Paul Sloan Larson

Interests

Research

Deep brain stimulation (DBS), gene therapy, cell transplantation, interventional MRI-guided surgery,movement disorders (Parkinson’s disease, essential tremor), auditory disorders (tinnitus), psychiatricdisorders (obsessive compulsive disorder, Tourette’s syndrome, major depressive disorder), Huntington’sdisease, basal ganglia physiology, high field MRI imaging, device development

Teaching

Deep brain stimulation (DBS) and interventional MRI-guided surgery

Courses

No activities entered.

Scholarly Contributions

Journals/Publications

• D'Souza, S., Seshadri, V., Toms, J., D'Haese, P., Dawant, B. M., Li, R., Shah, H. P., Koch, P., Larson, P., & Holloway, K. L. (2024). Precision targeting in the globus pallidus interna: insights from the multicenter, prospective, blinded VA/NINDS CSP 468 study. Journal of neurosurgery, 141(6), 1567-1577.
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  Deep brain stimulation (DBS) targeting the globus pallidus interna (GPi) has been shown to significantly improve motor symptoms for the treatment of medication-refractory Parkinson's disease. Yet, heterogeneity in clinical outcomes persists, possibly due to suboptimal target identification within the GPi. By leveraging robust sampling of the GPi and 6-month postsurgical outcomes, this study aims to determine optimal symptom-specific GPi DBS targets.
• Emborg, M. E., Mancinelli, A., Colwell, J. C., Zinnen, A. D., Pape, B., Brunner, K., Bondarenko, V., Fitz, C., Coonen, J., Menna, V., Fuchs, K., Schultz-Darken, N., Simmons, H. A., Tran, H., Larson, P., Olsen, M., Hurley, S., Bratt-Leal, A. M., Wirth, E., & Metzger, J. M. (2024). Preclinical evaluation of transaxial intraputaminal trajectory for enhanced distribution of grafted cells in Parkinson's disease. Journal of neurosurgery, 141(6), 1554-1566.
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  The objective of this study was to develop and evaluate the feasibility and safety of a novel transaxial surgical approach for the delivery of human induced pluripotent stem cell-derived dopaminergic neuroprogenitor cells (DANPCs) into the putamen nucleus using nonhuman primates and surgical techniques and tools relevant to human clinical translation.
• Fan, J. M., De, B., Frank, A. C., Basich-Pease, G., Norbu, T., Morrison, M. A., Larson, P., Starr, P. A., Krystal, A. D., & Lee, A. M. (2024). Intracranial beta activity is a biomarker of circadian and stimulation-induced arousal in obsessive compulsive disorder. Brain stimulation, 17(1), 29-31.
• Slepneva, N., Basich-Pease, G., Reid, L., Frank, A. C., Norbu, T., Krystal, A. D., Sugrue, L. P., Motzkin, J. C., Larson, P. S., Starr, P. A., Morrison, M. A., & Lee, A. M. (2024). Therapeutic DBS for OCD Suppresses the Default Mode Network. Human brain mapping, 45(18), e70106.
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  Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) is a circuit-based treatment for severe, refractory obsessive-compulsive disorder (OCD). The therapeutic effects of DBS are hypothesized to be mediated by direct modulation of a distributed cortico-striato-thalmo-cortical network underlying OCD symptoms. However, the exact underlying mechanism by which DBS exerts its therapeutic effects still remains unclear. In five participants receiving DBS for severe, refractory OCD (3 responders, 2 non-responders), we conducted a DBS On/Off cycling paradigm during the acquisition of functional MRI (23 fMRI runs) to determine the network effects of stimulation across a variety of bipolar configurations. We also performed tractography using diffusion-weighted imaging (DWI) to relate the functional impact of DBS to the underlying structural connectivity between active stimulation contacts and functional brain networks. We found that therapeutic DBS had a distributed effect, suppressing BOLD activity within regions such as the orbitofrontal cortex, dorsomedial prefrontal cortex, and subthalamic nuclei compared to non-therapeutic configurations. Many of the regions suppressed by therapeutic DBS were components of the default mode network (DMN). Moreover, the estimated stimulation field from the therapeutic configurations exhibited significant structural connectivity to core nodes of the DMN. Based upon these findings, we hypothesize that the suppression of the DMN by ALIC DBS is mediated by interruption of communication through structural white matter connections surrounding the DBS active contacts.
• Slepneva, N., Basich-Pease, G., Reid, L., Frank, A. C., Norbu, T., Krystal, A. D., Sugrue, L. P., Motzkin, J. C., Larson, P. S., Starr, P. A., Morrison, M. A., & Lee, A. M. (2024). Therapeutic DBS for OCD Suppresses the Default Mode Network. bioRxiv : the preprint server for biology.
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  Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) is an emerging treatment for severe, refractory obsessive-compulsive disorder (OCD). The therapeutic effects of DBS are hypothesized to be mediated by direct modulation of a distributed cortico-striato-thalmo-cortical network underlying OCD symptoms. However, the exact underlying mechanism by which DBS exerts its therapeutic effects still remains unclear.
• Basich-Pease, G., Slepneva, N., Frank, A. C., Norbu, T., Morrison, M. A., Sugrue, L. P., Larson, P. S., Starr, P. A., & Lee, A. M. (2023). Tractography-based DBS lead repositioning improves outcome in refractory OCD and depression. Frontiers in human neuroscience, 17, 1339340.
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  Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) has been used to treat refractory obsessive-compulsive disorder (OCD) and depression, but outcomes are variable, with some patients not responding to this form of invasive neuromodulation. A lack of benefit in some patients may be due to suboptimal positioning of DBS leads. Recently, studies have suggested that specific white matter tracts within the ALIC are associated with improved outcomes. Here, we present the case of a patient who initially had a modest improvement in OCD and depressive symptoms after receiving DBS within the ALIC. Subsequently, he underwent unilateral DBS lead repositioning informed by tractography targeting the ventrolateral and medial prefrontal cortex's connection with the mediodorsal thalamus. In this patient, we also conducted post-implant and post-repositioning diffusion imaging and found that we could successfully perform tractography even with DBS leads in place. Following lead repositioning into tracts predictive of benefit, the patient reached responder criteria for his OCD, and his depression was remitted. This case illustrates that tractography can potentially be used in the evaluation and planning of lead repositioning to achieve therapeutic outcomes.
• Mamaril-Davis, J. C., Gelb, A. W., & Larson, P. S. (2023). Procedure-Related Complications in Sham Surgeries for Parkinson's Clinical Trials: A Meta-analysis. Movement disorders : official journal of the Movement Disorder Society, 38(7), 1223-1235.
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  Double-blind, sham-controlled neurosurgical trials for neurodegenerative disorders are debated as an ethical dilemma, particularly regarding subjects randomized to the sham surgery group with general anesthesia.
• Mamaril-Davis, J., Palsma, R., Riordan, K., Griffith, N., Meyer, B., Rulney, J., Coopwood, C., Alan, A., Eversman, H., Khoshaba, R., Aguilar-Salinas, P., Larson, P., & Weinand, M. (2023). Letter to the Editor: Experiences from a Virtual Neurosurgery Research Conference for Medical Students in Arizona. World neurosurgery, 176, 243-245.
• Christine, C. W., Richardson, R. M., Fine, E. M., Khwaja, O. S., Liang, G. S., Meier, A., Roberts, E. W., Bankiewicz, K., & Larson, P. S. (2022). Author Response: Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial. Neurology, 99(6), 259.
• Christine, C. W., Richardson, R. M., Van Laar, A. D., Thompson, M. E., Fine, E. M., Khwaja, O. S., Li, C., Liang, G. S., Meier, A., Roberts, E. W., Pfau, M. L., Rodman, J. R., Bankiewicz, K. S., & Larson, P. S. (2022). Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial. Neurology, 98(1), e40-e50.
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  To report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson disease (PD) and motor fluctuations.
• Christine, C. W., Richardson, R. M., Van Laar, A., Fine, E. M., Khwaja, O. S., Liang, G. S., Bankiewicz, K., & Larson, P. S. (2022). Author Response: Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial. Neurology, 99(6), 260-261.
