trunk and/or limbs. Materials and Methods. Sixty-five subjects tested a rechargeable 16-channel SCS system with individual current control of each contact on one or two percutaneous eight-contact epidural leads. After baseline measurements, subjects were tracked on pain ratings and complication rates for up to 18 months. Results. After a trial period, 75% of subjects underwent permanent implantation of the entire SCS system. More than one-half the implanted subjects experienced 50% or greater relief of pain after permanent implantation; some subjects reported relief of 90% or more of their pain. The most common complications after permanent implantation were lead migration, uncomfortable stimulation, and component failure; most resolved after reprogramming or device replacement. Conclusions. The new SCS system provided good pain relief to a majority of subjects, and the results confirm a favorable safety and efficacy profile for the SCS system.
View details for Web of Science ID 000247477400007
View details for PubMedID 22150839
- CyberKnife targeting the pterygopalatine ganglion for the treatment of chronic cluster headaches NEUROSURGERY 2007; 60 (3): 580-581
Cyberknife targeting the pterygopalatine ganglion for the treatment of chronic cluster headaches.
2007; 60 (3): E580-?
Cluster headache (CH) is a severe unilateral and periorbital facial pain syndrome that is often associated with autonomic symptoms, including ipsilateral lacrimation, nasal congestion, conjunctival injection, miosis, ptosis, and eyelid edema. We evaluated the treatment of medically refractory CH with CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiosurgery targeting the pterygopalatine ganglion.A 56-year-old man presented with a 20-year history of medically refractory CH. His symptoms were described as left-sided, severe, stabbing, burning, and often being associated with tearing and rhinorrhea. These headaches occurred virtually every morning and interfered with sleep, lifestyle, and work performance.The patient underwent two pterygopalatine nerve block trials, both of which resulted in the complete relief of headaches for a 24-hour period. Contrast-enhanced computed axial tomography and magnetic resonance imaging scans were fused for target identification and treatment planning. The target volume measured 0.296 cm3 and a single fraction of 45.50 Gy was delivered to the 78% isodose line with a maximum dose of 65 Gy. The patient kept a detailed diary of his headaches and was followed for 12 months after treatment.Results of CyberKnife targeting of the pterygopalatine ganglion in a patient with medically intractable CHs have revealed a significant decrease in the severity and frequency of headaches after a 12-month follow-up period. In addition, the patient has been able to reduce his medication intake, allowing for a significant decrease in medication-related side effects. Longer follow-up periods and additional studies are required to determine the long-term efficacy and late side effects of this treatment strategy.
View details for PubMedID 17327771
Patient-speciftic analysis of the volume of tissue activated during deep brain stimulation
2007; 34 (2): 661-670
Despite the clinical success of deep brain stimulation (DBS) for the treatment of movement disorders, many questions remain about its effects on the nervous system. This study presents a methodology to predict the volume of tissue activated (VTA) by DBS on a patient-specific basis. Our goals were to identify the intersection between the VTA and surrounding anatomical structures and to compare activation of these structures with clinical outcomes. The model system consisted of three fundamental components: (1) a 3D anatomical model of the subcortical nuclei and DBS electrode position in the brain, each derived from magnetic resonance imaging (MRI); (2) a finite element model of the DBS electrode and electric field transmitted to the brain, with tissue conductivity properties derived from diffusion tensor MRI; (3) VTA prediction derived from the response of myelinated axons to the applied electric field, which is a function of the stimulation parameters (contact, impedance, voltage, pulse width, frequency). We used this model system to analyze the effects of subthalamic nucleus (STN) DBS in a patient with Parkinson's disease. Quantitative measurements of bradykinesia, rigidity, and corticospinal tract (CST) motor thresholds were evaluated over a range of stimulation parameter settings. Our model predictions showed good agreement with CST thresholds. Additionally, stimulation through electrode contacts that improved bradykinesia and rigidity generated VTAs that overlapped the zona incerta/fields of Forel (ZI/H2). Application of DBS technology to various neurological disorders has preceded scientific characterization of the volume of tissue directly affected by the stimulation. Synergistic integration of clinical analysis, neuroimaging, neuroanatomy, and neurostimulation modeling provides an opportunity to address wide ranging questions on the factors linked with the therapeutic benefits and side effects of DBS.
View details for DOI 10.1016/j.neuroimage.2006.09.034
View details for Web of Science ID 000242901100016
View details for PubMedID 17113789
- A new spinal cord stimulation system effectively relieves chronic, intractable pain: A multicenter prospective study Neuromodulation 2007; 10: 262-278
Vagal nerve stimulation versus deep brain stimulation for treatment-resistant depression: show me the data.
2007; 54: 88-90
View details for PubMedID 18504902
A 12-month prospective study of gasserian ganglion stimulation for trigeminal neuropathic pain
STEREOTACTIC AND FUNCTIONAL NEUROSURGERY
2007; 85 (5): 216-224
Trigeminal neuropathic pain is a broad diagnostic category that includes pain of several etiologies and excludes trigeminal neuralgia. The authors report a prospective series of percutaneous gasserian ganglion stimulation for trigeminal neuropathic pain.Patients who experienced >50% reduction in pain from a 7- to 10-day trial period underwent permanent implantation and were prospectively followed.Eight of 10 trialed patients received a permanent implant. At the 12-month follow-up, 2 patients had been explanted and 1 was lost to follow-up. Three (all working at that the time) continued to experience >50% improvement in pain.The results in this series were variable but 3 patients showed long-term improvements. Patients who continued to work responded better to treatment.
View details for DOI 10.1159/000103260
View details for Web of Science ID 000248238000003
View details for PubMedID 17534134
- The clinical and research ethics of neuromodulation NEUROMODULATION 2006; 9 (4): 250-252
Failure modes of spinal cord stimulation hardware
JOURNAL OF NEUROSURGERY-SPINE
2006; 5 (3): 183-190
Epidural spinal cord stimulation (SCS) is effective at treating refractory pain. The failure modes of the implanted hardware, however, have not been well studied. A better understanding of this could aid in improving the current procedure or designing future devices.The authors reviewed electronic charts and operative reports of 289 patients who had undergone SCS implantation between 1998 and 2002 at the Cleveland Clinic Foundation. Data were collected on demographics, type of hardware, date of implantation procedure, indication for treatment, time to failure, and failure mode. Data were then analyzed to identify significant differences. A total of 577 procedures were performed, 43.5% of which involved revision or removal of SCS hardware. The most common indication was complex regional pain syndrome 1, and this was followed by failed-back surgery syndrome. The median number of procedures per patient was two. Approximately 80% of all leads were the percutaneous type. The majority (62%) of leads were placed in the thoracic region, and 33.5% of all leads required revision. Poor pain relief coverage was the most common indication for revision. Surgically implanted leads broke twice as often as percutaneous leads. In 46% of the patients, hardware revision was required, and multiple revisions were necessary in 22.5%. Three-way ANOVA revealed significant differences in failure mode rates according to location (cervical compared with thoracic, p = 0.037) and failure modes (p = 0.019). Laminotomy leads tended to break and migrate sooner than percutaneous leads. Thoracic leads became infected sooner than cervical leads.The results of this analysis of SCS hardware failures may be used as a basis for refining surgical technique and designing the next generation of SCS hardware.
View details for Web of Science ID 000239934100001
View details for PubMedID 16961078
Prevention of mechanical failures in implanted spinal cord stimulation systems
2006; 9 (3): 183-191
Introduction. Spinal cord stimulation (SCS) is an effective procedure for the treatment of neuropathic extremity pain, with success rates approaching 70%. However, mechanical failures, including breakage and migration, can significantly limit the long-term effectiveness of SCS. A systematic analysis of surgical techniques was undertaken by a consensus group, coupled with extensive in vivo and in vitro biomechanical testing of system components. Methods. A computer model based on morphometric data was used to predict movement in a standard SCS system between an anchored lead and pulse generator placed in various locations. These displacements were then used to determine a realistic range of forces exerted on components of the SCS system. Laboratory fixtures were constructed to subject leads and anchors to repetitive stresses until failure occurred. An in vivo sheep model also was used to determine system compliances and failure thresholds in a biologically realistic setting. A panel of experienced implanters then interpreted the results and related them to clinical observations. Results. Use of a soft silastic anchor pushed through the fascia to provide a larger bend radius for the lead was associated with a time to failure 65 times longer than an anchored but unsupported lead. In addition, failures of surgical paddle leads occurred when used with an anchor, whereas without an anchor, no failures occurred to 1 million cycles. Based on these findings, the panel recommended a paramedian approach, abdominal pulse generator placement, maximizing bend radius by pushing the anchor through the fascia, and anchoring of the extension connector near the lead anchor. Discussion. Several factors are important in longevity of SCS systems. We discovered that technical factors can make a large difference in SCS reliability and that strict attention to these "best practices" will provide the best chance for maintaining the integrity of SCS systems over the long term.