• Hinkley, L. B., Larson, P. S., Henderson Sabes, J., Mizuiri, D., Demopoulos, C., Adams, M. E., Neylan, T. C., Hess, C. P., Nagarajan, S. S., & Cheung, S. W. (2022). Striatal networks for tinnitus treatment targeting. Human brain mapping, 43(2), 633-646.
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  Neuromodulation treatment effect size for bothersome tinnitus may be larger and more predictable by adopting a target selection approach guided by personalized striatal networks or functional connectivity maps. Several corticostriatal mechanisms are likely to play a role in tinnitus, including the dorsal/ventral striatum and the putamen. We examined whether significant tinnitus treatment response by deep brain stimulation (DBS) of the caudate nucleus may be related to striatal network increased functional connectivity with tinnitus networks that involve the auditory cortex or ventral cerebellum. The first study was a cross-sectional 2-by-2 factorial design (tinnitus, no tinnitus; hearing loss, normal hearing, n = 68) to define cohort level abnormal functional connectivity maps using high-field 7.0 T resting-state fMRI. The second study was a pilot case-control series (n = 2) to examine whether tinnitus modulation response to caudate tail subdivision stimulation would be contingent on individual level striatal connectivity map relationships with tinnitus networks. Resting-state fMRI identified five caudate subdivisions with abnormal cohort level functional connectivity maps. Of those, two connectivity maps exhibited increased connectivity with tinnitus networks-dorsal caudate head with Heschl's gyrus and caudate tail with the ventral cerebellum. DBS of the caudate tail in the case-series responder resulted in dramatic reductions in tinnitus severity and loudness, in contrast to the nonresponder who showed no tinnitus modulation. The individual level connectivity map of the responder was in alignment with the cohort expectation connectivity map, where the caudate tail exhibited increased connectivity with tinnitus networks, whereas the nonresponder individual level connectivity map did not.
• Lee, A. T., Han, K. J., Nichols, N., Sudhakar, V. R., Burke, J. F., Wozny, T. A., Chung, J. E., Volz, M. M., Ostrem, J. L., Martin, A. J., Larson, P. S., Starr, P. A., & Wang, D. D. (2022). Targeting Accuracy and Clinical Outcomes of Awake versus Asleep Interventional Magnetic Resonance Imaging-Guided Deep Brain Stimulation for Parkinson's Disease: The University of California, San Francisco Experience. Neurosurgery, 91(5), 717-725.
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  Interventional MRI (iMRI)-guided implantation of deep brain stimulator (DBS) leads has been developed to treat patients with Parkinson's disease (PD) without the need for awake testing.
• Prakash, P., Deuschl, G., Ozinga, S., Mitchell, K. T., Cheeran, B., Larson, P. S., Merola, A., Groppa, S., Tomlinson, T., & Ostrem, J. L. (2022). Benefits and Risks of a Staged-Bilateral VIM Versus Unilateral VIM DBS for Essential Tremor. Movement disorders clinical practice, 9(6), 775-784.
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  Despite over 30 years of clinical experience, high-quality studies on the efficacy of bilateral versus unilateral deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus for medically refractory essential tremor (ET) remain limited.
• Rothlind, J. C., York, M. K., Luo, P., Carlson, K., Marks, W. J., Weaver, F. M., Stern, M., Follett, K. A., Duda, J. E., Reda, D. J., & , C. s. (2022). Predictors of multi-domain cognitive decline following DBS for treatment of Parkinson's disease. Parkinsonism & related disorders, 95, 23-27.
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  Statistically and clinically significant cognitive declines are observed in a small subset of individuals with Parkinson's Disease (PD) following treatment with Deep Brain Stimulation (DBS).
• Ammanuel, S. G., Edwards, C. S., Chan, A. K., Mummaneni, P. V., Kidane, J., Vargas, E., D'Souza, S., Nichols, A. D., Sankaran, S., Abla, A. A., Aghi, M. K., Chang, E. F., Hervey-Jumper, S. L., Kunwar, S., Larson, P. S., Lawton, M. T., Starr, P. A., Theodosopoulos, P. V., Berger, M. S., & McDermott, M. W. (2021). Are preoperative chlorhexidine gluconate showers associated with a reduction in surgical site infection following craniotomy? A retrospective cohort analysis of 3126 surgical procedures. Journal of neurosurgery, 1-9.
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  Surgical site infection (SSI) is a complication linked to increased costs and length of hospital stay. Prevention of SSI is important to reduce its burden on individual patients and the healthcare system. The authors aimed to assess the efficacy of preoperative chlorhexidine gluconate (CHG) showers on SSI rates following cranial surgery.
• Burke, J. F., Tanzillo, D., Starr, P. A., Lim, D. A., & Larson, P. S. (2021). CT and MRI Image Fusion Error: An Analysis of Co-Registration Error Using Commercially Available Deep Brain Stimulation Surgical Planning Software. Stereotactic and functional neurosurgery, 99(3), 196-202.
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  During deep brain stimulation (DBS) surgery, computed tomography (CT) and magnetic resonance imaging (MRI) scans need to be co-registered or fused. Image fusion is associated with the error that can distort the location of anatomical structures. Co-registration in DBS surgery is usually performed automatically by proprietary software; the amount of error during this process is not well understood. Here, our goal is to quantify the error during automated image co-registration with FrameLink™, a commonly used software for DBS planning and clinical research.
• Frank, A. C., Scangos, K. W., Larson, P. S., Norbu, T., Lee, A. T., & Lee, A. M. (2021). Identification of a personalized intracranial biomarker of depression and response to DBS therapy. Brain stimulation, 14(4), 1002-1004.
• Gilron, R., Little, S., Perrone, R., Wilt, R., de Hemptinne, C., Yaroshinsky, M. S., Racine, C. A., Wang, S. S., Ostrem, J. L., Larson, P. S., Wang, D. D., Galifianakis, N. B., Bledsoe, I. O., San Luciano, M., Dawes, H. E., Worrell, G. A., Kremen, V., Borton, D. A., Denison, T., & Starr, P. A. (2021). Long-term wireless streaming of neural recordings for circuit discovery and adaptive stimulation in individuals with Parkinson's disease. Nature biotechnology, 39(9), 1078-1085.
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  Neural recordings using invasive devices in humans can elucidate the circuits underlying brain disorders, but have so far been limited to short recordings from externalized brain leads in a hospital setting or from implanted sensing devices that provide only intermittent, brief streaming of time series data. Here, we report the use of an implantable two-way neural interface for wireless, multichannel streaming of field potentials in five individuals with Parkinson's disease (PD) for up to 15 months after implantation. Bilateral four-channel motor cortex and basal ganglia field potentials streamed at home for over 2,600 h were paired with behavioral data from wearable monitors for the neural decoding of states of inadequate or excessive movement. We validated individual-specific neurophysiological biomarkers during normal daily activities and used those patterns for adaptive deep brain stimulation (DBS). This technological approach may be widely applicable to brain disorders treatable by invasive neuromodulation.
• Larson, P. S. (2021). Improved Delivery Methods for Gene Therapy and Cell Transplantation in Parkinson's Disease. Journal of Parkinson's disease, 11(s2), S199-S206.
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  A number of cell transplantation and gene therapy trials have been performed over the last three decades in an effort to restore function in Parkinson's disease. Much has been learned about optimizing delivery methods for these therapeutics. This is particularly true in gene therapy, which has predominated the clinical trial landscape in recent years; however, cell transplantation for Parkinson's disease is currently undergoing a renaissance. Innovations such as cannula design, iMRI-guided surgery and an evolution in delivery strategy has radically changed the way investigators approach clinical trial design. Future therapeutic strategies may employ newer delivery methods such as chronically implanted infusion devices and focal opening of the blood brain barrier with focused ultrasound.
• Luo, M., Narasimhan, S., Larson, P. S., Martin, A. J., Konrad, P. E., & Miga, M. I. (2021). Impact of brain shift on neural pathways in deep brain stimulation: a preliminary analysis via multi-physics finite element models. Journal of neural engineering, 18(5).