View details for Web of Science ID 000238487500002
View details for PubMedID 22151706
Predicting the effects of deep brain stimulation with diffusion tensor based electric field models.
Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention
2006; 9: 429-437
Deep brain stimulation (DBS) is an established therapy for the treatment of movement disorders, and has shown promising results for the treatment of a wide range of other neurological disorders. However, little is known about the mechanism of action of DBS or the volume of brain tissue affected by stimulation. We have developed methods that use anatomical and diffusion tensor MRI (DTI) data to predict the volume of tissue activated (VTA) during DBS. We co-register the imaging data with detailed finite element models of the brain and stimulating electrode to enable anatomically and electrically accurate predictions of the spread of stimulation. One critical component of the model is the DTI tensor field that is used to represent the 3-dimensionally anisotropic and inhomogeneous tissue conductivity. With this system we are able to fuse structural and functional information to study a relevant clinical problem: DBS of the subthalamic nucleus for the treatment of Parkinsons disease (PD). Our results show that inclusion of the tensor field in our model caused significant differences in the size and shape of the VTA when compared to a homogeneous, isotropic tissue volume. The magnitude of these differences was proportional to the stimulation voltage. Our model predictions are validated by comparing spread of predicted activation to observed effects of oculomotor nerve stimulation in a PD patient. In turn, the 3D tissue electrical properties of the brain play an important role in regulating the spread of neural activation generated by DBS.
View details for PubMedID 17354801
Predicting the effects of deep brain stimulation with diffusion tensor based electric field models
9th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI 2006)
SPRINGER-VERLAG BERLIN. 2006: 429–437
View details for Web of Science ID 000241556700053
Motor cortex stimulation and neuropathic facial pain.
2006; 21 (6): E6-?
Trigeminal neuropathic pain is a syndrome of severe, constant facial pain related to disease of or injury to the trigeminal nerve or ganglion. Causes of this type of pain can include injury from sinus or dental surgery, skull and/or facial trauma, or intentional destruction for therapeutic reasons (deafferentation) as well as intrinsic pathological conditions in any part of the trigeminal system. Motor cortex stimulation (MCS) is a relatively new technique that has shown some promise in the treatment of trigeminal neuropathic pain. This technique has the potential to revolutionize the treatment of chronic pain. The authors present a review of the literature, focusing on surgical technique, device programming, safety, and efficacy, and suggest some initial guidelines for standardization of these aspects. It is important to evaluate MCS critically in a prospective, controlled fashion.
View details for PubMedID 17341050
Permanent neurological deficit related to magnetic resonance imaging in a patient with implanted deep brain stimulation electrodes for Parkinson's disease: case report.
2005; 57 (5): E1063-?
Deep brain stimulation (DBS) is an accepted treatment for patients with Parkinson's disease refractory to medication. The efficacy of this therapy has led to increasing numbers of patients receiving DBS implants. Importantly, physicians caring for patients with implantable neurostimulators must be aware of treatment guidelines for these patients, including the use of therapeutic ultrasound, diathermy, and imaging studies such as magnetic resonance imaging (MRI).We describe a case of serious, permanent neurological injury secondary to a radiofrequency lesion produced by heating of a DBS electrode associated with MRI of the lumbar spine in a patient with Parkinson's disease.MRI may be performed safely in patients with DBS devices only by following the specific guidelines of the manufacturer. The generalization of these conditions to other neurostimulation system positioning schemes, other scanners, and other imaging scenarios can lead to significant patient injuries.To prevent catastrophic incidents, the manufacturer's guidelines should be followed carefully because they are known to result in the safe performance of MRI examinations of patients with neurostimulation systems used for DBS.
View details for PubMedID 16284543
- Is magnetic resonance imaging safe for patients with neurostimulation systems used for deep brain stimulation? NEUROSURGERY 2005; 57 (5): 1056-1060
Frameless stereotaxy using bone fiducial markers for deep brain stimulation
JOURNAL OF NEUROSURGERY
2005; 103 (3): 404-413
Functional neurosurgical interventions such as deep brain stimulation (DBS) are traditionally performed with the aid of a stereotactic frame. Although frameless techniques have been perceived as less accurate, data from a recent phantom study of a modified frameless approach demonstrated a laboratory accuracy exceeding that obtained using a common frame system. The present study was conducted to evaluate the accuracy of a frameless system in routine clinical use.Deep brain stimulation leads were implanted in 38 patients by using a skull-mounted trajectory guide and an image-guided workstation. Registration was accomplished with bone fiducial markers. Final lead positions were measured on postoperative computerized tomography scans and compared with the planned lead positions. The accuracy of the Leksell frame within the clinical situation has been reported on in a recent study; these raw data served as a comparison data set. The difference between expected and actual lead locations in the x plane was 1.4 mm in the frame-based procedure and 1.6 mm in the frameless procedure. Similarly, the difference in the y plane was 1.6 mm in the frame-based system and 1.3 mm in the frameless one. The error was greatest in the z plane, that is, 1.7 mm in the frame-based method and 2 mm in the frameless system. Multivariate analysis of variance demonstrated no statistically significant difference in the accuracy of the two methods.The accuracy of the frame-based and frameless systems was not statistically significantly different (p = 0.22). Note, however, that frameless techniques offer advantages in patient comfort, separation of imaging from surgery, and decreased operating time.
View details for Web of Science ID 000232287000004
View details for PubMedID 16235670
A preliminary study of transient confusional states following bilateral subthalamic stimulation for Parkinson's disease
ASSFN 2004 Conference
KARGER. 2005: 67–70
Transient postoperative confusion (POC) occurs in 5-25% of patients following bilateral subthalamic nucleus stimulation. We retrospectively reviewed data on 96 patients who underwent bilateral subthalamic nucleus deep brain stimulation for Parkinson's disease. Nine percent of patients developed POC. There was no significant correlation between age/perioperative factors and POC. The POC group had a significantly higher incidence of depression and frontal-subcortical dysfunction on preoperative evaluation than patients without POC. Postoperative neuropsychological evaluations revealed declines on measures of general cognitive function and memory in the POC group. We provide preliminary evidence that patients with depression and frontal-subcortical dysfunction are more likely to develop POC, and that POC is more often associated with cognitive decline following surgery.
View details for DOI 10.1159/000086676
View details for Web of Science ID 000231539200004
View details for PubMedID 15990470
Venous air embolism during deep brain stimulation surgery in an awake supine patient
STEREOTACTIC AND FUNCTIONAL NEUROSURGERY
2005; 83 (1): 32-35
Deep brain stimulation (DBS) of the subthalamic nucleus and globus pallidus is used to improve Parkinsonian symptoms and reduce levodopa-induced motor complications in Parkinson's disease (PD). This procedure is usually performed with minimal or no sedation to allow accurate feedback from patients during surgery. Venous air embolism (VAE) has been previously reported in patients undergoing awake neurosurgical procedures for brain tumors or pallidotomy for PD. We describe a case of intraoperative VAE in an awake, supine patient while undergoing DBS surgery for PD who presented with coughing, tachypnea and hypoxemia. The difference in clinical presentation between VAE in awake vs. anesthetized patients is discussed as are intraoperative monitoring techniques and management options.