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  The effectiveness of deep brain stimulation (DBS) depends on electrode placement accuracy, which can be compromised by brain shift during surgery. While there have been efforts in assessing the impact of electrode misplacement due to brain shift using preop- and postop-imaging data, such analysis using preop- and intraop-imaging data via biophysical modeling has not been conducted. This work presents a preliminary study that applies a multi-physics analysis framework using finite element biomechanical and bioelectric models to examine the impact of realistic intraoperative shift on neural pathways determined by tractography.The study examined six patients who had undergone interventional magnetic resonance-guided DBS surgery. The modeling framework utilized a biomechanical approach to update preoperative MR to reflect shift-induced anatomical changes. Using this anatomically deformed image and its undeformed counterpart, bioelectric effects from shifting electrode leads could be simulated and neural activation differences were approximated. Specifically, for each configuration, volume of tissue activation was computed and subsequently used for tractography estimation. Total tract volume and overlapping volume with motor regions as well as connectivity profile were compared. In addition, volumetric overlap between different fiber bundles among configurations was computed and correlated to estimated shift.The study found deformation-induced differences in tract volume, motor region overlap, and connectivity behavior, suggesting the impact of shift. There is a strong correlation (= -0.83) between shift from intended target and intended neural pathway recruitment, where at threshold of ∼2.94 mm, intended recruitment completely degrades. The determined threshold is consistent with and provides quantitative support to prior observations and literature that deviations of 2-3 mm are detrimental.The findings support and advance prior studies and understanding to illustrate the need to account for shift in DBS and the potentiality of computational modeling for estimating influence of shift on neural activation.
• Pearson, T. S., Gupta, N., San Sebastian, W., Imamura-Ching, J., Viehoever, A., Grijalvo-Perez, A., Fay, A. J., Seth, N., Lundy, S. M., Seo, Y., Pampaloni, M., Hyland, K., Smith, E., de Oliveira Barbosa, G., Heathcock, J. C., Minnema, A., Lonser, R., Elder, J. B., Leonard, J., , Larson, P., et al. (2021). Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons. Nature communications, 12(1), 4251.
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  Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4-9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 10 vg (n = 3), and 4.2 × 10 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.
• Wu, C., Nagel, S. J., Agarwal, R., Pötter-Nerger, M., Hamel, W., Sharan, A. D., Connolly, A. T., Cheeran, B., & Larson, P. S. (2021). Reduced Risk of Reoperations With Modern Deep Brain Stimulator Systems: Big Data Analysis From a United States Claims Database. Frontiers in neurology, 12, 785280.
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  There have been significant improvements in the design and manufacturing of deep brain stimulation (DBS) systems, but no study has considered the impact of modern systems on complications. We sought to compare the relative occurrence of reoperations after implantation of modern and traditional DBS systems in patients with Parkinson's disease (PD) or essential tremor (ET) in the United States. Retrospective, contemporaneous cohort study. Multicenter data from the United States Centers for Medicare and Medicaid Services administrative claims database between 2016 and 2018. This population-based sample consisted of 5,998 patients implanted with a DBS system, of which 3,869 patients had a implant and primary diagnosis of PD or ET. Follow-up of 3 months was available for 3,810 patients, 12 months for 3,561 patients, and 24 months for 1,812 patients. Implantation of a modern directional (MD) or traditional omnidirectional (TO) DBS system. We hypothesized that MD systems would impact complication rates. Reoperation rate was the primary outcome. Associated diagnoses, patient characteristics, and implanting center details served as covariates. Kaplan-Meier analysis was performed to compare rates of event-free survival and regression models were used to determine covariate influences. Patients implanted with modern systems were 36% less likely to require reoperation, largely due to differences in acute reoperations and intracranial lead reoperations. Risk reduction persisted while accounting for practice differences and implanting center experience. Risk reduction was more pronounced in patients with PD. In the first multicenter analysis of device-related complications including modern DBS systems, we found that modern systems are associated with lower reoperation rates. This risk profile should be carefully considered during device selection for patients undergoing DBS for PD or ET. Prospective studies are needed to further investigate underlying causes.
• Chen, W., de Hemptinne, C., Miller, A. M., Leibbrand, M., Little, S. J., Lim, D. A., Larson, P. S., & Starr, P. A. (2020). Prefrontal-Subthalamic Hyperdirect Pathway Modulates Movement Inhibition in Humans. Neuron, 106(4), 579-588.e3.
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  The ability to dynamically change motor outputs, such as stopping an initiated response, is an important aspect of human behavior. A hyperdirect pathway between the inferior frontal gyrus and subthalamic nucleus is hypothesized to mediate movement inhibition, but there is limited evidence for this in humans. We recorded high spatial and temporal resolution field potentials from both the inferior frontal gyrus and subthalamic nucleus in 21 subjects. Cortical potentials evoked by subthalamic stimulation revealed short latency events indicative of monosynaptic connectivity between the inferior frontal gyrus and ventral subthalamic nucleus. During a stop signal task, stopping-related potentials in the cortex preceded stopping-related activity in the subthalamic nucleus, and synchronization between these task-evoked potentials predicted the stop signal reaction time. Thus, we show that a prefrontal-subthalamic hyperdirect pathway is present in humans and mediates rapid stopping. These findings may inform therapies to treat disorders featuring perturbed movement inhibition.
• Luo, M., Larson, P. S., Martin, A. J., & Miga, M. I. (2020). Accounting for Deformation in Deep Brain Stimulation Surgery With Models: Comparison to Interventional Magnetic Resonance Imaging. IEEE transactions on bio-medical engineering, 67(10), 2934-2944.
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  The efficacy of deep brain stimulation (DBS) depends on electrode placement accuracy, which can be jeopardized by brain shift due to burr hole and dura opening during surgery. Brain shift violates assumed rigid alignment between preoperative image and intraoperative anatomy, negatively impacting therapy.
• Nutt, J. G., Curtze, C., Hiller, A., Anderson, S., Larson, P. S., Van Laar, A. D., Richardson, R. M., Thompson, M. E., Sedkov, A., Leinonen, M., Ravina, B., Bankiewicz, K. S., & Christine, C. W. (2020). Aromatic L-Amino Acid Decarboxylase Gene Therapy Enhances Levodopa Response in Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society, 35(5), 851-858.
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  As Parkinson's disease progresses, levodopa treatment loses efficacy, partly through the loss of the endogenous dopamine-synthesizing enzyme L-amino acid decarboxylase (AADC). In the phase I PD-1101 study, putaminal administration of VY-AADC01, an investigational adeno-associated virus serotype-2 vector for delivery of the AADC gene in patients with advanced Parkinson's disease, was well tolerated, improved motor function, and reduced antiparkinsonian medication requirements.
• Richardson, R. M., Bankiewicz, K. S., Christine, C. W., Van Laar, A. D., Gross, R. E., Lonser, R., Factor, S. A., Kostyk, S. K., Kells, A. P., Ravina, B., & Larson, P. S. (2020). Data-driven evolution of neurosurgical gene therapy delivery in Parkinson's disease. Journal of neurology, neurosurgery, and psychiatry, 91(11), 1210-1218.
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  Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson's disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.
• Chen, W., de Hemptinne, C., Leibbrand, M., Miller, A. M., Larson, P. S., & Starr, P. A. (2019). Altered Prefrontal Theta and Gamma Activity during an Emotional Face Processing Task in Parkinson Disease. Journal of cognitive neuroscience, 31(11), 1768-1776.
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  Patients with Parkinson disease (PD) often experience nonmotor symptoms including cognitive deficits, depression, and anxiety. Cognitive and affective processes are thought to be mediated by prefrontal cortico-basal ganglia circuitry. However, the topography and neurophysiology of prefrontal cortical activity during complex tasks are not well characterized. We used high-resolution electrocorticography in pFC of patients with PD and essential tremor, during implantation of deep brain stimulator leads in the awake state, to understand disease-specific changes in prefrontal activity during an emotional face processing task. We found that patients with PD had less task-related theta-alpha power and greater task-related gamma power in the dorsolateral pFC, inferior frontal cortex, and lateral OFC. These findings support a model of prefrontal neurophysiological changes in the dopamine-depleted state, in which focal areas of hyperactivity in prefrontal cortical regions may compensate for impaired long-range interactions mediated by low-frequency rhythms. These distinct neurophysiological changes suggest that nonmotor circuits undergo characteristic changes in PD.
• Cheung, S. W., Racine, C. A., Henderson-Sabes, J., Demopoulos, C., Molinaro, A. M., Heath, S., Nagarajan, S. S., Bourne, A. L., Rietcheck, J. E., Wang, S. S., & Larson, P. S. (2019). Phase I trial of caudate deep brain stimulation for treatment-resistant tinnitus. Journal of neurosurgery, 1-10.
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  The objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus.
• Christine, C. W., Bankiewicz, K. S., Van Laar, A. D., Richardson, R. M., Ravina, B., Kells, A. P., Boot, B., Martin, A. J., Nutt, J., Thompson, M. E., & Larson, P. S. (2019). Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease. Annals of neurology, 85(5), 704-714.
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  To understand the safety, putaminal coverage, and enzyme expression of adeno-associated viral vector serotype-2 encoding the complementary DNA for the enzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novel intraoperative monitoring to optimize delivery.
• Mitchell, K. T., Larson, P., Starr, P. A., Okun, M. S., Wharen, R. E., Uitti, R. J., Guthrie, B. L., Peichel, D., Pahwa, R., Walker, H. C., Foote, K., Marshall, F. J., Jankovic, J., Simpson, R., Phibbs, F., Neimat, J. S., Stewart, R. M., Dashtipour, K., & Ostrem, J. L. (2019). Benefits and risks of unilateral and bilateral ventral intermediate nucleus deep brain stimulation for axial essential tremor symptoms. Parkinsonism & related disorders, 60, 126-132.
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  Many experts assume bilateral deep brain stimulation (DBS) is necessary to improve axial tremor in essential tremor (ET). In the largest clinical trial of DBS for ET to date evaluating a non-directional, constant current device, we studied the effects of unilateral and staged bilateral DBS on axial tremor.
• Mitchell, K. T., Volz, M., Lee, A., San Luciano, M., Wang, S., Starr, P. A., Larson, P., Galifianakis, N. B., & Ostrem, J. L. (2019). Patient Experience with Rechargeable Implantable Pulse Generator Deep Brain Stimulation for Movement Disorders. Stereotactic and functional neurosurgery, 97(2), 113-119.
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  Nonrechargeable deep brain stimulation implantable pulse generators (IPGs) for movement disorders require surgical replacement every few years due to battery depletion. Rechargeable IPGs reduce frequency of replacement surgeries and inherent risks of complications but require frequent recharging. Here, we evaluate patient experience with rechargeable IPGs and define predictive characteristics for higher satisfaction.
• Perez, P. L., Wang, S. S., Heath, S., Henderson-Sabes, J., Mizuiri, D., Hinkley, L. B., Nagarajan, S. S., Larson, P. S., & Cheung, S. W. (2019). Human caudate nucleus subdivisions in tinnitus modulation. Journal of neurosurgery, 132(3), 705-711.
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  The object of this study was to define caudate nucleus locations responsive to intraoperative direct electrical stimulation for tinnitus loudness modulation and relate those locations to functional connectivity maps between caudate nucleus subdivisions and auditory cortex.
• Chan, A. K., Chan, A. Y., Lau, D., Durcanova, B., Miller, C. A., Larson, P. S., Starr, P. A., & Mummaneni, P. V. (2018). Surgical management of camptocormia in Parkinson's disease: systematic review and meta-analysis. Journal of neurosurgery, 131(2), 368-375.
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  Camptocormia is a potentially debilitating condition in the progression of Parkinson's disease (PD). It is described as an abnormal forward flexion while standing that resolves when lying supine. Although the condition is relatively common, the underlying pathophysiology and optimal treatment strategy are unclear. In this study, the authors systematically reviewed the current surgical management strategies for camptocormia.
• Fezeu, F., Ramesh, A., Melmer, P. D., Moosa, S., Larson, P. S., & Henderson, F. (2018). Challenges and Solutions for Functional Neurosurgery in Developing Countries. Cureus, 10(9), e3314.
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  Functional neurosurgery techniques remain integral to the neurosurgical treatment armamentarium but data on global implementation remains scarce. In comparison to high-income countries (HIC), low- and middle-income countries (LMIC) suffer from an increased prevalence of diseases like epilepsy, which may be amenable to functional techniques, and therefore, LMIC may benefit from an increased utilization of these treatment modalities. However, functional techniques tend to be expensive and thus difficult to implement in the LMIC setting. A review was performed to assess the current status of functional neurosurgical techniques in LMIC as a starting point for future initiatives. For methodology, a review of the current body of literature on functional neurosurgery in LMIC was conducted through the United States National Library of Medicine Pubmed search engine. Search terms included "functional neurosurgery," "developing countries," "low and middle income," and other related terms. It was found that though five billion people lack access to safe surgical care, the burden of disease amenable to treatment with functional neurosurgical procedures remains unknown. Increasingly, reports of successful, long-term, international neurosurgical collaborations are being reported, but reports in the sub-field of functional neurosurgery are lacking. In conclusion, awareness of global surgical disparities has increased dramatically while global guidelines for functional techniques are currently lacking. A concerted effort can harness these techniques for wider practice. Partnerships between centers in LMIC and HIC are making progress to better understand the burden of disease in LMIC and to create context-specific solutions for practice in the LMIC setting, but more collaborations are warranted.
• Kundishora, A. J., Englot, D. J., Starr, P. A., Martin, A. J., & Larson, P. S. (2018). Venous Thromboembolism during Interventional MRI-Guided Stereotactic Surgery. Stereotactic and functional neurosurgery, 96(1), 40-45.
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  Interventional MRI (iMRI) allows real-time confirmation of electrode and microcatheter location in anesthetized patients; however, MRI-compatible pneumatic compression devices (PCD) to reduce the periprocedural venous thromboembolism (VTE) risk are not commercially available. Given the paucity of literature on VTE following iMRI surgery, better characterizing patients suffering this complication and the incidence of this event following iMRI procedures is pivotal for defining best surgical practices. We aim to investigate the incidence of postoperative VTE in iMRI procedures without the use of PCD.
• Larson, P. S., Starr, P. A., & Martin, A. J. (2018). Deep Brain Stimulation: Interventional and Intraoperative MRI Approaches. Progress in neurological surgery, 33, 187-197.
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  Interventional and intraoperative MRI approaches to deep brain stimulator implantation are relatively new, and in their purest form represent a distinct departure from traditional stereotactic techniques. They employ a novel means of stereotaxis based on regions of interest in the MR space and simple geometric principles, which eliminate the need for a stereotactic frame. This approach is appropriate for targets that are MR visible, and for whom the local anatomy and function are well characterized. It may also be appropriate for targets that do not have a well-described physiologic signature and for which clinical response to macrostimulation does not play a critical role. We will discuss the rationale and principles of this new technique as well as its advantages and disadvantages relative to awake, physiologically guided deep brain stimulation surgery.
• Southwell, D. G., Birk, H. S., Larson, P. S., Starr, P. A., Sugrue, L. P., & Auguste, K. I. (2018). Laser ablative therapy of sessile hypothalamic hamartomas in children using interventional MRI: report of 5 cases. Journal of neurosurgery. Pediatrics, 21(5), 460-465.
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  Hypothalamic hamartomas (HHs) are benign lesions that cause medically refractory seizures, behavioral disturbances, and endocrine dysfunction. Open resection of HHs does not guarantee seizure freedom and carries a relatively high risk of morbidity. Minimally invasive stereotactic laser ablation has recently been described as an effective and safe alternative for HH treatment. Prior studies have not, however, assessed HH lesion size and morphology, 2 factors that may influence treatment results and, ultimately, the generalizability of their findings. In this paper, the authors describe seizure outcomes for 5 pediatric patients who underwent laser ablation of sessile HHs. Lesions were treated using a frameless, interventional MRI-guided approach, which facilitated laser targeting to specific components of these complex lesions. The authors' experiences in these cases substantiate prior work demonstrating the effectiveness of laser therapy for HHs, while elucidating HH complexity as a potentially important factor in laser treatment planning, and in the interpretation of early studies describing this treatment method.