View details for DOI 10.1159/000085024
View details for Web of Science ID 000229431200006
View details for PubMedID 15821367
Neurostimulation system used for deep brain stimulation (DBS): MR safety issues and implications of failing to follow safety recommendations
2004; 39 (5): 300-303
The use of magnetic resonance imaging (MRI) in patients with neurostimulation systems used for deep brain stimulation requires the utmost care, and no individual should undergo an MR examination in the absence of empirical evidence that the procedure can be performed safely. The risks of performing MRI in patients with neurostimulators include those associated with heating, magnetic field interactions, induced currents, and the functional disruption of these devices. The exact safety recommendations for the particular neurostimulation system with regard to the pulse generator, leads, electrodes, operational conditions for the device, the positioning of these components, and the MR system conditions must be carefully followed for MRI. As highlighted by 2 recent accidents, the failure to strictly follow safety recommendations (eg, use a 1.5-T MR system with a send/receive head radiofrequency coil only; limit the specific absorption rate to 0.4 W/kg; etc.) may result in serious, temporary, or permanent injury to the patient including the possibility of transient dystonia, paralysis, coma, or even death.
View details for DOI 10.1097/01.rli.0000124940.02340.ab
View details for Web of Science ID 000220990600007
View details for PubMedID 15087724
Frameless localization for functional neurosurgical procedures: A preliminary accuracy study
STEREOTACTIC AND FUNCTIONAL NEUROSURGERY
2004; 82 (4): 135-141
Targeting for functional stereotactic procedures is traditionally carried out in a noninteractive fashion, without real-time positional feedback. In addition, stereotactic frames are uncomfortable for patients and may impede intraoperative neurological evaluation. As an initial step toward a fully frameless approach to functional surgery, we have investigated the use of an image-guided microdrive coupled to a stereotactic frame system.For initial laboratory tests, a stereotactic phantom was imaged using high-resolution CT scanning. Three representative targets were chosen within the phantom. Targeting was carried out in the usual fashion using the StealthStation planning suite, utilizing the Radionics CRW system. An LED-equipped reference arc was attached to the CRW base ring. Registration of the base ring was accomplished using a spherical probe. A custom-built microdrive was fitted with an LED array, mounted on the CRW arc and tracked by the StealthStation. The distance between the Stealth real-time localization and the CRW localization was measured on-screen. To evaluate the accuracy of the system in the operating room, a similar procedure was carried out in 13 functional neurosurgical operations (pallidotomy or deep brain stimulator placement).Errors of localization in the laboratory setting ranged from 0.53 to 0.70 mm. In 11 operative cases, the average difference between the CRW localization and the Stealth localization was 1.77 mm. In the remaining 2 cases, equipment malfunction prevented measurement of localization error.Frameless image-guided localization compares favorably to targeting performed noninteractively. In addition, real-time positional feedback confers advantages in target region visualization and confidence in placement of lesions and stimulators for functional procedures. With small improvements in accuracy and system reliability, fully frameless functional procedures could be safely carried out.
View details for DOI 10.1159/000081345
View details for Web of Science ID 000226047800001
View details for PubMedID 15467380
Recovery of pain control by intensive reprogramming after loss of benefit from motor cortex stimulation for neuropathic pain
STEREOTACTIC AND FUNCTIONAL NEUROSURGERY
2004; 82 (5-6): 207-213
Motor cortex stimulation (MCS) may serve as an adjunct in managing neuropathic pain after other conservative and interventional methods have failed. However, the magnitude and duration of the benefit are highly variable, with a significant percentage of patients losing pain relief over time. We investigated whether intensive reprogramming could recapture the beneficial effects of MCS.Six patients who had previously undergone MCS implantation for neuropathic pain but had lost benefit were brought back for 1-5 days of intensive reprogramming. Four patients were evaluated as inpatients while the others were seen as outpatients during multiple visits over several days. Several hours a day were spent with each patient. Patients completed visual analog scale (VAS) ratings at intervals throughout the reprogramming period to judge effectiveness of stimulation. Pre- and postadjustment VAS were compared using a paired t test.The patients' average age was 50 years (range 26-71). The diagnoses were trigeminal neuropathic pain (2 patients), complex regional pain syndrome I (2), phantom limb pain (1) and poststroke pain (1). The mean duration of pain was 6 years. The MCS benefit had initially lasted for a mean of 7.16 months (range 2-18 months). After reprogramming, 5 of 6 patients experienced improvement in pain. Average VAS scores decreased from 7.44 to 2.28 (p < 0.001) in those patients who responded to reprogramming. The average stimulation parameters in these patients were 5 V amplitude (range 1.7-10), 313 micros pulse width (range 240-390) and frequency of 84 Hz (range 55-130). Three patients experienced seizures during reprogramming. The mean seizure threshold was 8.9 V. No patient experienced seizures at their therapeutic settings. Pain control has been maintained after discharge.Intensive reprogramming can recapture the benefit of MCS in patients who have lost pain control. The use of broad dipoles using two contacts rather than one contact of the 1 x 4 electrode array improved the ability to recapture beneficial stimulation. There is a significant risk of seizures during aggressive reprogramming.