• Southwell, D. G., Rutkowski, M. J., San Luciano, M., Racine, C., Ostrem, J., Starr, P. A., & Larson, P. S. (2018). Before and after the veterans affairs cooperative program 468 study: Deep brain stimulator target selection for treatment of Parkinson's disease. Parkinsonism & related disorders, 48, 40-44.
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  The Veterans Affairs Cooperative Study Program 468 study (CSP 468) produced significant findings regarding deep brain stimulation (DBS) target selection for Parkinson's Disease (PD) treatment, yet its impact on clinical practices has not been described. Here we assess how CSP 468 influenced target selection at a high-volume movement disorders treatment center.
• Talbott, J. F., Cooke, D. L., Mabray, M. C., Larson, P. S., Amans, M. R., Hetts, S. W., Wilson, M. W., Moore, T., & Salegio, E. A. (2018). Accuracy of image-guided percutaneous injection into a phantom spinal cord utilizing flat panel detector CT with MR fusion and integrated navigational software. Journal of neurointerventional surgery, 10(12), e37.
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  To evaluate the accuracy of percutaneous fluoroscopic injection into the spinal cord of a spine phantom utilizing integrated navigational guidance from fused flat panel detector CT (FDCT) and MR datasets. Conventional and convection-enhanced delivery (CED) techniques were evaluated.
• LaHue, S. C., Ostrem, J. L., Galifianakis, N. B., San Luciano, M., Ziman, N., Wang, S., Racine, C. A., Starr, P. A., Larson, P. S., & Katz, M. (2017). Parkinson's disease patient preference and experience with various methods of DBS lead placement. Parkinsonism & related disorders, 41, 25-30.
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  Physiology-guided deep brain stimulation (DBS) surgery requires patients to be awake during a portion of the procedure, which may be poorly tolerated. Interventional MRI-guided (iMRI) DBS surgery was developed to use real-time image guidance, obviating the need for patients to be awake during lead placement.
• Larson, P. S., Vadivelu, S., Azmi-Ghadimi, H., Nichols, A., Fauerbach, L., & Johnson, H. B. (2017). Neurosurgical laser ablation and MR thermometry: Risks of multisite workflow pattern. Journal of healthcare risk management : the journal of the American Society for Healthcare Risk Management, 36(4), 7-18.
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  Neurosurgical laser ablation is a relatively new but rapidly growing application of stereotactic neurosurgery that allows neurosurgeons to treat many previously untreatable conditions with the added benefit of shorter hospitalizations and recovery times. The vast majority of these procedures, however, are performed using a multisite workflow pattern involving transport of the patient between the operating room (OR), the computed tomography (CT) suite, and the magnetic resonance imaging (MRI) suite, often necessitating patient transfer through public pathways and requiring multiple trips if laser fiber placement is not accurate. There are significant risks posed to the patient with this practice and no existing guidelines addressing it. This article serves to identify those risks and present recommendations for safety optimization and risk reduction for those health care facilities using a multisite workflow pattern.
• Larson, P. S., Willie, J. T., Vadivelu, S., Azmi-Ghadimi, H., Nichols, A., Fauerbach, L. L., Johnson, H. B., & Graham, D. (2017). MRI-guided stereotactic neurosurgical procedures in a diagnostic MRI suite: Background and safe practice recommendations. Journal of healthcare risk management : the journal of the American Society for Healthcare Risk Management, 37(1), 31-39.
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  The development of navigation technology facilitating MRI-guided stereotactic neurosurgery has enabled neurosurgeons to perform a variety of procedures ranging from deep brain stimulation to laser ablation entirely within an intraoperative or diagnostic MRI suite while having real-time visualization of brain anatomy. Prior to this technology, some of these procedures required multisite workflow patterns that presented significant risk to the patient during transport. For those facilities with access to this technology, safe practice guidelines exist only for procedures performed within an intraoperative MRI. There are currently no safe practice guidelines or parameters available for facilities looking to integrate this technology into practice in conventional MRI suites. Performing neurosurgical procedures in a diagnostic MRI suite does require precautionary measures. The relative novelty of technology and workflows for direct MRI-guided procedures requires consideration of safe practice recommendations, including those pertaining to infection control and magnet safety issues. This article proposes a framework of safe practice recommendations designed for assessing readiness and optimization of MRI-guided neurosurgical interventions in the diagnostic MRI suite in an effort to mitigate patient risk. The framework is based on existing clinical evidence, recommendations, and guidelines related to infection control and prevention, health care-associated infections, and magnet safety, as well as the clinical and practical experience of neurosurgeons utilizing this technology.
• Martin, A. J., Larson, P. S., Ziman, N., Levesque, N., Volz, M., Ostrem, J. L., & Starr, P. A. (2017). Deep brain stimulator implantation in a diagnostic MRI suite: infection history over a 10-year period. Journal of neurosurgery, 126(1), 108-113.
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  OBJECTIVE The objective of this study was to assess the incidence of postoperative hardware infection following interventional (i)MRI-guided implantation of deep brain stimulation (DBS) electrodes in a diagnostic MRI scanner. METHODS A diagnostic 1.5-T MRI scanner was used over a 10-year period to implant DBS electrodes for movement disorders. The MRI suite did not meet operating room standards with respect to airflow and air filtration but was prepared and used with conventional sterile procedures by an experienced surgical team. Deep brain stimulation leads were implanted while the patient was in the magnet, and patients returned 1-3 weeks later to undergo placement of the implantable pulse generator (IPG) and extender wire in a conventional operating room. Surgical site infections requiring the removal of part or all of the DBS system within 6 months of implantation were scored as postoperative hardware infections in a prospective database. RESULTS During the 10-year study period, the authors performed 164 iMRI-guided surgical procedures in which 272 electrodes were implanted. Patients ranged in age from 7 to 78 years, and an overall infection rate of 3.6% was found. Bacterial cultures indicated Staphylococcus epidermis (3 cases), methicillin-susceptible Staphylococcus aureus (2 cases), or Propionibacterium sp. (1 case). A change in sterile practice occurred after the first 10 patients, leading to a reduction in the infection rate to 2.6% (4 cases in 154 procedures) over the remainder of the procedures. Of the 4 infections in this patient subset, all occurred at the IPG site. CONCLUSIONS Interventional MRI-guided DBS implantation can be performed in a diagnostic MRI suite with an infection risk comparable to that reported for traditional surgical placement techniques provided that sterile procedures, similar to those used in a regular operating room, are practiced.
• Martin, A. J., Starr, P. A., Ostrem, J. L., & Larson, P. S. (2017). Hemorrhage Detection and Incidence during Magnetic Resonance-Guided Deep Brain Stimulator Implantations. Stereotactic and functional neurosurgery, 95(5), 307-314.
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  Intraoperative magnetic resonance imaging (iMRI) is increasingly used to implant deep brain stimulator (DBS) electrodes. The approach has the advantages of a high targeting accuracy, minimization of brain penetrations, and allowance of implantation under general anesthesia. The hemorrhagic complications of iMRI-guided DBS implantation have not been studied in a large series. We report on the incidence and characteristics of hemorrhage during these procedures.
• Srejic, U., Larson, P., & Bickler, P. E. (2017). Little Black Boxes: Noncardiac Implantable Electronic Medical Devices and Their Anesthetic and Surgical Implications. Anesthesia and analgesia, 125(1), 124-138.
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  Implanted electronic medical devices. or stimulators such as pacemakers and nerve stimulators have grown enormously in diversity and complexity over recent decades. The function and potential interaction of these devices with the perioperative environment is of increasing concern for anesthesiologists and surgeons. Because of the innate electromagnetic environment of the hospital (operating room, gastrointestinal procedure suite, and imaging suite), implanted device malfunction, reprogramming, or destruction may occur and cause physical harm (including nerve injury, blindness, deafness, burn, stroke, paralysis, or coma) to the patient. It is critical for the anesthesiologist and surgeon to be aware of the function and interaction of implanted devices, both with other implanted devices and procedures (such as magnetic resonance imaging and cardioversion) in the hospital environment. Because of these interactions, it is imperative that proper device function is assessed when the surgical procedure is complete. This review article will discuss these important issues for 12 different types of "little black boxes," or noncardiac implantable electronic medical devices.
• Wharen, R. E., Okun, M. S., Guthrie, B. L., Uitti, R. J., Larson, P., Foote, K., Walker, H., Marshall, F. J., Schwalb, J., Ford, B., Jankovic, J., Simpson, R., Dashtipour, K., Phibbs, F., Neimat, J. S., Stewart, R. M., Peichel, D., Pahwa, R., Ostrem, J. L., & , S. D. (2017). Thalamic DBS with a constant-current device in essential tremor: A controlled clinical trial. Parkinsonism & related disorders, 40, 18-26.
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  This study of thalamic deep brain stimulation (DBS) investigated whether a novel constant-current device improves tremor and activities of daily living (ADL) in patients with essential tremor (ET).
• Han, S. J., Bankiewicz, K., Butowski, N. A., Larson, P. S., & Aghi, M. K. (2016). Interventional MRI-guided catheter placement and real time drug delivery to the central nervous system. Expert review of neurotherapeutics, 16(6), 635-9.
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  Local delivery of therapeutic agents into the brain has many advantages; however, the inability to predict, visualize and confirm the infusion into the intended target has been a major hurdle in its clinical development. Here, we describe the current workflow and application of the interventional MRI (iMRI) system for catheter placement and real time visualization of infusion. We have applied real time convection-enhanced delivery (CED) of therapeutic agents with iMRI across a number of different clinical trials settings in neuro-oncology and movement disorders. Ongoing developments and accumulating experience with the technique and technology of drug formulations, CED platforms, and iMRI systems will continue to make local therapeutic delivery into the brain more accurate, efficient, effective and safer.
• Mabray, M. C., Datta, S., Lillaney, P. V., Moore, T., Gehrisch, S., Talbott, J. F., Levitt, M. R., Ghodke, B. V., Larson, P. S., & Cooke, D. L. (2016). Accuracy of flat panel detector CT with integrated navigational software with and without MR fusion for single-pass needle placement. Journal of neurointerventional surgery, 8(7), 731-5.
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  Fluoroscopic systems in modern interventional suites have the ability to perform flat panel detector CT (FDCT) with navigational guidance. Fusion with MR allows navigational guidance towards FDCT occult targets. We aim to evaluate the accuracy of this system using single-pass needle placement in a deep brain stimulation (DBS) phantom.
• Marks, W. J., Baumann, T. L., & Bartus, R. T. (2016). Long-Term Safety of Patients with Parkinson's Disease Receiving rAAV2-Neurturin (CERE-120) Gene Transfer. Human gene therapy, 27(7), 522-7.
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  The objective of this study was to assess the long-term safety of surgically administered recombinant adeno-associated virus serotype-2 (rAAV2)-neurturin (NRTN) to patients with advanced Parkinson's disease. Publications from prior trials reported no unexpected or troubling adverse events related to the vector or transgene comprising rAAV2-NRTN. Because rAAV2-NRTN produces long-term NRTN expression, subjects were enrolled in a long-term safety assessment protocol of rAAV2-NRTN. This article presents safety data for up to 5 years, well beyond that reported in the initial publications. Data from 53 patients are included; 47 received rAAV2-NRTN bilaterally to the putamen, whereas 6 subjects received rAAV2-NRTN bilaterally into putamen-plus-substantia nigra. Patients underwent in-person safety assessments on a quarterly to bi-annual basis, including adverse event monitoring, physical and neurological examinations, brain MRI, and laboratory testing. Parkinsonian status was assessed in an unblinded fashion. Fifty-three subjects completed the long-term safety protocol. Nine nonserious adverse events (non-SAEs) in 6 subjects were deemed "possibly related" to rAAV2-NRTN by the principal investigator, whereas none were deemed "related" to rAAV2-NRTN. Over the course of long-term observation, 33 SAEs were reported in 18 subjects, all of who received rAAV2-NRTN into putamen-only; 31 SAEs were deemed not related to rAAV2-NRTN, and 2 were deemed unlikely related. Safety assessments showed no clinically relevant changes in examination, imaging, or laboratory studies. Motor status, on average, was stable or apparently modestly improved (relative to baseline) over the course of the open-label, long-term follow-up. These findings provide evidence for the long-term safety of neurturin when delivered to the putamen or the putamen-plus-substantia nigra via stereotactic surgery and rAAV2 gene transfer. They therefore supplement the safety results reported in four prior publications from the same subjects, significantly extending the safety data for gene therapy and neurotrophic factor expression targeting the brain and adding to growing evidence that rAAV vector-mediated gene therapy to the CNS can be administered safely.
• Ostrem, J. L., Ziman, N., Galifianakis, N. B., Starr, P. A., Luciano, M. S., Katz, M., Racine, C. A., Martin, A. J., Markun, L. C., & Larson, P. S. (2016). Clinical outcomes using ClearPoint interventional MRI for deep brain stimulation lead placement in Parkinson's disease. Journal of neurosurgery, 124(4), 908-16.
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  The ClearPoint real-time interventional MRI-guided methodology for deep brain stimulation (DBS) lead placement may offer advantages to frame-based approaches and allow accurate implantation under general anesthesia. In this study, the authors assessed the safety and efficacy of DBS in Parkinson's disease (PD) using this surgical method.
• Ramos, A. D., Rolston, J. D., Gauger, G. E., & Larson, P. S. (2016). Spinal Subdural Abscess Following Laminectomy for Symptomatic Stenosis: A Report of 2 Cases and Review of the Literature. The American journal of case reports, 17, 476-83.
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  BACKGROUND Spinal subdural abscesses, also known as empyemas, are rare infectious lesions, the exact incidence of which is unknown. Presentation is typically dramatic, with back pain, fever, motor, and sensory deficits. Rapid identification and surgical intervention with laminectomy, durotomy, and washout provides the best outcomes. While hematogenous spread of an extra-spinal infection is the most common cause of this condition, a significant number of cases result from iatrogenic mechanisms, including lumbar punctures, epidural injections, and surgery. CASE REPORT Here we present 2 cases: 1) an 87-year-old man with type 2 diabetes, schizophrenia, mild cognitive impairment, and symptomatic lumbar spinal stenosis and 2) a 62-year-old man with a prior L3-4 spinal fusion with symptomatic lumbar spinal stenosis. In both cases, patients underwent laminectomy for spinal stenosis and developed epidural abscess. Following successful drainage of the epidural abscess, they continued to be symptomatic, and repeat imaging revealed the presence of a subdural abscess that was subsequently evacuated. Case 1 had significant improvement with residual lower-extremity weakness, while Case 2 made a complete neurological recovery. CONCLUSIONS These cases illustrate patients at increased risk for developing this rare spinal infection, and demonstrate that rapid recognition and surgical treatment is key to cure and recovery. Review of the literature highlights pertinent risk factors and demonstrates nearly one-third of reported cases have an iatrogenic etiology. The cases presented here demonstrate that a subdural process should be suspected in any patient with intractable pain following treatment of an epidural abscess.
• Rolston, J. D., Englot, D. J., Starr, P. A., & Larson, P. S. (2016). An unexpectedly high rate of revisions and removals in deep brain stimulation surgery: Analysis of multiple databases. Parkinsonism & related disorders, 33, 72-77.
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  Deep brain stimulation (DBS) is an established therapy for movement disorders, and is under active investigation for other neurologic and psychiatric indications. While many studies describe outcomes and complications related to stimulation therapies, the majority of these are from large academic centers, and results may differ from those in general neurosurgical practice.
• Rowland, N. C., Kalia, S. K., Kalia, L. V., Larson, P. S., Lim, D. A., & Bankiewicz, K. S. (2016). Merging DBS with viral vector or stem cell implantation: "hybrid" stereotactic surgery as an evolution in the surgical treatment of Parkinson's disease. Molecular therapy. Methods & clinical development, 3, 15051.