View details for DOI 10.1159/000082447
View details for Web of Science ID 000227207300002
View details for PubMedID 15583465
The application accuracy of a skull-mounted trajectory guide system for image-guided functional neurosurgery.
Computer aided surgery
2004; 9 (4): 155-160
Frameless image guided systems have traditionally been perceived as being less accurate than stereotactic frames, limiting their adoption for trajectory-based procedures such as deep brain stimulator placement which require submillimetric accuracy. However, some studies have suggested that high degrees of accuracy are attainable with optical localization systems. We evaluated the application accuracy of a skull-mounted trajectory guide coupled to an optical image-guided surgery system in a laboratory setting.A plastic skull phantom was fitted with five fiducial markers rigidly attached via self-drilling bone screws. Varying MRI and CT imaging protocols were obtained at 25 different centers. A metal disc marked in 1-mm increments was placed at the expected target point. Following registration and alignment of the trajectory guide, radial and depth localization errors were measured. A total of 560 measurements were obtained and detailed statistical analyses were performed.Mean localization error was 1.25 mm with a 95% confidence interval of 2.7 mm and a 99.9% confidence interval of 4.0 mm. These values were significantly lower than those published for the two most widely used frame systems (p<0.001).Accuracy of image-guided localization using a rigid trajectory guide can meet or exceed that achievable with a stereotactic frame.
View details for PubMedID 16192055
Anatomy and physiology of chronic pain
NEUROSURGERY CLINICS OF NORTH AMERICA
2003; 14 (3): 445-?
Although much has been accomplished in the past several decades, treatment of chronic pain remains imperfect. This article presents the anatomy and physiology of the pain system along with the neurobiologic changes that occur in the establishment and maintenance of chronic pain states.
View details for DOI 10.1016/S1042-3680(03)00009-3
View details for Web of Science ID 000184145400012
View details for PubMedID 14567145
- Neuroaugmentation for chronic pain - Preface NEUROSURGERY CLINICS OF NORTH AMERICA 2003; 14 (3): IX-X
- The role of computer-assisted image-guided techniques Seminars in Neurosurgery 2001; 12: 175-181
- An Internet-connected, patient-specific, deformable brain atlas integrated into a surgical navigation system 14th Symposium for Computer Applications in Radiology SPRINGER. 1997: 231–37
The correction of stereotactic inaccuracy caused by brain shift using an intraoperative ultrasound device
1st Joint Conference on Computer Vision, Virtual Reality and Robotics in Medicine / Medical Robotics and Computer-Assisted Surgery (CVRMed-MRCAS 97)
SPRINGER-VERLAG BERLIN. 1997: 459–466
View details for Web of Science ID A1997BJ58E00050
Anatomical surface contour matching for efficient registration in image guided neurosurgery
11th International Symposium and Exhibition on Computer Assisted Radiology and Surgery (CAR 97) / 1st Annual Conference of ISCAS
ELSEVIER SCIENCE BV. 1997: 772–777
View details for Web of Science ID 000070984600130
Epidural hematoma producing brown-sequard syndrome: A case due to ruptured hemangioma with magnetic resonance imaging findings
JOURNAL OF NEUROIMAGING
1996; 6 (1): 62-63
A man developed spontaneous spinal epidural hematoma secondary to ruptured hemangioma with a clinical picture resembling acute partial Brown-Séquard syndrome. Diagnosis by magnetic resonance imaging (MRI) allowed prompt surgical decompression and complete reversal of the neurological deficits. The diagnosis, etiology, and MRI findings of spinal epidural hematomas are discussed.
View details for Web of Science ID A1996TP92800014
View details for PubMedID 8555668
Combined stereotactic thalamotomy and posteroventral pallidotomy for Parkinson's disease.