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  Parkinson's disease (PD) is a complex neurodegenerative disorder that is currently managed using a broad array of symptom-based strategies. However, targeting its molecular origins represents the potential to discover disease-modifying therapies. Deep brain stimulation (DBS), a highly successful treatment modality for PD symptoms, addresses errant electrophysiological signaling pathways in the basal ganglia. In contrast, ongoing clinical trials testing gene and cell replacement therapies propose to protect or restore neuronal-based physiologic dopamine transmission in the striatum. Given promising new platforms to enhance target localization-such as interventional MRI-guided stereotaxy-the opportunity now exists to create hybrid therapies that combine DBS with gene therapy and/or cell implantation. In this mini-review, we discuss approaches used for central nervous system biologic delivery in PD patients in previous trials and propose a new set of strategies based on novel molecular targets. A multifaceted approach, if successful, may not only contribute to our understanding of PD pathology but could introduce a new era of disease modification.
• San Luciano, M., Katz, M., Ostrem, J., Martin, A., Starr, P., Ziman, N., & Larson, P. (2016). Effective Interventional Magnetic Resonance Image-Guided Laser Ablations in a Parkinson's Disease Patient with Refractory Tremor. Movement disorders clinical practice, 3(3), 312-314.
• Southwell, D. G., Narvid, J. A., Martin, A. J., Qasim, S. E., Starr, P. A., & Larson, P. S. (2016). Comparison of Deep Brain Stimulation Lead Targeting Accuracy and Procedure Duration between 1.5- and 3-Tesla Interventional Magnetic Resonance Imaging Systems: An Initial 12-Month Experience. Stereotactic and functional neurosurgery, 94(2), 102-7.
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  Interventional magnetic resonance imaging (iMRI) allows deep brain stimulator lead placement under general anesthesia. While the accuracy of lead targeting has been described for iMRI systems utilizing 1.5-tesla magnets, a similar assessment of 3-tesla iMRI procedures has not been performed.
• Chabardes, S., Isnard, S., Castrioto, A., Oddoux, M., Fraix, V., Carlucci, L., Payen, J. F., Krainik, A., Krack, P., Larson, P., & Le Bas, J. F. (2015). Surgical implantation of STN-DBS leads using intraoperative MRI guidance: technique, accuracy, and clinical benefit at 1-year follow-up. Acta neurochirurgica, 157(4), 729-37.
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  Improvement of surgical accuracy during DBS-lead implantation has been described recently, leading to "frameless" or "MRI-verified" techniques. However, combining a high-quality definition of the STN using intraoperative 1.5 MRI with the possibility to reduce errors due to co-registration and to monitor lead progression during surgical insertion while checking the absence of surgical complication is an appealing method. We report here surgical methodology, safety, application accuracy, and clinical benefit of STN-lead implantation under MRI guidance.
• Katz, M., Luciano, M. S., Carlson, K., Luo, P., Marks, W. J., Larson, P. S., Starr, P. A., Follett, K. A., Weaver, F. M., Stern, M. B., Reda, D. J., Ostrem, J. L., & , C. 4. (2015). Differential effects of deep brain stimulation target on motor subtypes in Parkinson's disease. Annals of neurology, 77(4), 710-9.
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  The Veterans Administration Cooperative Studies Program #468, a multicenter study that randomized Parkinson's disease (PD) patients to either subthalamic nucleus (STN) or globus pallidus internus (GPi) deep brain stimulation (DBS), found that stimulation at either target provided similar overall motoric benefits. We conducted an additional analysis of this data set to evaluate whether PD motor subtypes responded differently to the 2 stimulation targets.
• Rothlind, J. C., York, M. K., Carlson, K., Luo, P., Marks, W. J., Weaver, F. M., Stern, M., Follett, K., Reda, D., & , C. S. (2015). Neuropsychological changes following deep brain stimulation surgery for Parkinson's disease: comparisons of treatment at pallidal and subthalamic targets versus best medical therapy. Journal of neurology, neurosurgery, and psychiatry, 86(6), 622-9.
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  Deep brain stimulation (DBS) improves motor symptoms in Parkinson's disease (PD), but questions remain regarding neuropsychological decrements sometimes associated with this treatment, including rates of statistically and clinically meaningful change, and whether there are differences in outcome related to surgical target.
• Rowland, N. C., Starr, P. A., Larson, P. S., Ostrem, J. L., Marks, W. J., & Lim, D. A. (2015). Combining cell transplants or gene therapy with deep brain stimulation for Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society, 30(2), 190-5.
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  Cell transplantation and gene therapy each show promise to enhance the treatment of Parkinson's disease (PD). However, because cell transplantation and gene therapy generally require direct delivery to the central nervous system, clinical trial design involves unique scientific, ethical, and financial concerns related to the invasive nature of the procedure. Typically, such biologics have been tested in PD patients who have not received any neurosurgical intervention. Here, we suggest that PD patients undergoing deep brain stimulation (DBS) device implantation are an ideal patient population for the clinical evaluation of cell transplantation and gene therapy. Randomizing subjects to an experimental group that receives the biologic concurrently with the DBS implantation-or to a control group that receives the DBS treatment alone-has several compelling advantages. First, this study design enables the participation of patients likely to benefit from DBS, many of whom simultaneously meet the inclusion criteria of biologic studies. Second, the need for a sham neurosurgical procedure is eliminated, which may reduce ethical concerns, promote patient recruitment, and enhance the blinding of surgical trials. Third, testing the biologic by "piggybacking" onto an established, reimbursable procedure should reduce the cost of clinical trials, which may allow a greater number of biologics to reach this critical stage of research translation. Finally, this clinical trial design may lead to combinatorial treatment strategies that provide PD patients with more durable control over disabling motor symptoms. By combining neuromodulation with biologics, we may also reveal important treatment paradigms relevant to other diseases of the brain.
• Silvestrini, M. T., Yin, D., Martin, A. J., Coppes, V. G., Mann, P., Larson, P. S., Starr, P. A., Zeng, X., Gupta, N., Panter, S. S., Desai, T. A., & Lim, D. A. (2015). Interventional magnetic resonance imaging-guided cell transplantation into the brain with radially branched deployment. Molecular therapy : the journal of the American Society of Gene Therapy, 23(1), 119-29.
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  Intracerebral cell transplantation is being pursued as a treatment for many neurological diseases, and effective cell delivery is critical for clinical success. To facilitate intracerebral cell transplantation at the scale and complexity of the human brain, we developed a platform technology that enables radially branched deployment (RBD) of cells to multiple target locations at variable radial distances and depths along the initial brain penetration tract with real-time interventional magnetic resonance image (iMRI) guidance. iMRI-guided RBD functioned as an "add-on" to standard neurosurgical and imaging workflows, and procedures were performed in a commonly available clinical MRI scanner. Multiple deposits of super paramagnetic iron oxide beads were safely delivered to the striatum of live swine, and distribution to the entire putamen was achieved via a single cannula insertion in human cadaveric heads. Human embryonic stem cell-derived dopaminergic neurons were biocompatible with the iMRI-guided RBD platform and successfully delivered with iMRI guidance into the swine striatum. Thus, iMRI-guided RBD overcomes some of the technical limitations inherent to the use of straight cannulas and standard stereotactic targeting. This platform technology could have a major impact on the clinical translation of a wide range of cell therapeutics for the treatment of many neurological diseases.
• Warren Olanow, C., Bartus, R. T., Baumann, T. L., Factor, S., Boulis, N., Stacy, M., Turner, D. A., Marks, W., Larson, P., Starr, P. A., Jankovic, J., Simpson, R., Watts, R., Guthrie, B., Poston, K., Henderson, J. M., Stern, M., Baltuch, G., Goetz, C. G., , Herzog, C., et al. (2015). Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial. Annals of neurology, 78(2), 248-57.
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  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.
• Yoon, J. H., Larson, P., Grandelis, A., La, C., Cui, E., Carter, C. S., & Minzenberg, M. J. (2015). Delay Period Activity of the Substantia Nigra during Proactive Control of Response Selection as Determined by a Novel fMRI Localization Method. Journal of cognitive neuroscience, 27(6), 1238-48.
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  The ability to proactively control motor responses, particularly to overcome overlearned or automatic actions, is an essential prerequisite for adaptive, goal-oriented behavior. The substantia nigra (SN), an element of the BG, has figured prominently in current models of response selection. However, because of its small size and proximity to functionally distinct subcortical structures, it has been challenging to test the SN's involvement in response selection using conventional in vivo functional neuroimaging approaches. We developed a new fMRI localization method for directly distinguishing, on echo-planar images, the SN BOLD signal from that of neighboring structures, including the subthalamic nucleus (STN). Using this method, we tested the hypothesis that the SN supports the proactive control of response selection. We acquired high-resolution EPI volumes at 3 T from 16 healthy participants while they completed the Preparing to Overcome Prepotency task of proactive control. There was significantly elevated delay period signal selectively during high- compared with low-control trials in the SN. The STN did not show delay period activity in either condition. SN delay period signal was significantly inversely associated with task performance RTs across participants. These results suggest that our method offers a novel means for measuring SN BOLD responses, provides unique evidence of SN involvement in cognitive control in humans, and suggests a novel mechanism for proactive response selection.
• Ivan, M. E., Yarlagadda, J., Saxena, A. P., Martin, A. J., Starr, P. A., Sootsman, W. K., & Larson, P. S. (2014). Brain shift during bur hole-based procedures using interventional MRI. Journal of neurosurgery, 121(1), 149-60.
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  OBJECT.: Brain shift during minimally invasive, bur hole-based procedures such as deep brain stimulation (DBS) electrode implantation and stereotactic brain biopsy is not well characterized or understood. We examine shift in various regions of the brain during a novel paradigm of DBS electrode implantation using interventional imaging throughout the procedure with high-field interventional MRI.
• Larson, P. S. (2014). Deep brain stimulation for movement disorders. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 11(3), 465-74.
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  Deep brain stimulation (DBS) is an implanted electrical device that modulates specific targets in the brain resulting in symptomatic improvement in a particular neurologic disease, most commonly a movement disorder. It is preferred over previously used lesioning procedures due to its reversibility, adjustability, and ability to be used bilaterally with a good safety profile. Risks of DBS include intracranial bleeding, infection, malposition, and hardware issues, such migration, disconnection, or malfunction, but the risk of each of these complications is low--generally ≤ 5% at experienced, large-volume centers. It has been used widely in essential tremor, Parkinson's disease, and dystonia when medical treatment becomes ineffective, intolerable owing to side effects, or causes motor complications. Brain targets implanted include the thalamus (most commonly for essential tremor), subthalamic nucleus (most commonly for Parkinson's disease), and globus pallidus (Parkinson's disease and dystonia), although new targets are currently being explored. Future developments include brain electrodes that can steer current directionally and systems capable of "closed loop" stimulation, with systems that can record and interpret regional brain activity and modify stimulation parameters in a clinically meaningful way. New, image-guided implantation techniques may have advantages over traditional DBS surgery.
• Starr, P. A., Markun, L. C., Larson, P. S., Volz, M. M., Martin, A. J., & Ostrem, J. L. (2014). Interventional MRI-guided deep brain stimulation in pediatric dystonia: first experience with the ClearPoint system. Journal of neurosurgery. Pediatrics, 14(4), 400-8.
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  The placement of deep brain stimulation (DBS) leads in adults is traditionally performed using physiological confirmation of lead location in the awake patient. Most children are unable to tolerate awake surgery, which poses a challenge for intraoperative confirmation of lead location. The authors have developed an interventional MRI (iMRI)-guided procedure to allow for real-time anatomical imaging, with the goal of achieving very accurate lead placement in patients who are under general anesthesia.
• Vega, R. A., Holloway, K. L., & Larson, P. S. (2014). Image-guided deep brain stimulation. Neurosurgery clinics of North America, 25(1), 159-72.
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  Advances in deep brain stimulation (DBS) surgery have been achieved through the use of stereotactic targeting of key tracks in patients undergoing awake surgery. Intraoperative detection of track location has been useful in interpreting physiologic results, has limited the number of brain penetrations, and has decreased the incidence of reoperations. Alternatively, some centers are gaining experience with placement of the lead under general anesthesia using a purely anatomic approach, for which both computed tomography and magnetic resonance imaging have proved useful. In this article, the use of image guidance with both the anatomic and physiologic approaches is described.
• Silvestrini, M. T., Yin, D., Coppes, V. G., Mann, P., Martin, A. J., Larson, P. S., Starr, P. A., Gupta, N., Panter, S. S., Desai, T. A., & Lim, D. A. (2013). Radially branched deployment for more efficient cell transplantation at the scale of the human brain. Stereotactic and functional neurosurgery, 91(2), 92-103.
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  In preclinical studies, cell transplantation into the brain has shown great promise for the treatment of a wide range of neurological diseases. However, the use of a straight cannula and syringe for cell delivery to the human brain does not approximate cell distribution achieved in animal studies. This technical deficiency may limit the successful clinical translation of cell transplantation.
• Weintraub, D., Duda, J. E., Carlson, K., Luo, P., Sagher, O., Stern, M., Follett, K. A., Reda, D., Weaver, F. M., & , C. 4. (2013). Suicide ideation and behaviours after STN and GPi DBS surgery for Parkinson's disease: results from a randomised, controlled trial. Journal of neurology, neurosurgery, and psychiatry, 84(10), 1113-8.
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  The risk of suicide behaviours post-deep brain stimulation (DBS) surgery in Parkinson's disease (PD) remains controversial. We assessed if suicide ideation and behaviours are more common in PD patients (1) randomised to DBS surgery versus best medical therapy (BMT); and (2) randomised to subthalamic nucleus (STN) versus globus pallidus interna (GPi) DBS surgery.

Presentations

• Larson, P. (2024, April). Surgery for Gene and Cell-Based Therapies. American Society for Neural Therapy and Repair, Roy Bakay Memorial Lecture. Clearwater, FL.
• Larson, P. (2024, April). Surgery for Parkinson's Disease. Pima Medical Institute, Nursing Program. Tucson, AZ.
• Larson, P. (2024, December). How I Do It: Asleep Deep Brain Stimulation. International Parkinson and Movement Disorder Society. Virtual Webinar - London, Sydney and Tucson.
• Larson, P. (2024, June). Evolution of Surgery for Gene Therapy. American Society for Stereotactic and Functional Neurosurgery. Nashville, TN.
• Larson, P. (2024, June). How to Build an Academic Functional Practice. American Society for Stereotactic and Functional Neurosurgery. Nashville, TN.
• Larson, P. (2024, June). The History of MRI-Guided Surgery for Deep Brain Stimulation and Beyond. ClearPoint Neuro National Sales Meeting. Nashville, TN.
• Larson, P. (2024, March). Surgical Trials for Biologics: How should we partner with industry?. IGNITE II Summit. Columbus, OH.
• Larson, P. (2024, November). How Safe is Cell Transplantation for Parkinson's Diease?. Summit for Stem Cell Foundation Webinar Series. La Jolla, CA.
• Larson, P. (2024, October). Cell Transplantation for Parkinson's Disease. Living Well With Parkinson's Disease. Tucson, AZ.
• Larson, P. (2024, October). Intraoperative MRI-Guided Functional Neurosurgery. Stereotactic and Functional Neurosurgery: Hands-on Workshop. Denver, CO.
• Larson, P. (2024, October). Surgical Approaches for Gene Therapy and Cell Transplantation. Stereotactic and Functional Neurosurgery: Hands-on Workshop. Denver, CO.
• Larson, P. (2024, September). A History of MRI-Guided Neurosurgery. Clinical Laserthermia Systems AB Conference. Lund, Sweden.
• Larson, P. (2024, September). First in Human Administration of an Autologous Investigational Cell Therapy for Parkinson Disease Using an Intraoperative MRI-Guided Posterior Approach. International Parkinson and Movement Disorder Society. Philadelphia, PA.

Poster Presentations

• Larson, P. (2024, September). First in Human Administration of an Autologous Investigational Cell Therapy for Parkinson Disease Using an Intraoperative MRI-Guided Posterior Approach. International Parkinson and Movement Disorder Society. Philadelphia, PA.