Journal of image guided surgery
1995; 1 (3): 133-140
Stereotactic thalamotomy has traditionally provided good relief of tremor for patients with intractable tremor-dominant Parkinson's disease. However, bradykinesia, dyskinesia, and rigidity are often less reliably treated with this technique. Although posteroventral pallidotomy (PVP) can alleviate dyskinesias, appendicular bradykinesia, and rigidity, tremor may not be completely ameliorated. We have combined Vim/VOp junction thalamotomy and PVP in 29 patients with severe tremor, rigidity, and bradykinesia. Patients underwent unilateral Vim thalamotomy followed at the same sitting by PVP. The distinct physiological consequences of each procedure were documented by intraoperative electromyography (EMG) and video recording, revealing the effects on both tremor and agonist/antagonist co-contraction. Lack of reciprocal inhibition of antagonistic muscle groups often remained following thalamotomy but was eliminated by subsequent PVP. The complementary therapeutic effects of PVP and Vim thalamotomy may be due to the interruption of different neuronal circuits by the two procedures. The effect of Vim thalamotomy has been attributed to the interruption of the rubrothalamocortical loop. PVP interrupts the outflow of the globus pallidus interna (GPi), which may cause disinhibition of locomotor centers in the mesencephalon and spinal cord. There is no direct interruption of the rubrothalamocortical loop by PVP, explaining why this procedure sometimes exacerbates tremor in certain patients. The combination of the two procedures appears to provide excellent relief of the majority of symptoms in patients suffering from tremor-dominant Parkinson's disease.
View details for PubMedID 9079438
AN ACCURATE AND ERGONOMIC METHOD OF REGISTRATION FOR IMAGE-GUIDED NEUROSURGERY
COMPUTERIZED MEDICAL IMAGING AND GRAPHICS
1994; 18 (4): 273-277
We have developed a system for accurately and conveniently achieving surgical registration for image-guided neurosurgery, based on alignment and matching of patient forehead contours. The system consists of a contour digitizer that is used in the operating room to acquire patient contours, editing software for extracting contours from patient image data sets, and a contour-match algorithm for aligning the two contours and performing data set registration. Initial tests of the individual portions of the system have found each to be robust; we are in the process of refining the design of the optical digitizer in order to further automate the procedure as well as provide increased accuracy.
View details for Web of Science ID A1994NX03400006
View details for PubMedID 7923046
ACCURATE AND ERGONOMIC METHOD OF REGISTRATION FOR IMAGE-GUIDED NEUROSURGERY
Conference on Clinical Applications of Modern Imaging Technology II
SPIE - INT SOC OPTICAL ENGINEERING. 1994: 67–77
View details for Web of Science ID A1994BA44E00006
INTRAOPERATIVE LOCALIZATION USING A 3-DIMENSIONAL OPTICAL DIGITIZER
Conference on Clinical Applications of Modern Imaging Technology
SPIE - INT SOC OPTICAL ENGINEERING. 1993: 312–322
View details for Web of Science ID A1993BZ56Z00032
CHRONIC ACCESS TO ENDONEURIAL SPACE USING AN ARTERIAL AUTOGRAFT
JOURNAL OF NEUROSCIENCE METHODS
1989; 27 (2): 133-142
A technique for direct chronic infusion of compounds onto peripheral axons has been investigated in the rat sciatic nerve. A 2 cm segment of the femoral artery was removed and one end inserted into the endoneurial space of the contralateral peroneal nerve fascicle of the same animal. The other end of the artery was connected to a catheter system to allow infusion into the endoneurium, thus bypassing the barrier that the perineurium presents to hydrophilic compounds. The patency of this arterial access system was evaluated by the ability of 20 microliters of 2% lidocaine to inhibit the toe-spreading reflex. The results of the study were that the infusion system remained operational for 3-7 days after transplantation. There were histologic changes in the nerve but there were no functional deficits due to the surgery. Although a long-term endoneurial infusion was not achieved, the limited access time to the axons might be long enough for applications such as the delivery of nerve growth factors to injured nerve.
View details for Web of Science ID A1989T598300006
View details for PubMedID 2709882