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Background: 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. Method: 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 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. Results: 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. Conclusions: Therapeutic DBS for OCD suppresses BOLD activity within a distributed set of regions within the DMN relative to non-therapeutic configurations. We propose that these effects may be mediated by interruption of communication through structural white matter connections surrounding the DBS active contacts.
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BACKGROUND: 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. OBJECTIVE: The objective of this study was to examine the safety of sham surgeries in Parkinson's disease (PD) clinical trials through complications related to the procedure. METHODS: A systematic review and meta-analysis were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Rates and odds ratios (OR) were compared using random effects analysis. RESULTS: Seven studies, all randomized, double-blind, sham surgery-controlled trials, with 309 patients with PD, were qualitatively and quantitatively analyzed: 141 patients in sham groups and 168 patients in the experimental arms of gene or cell therapy trials. Sham subjects had lower rates of gastrointestinal, positioning, incision-site, respiratory (hypoxic or hypercapnic respiratory failure), cardiovascular, thromboembolism, postoperative cognitive decline, skull fracture, and intracranial or spinal complications when compared with active treatment subjects. Sham subjects, however, had a higher rate of perioperative respiratory infections, such as pneumonia or sinusitis. Further, sham subjects were less likely to experience postoperative cognitive decline (OR, 0.23; 95% confidence interval [CI]: 0.11-0.47), intracranial or spinal complications (OR, 0.10; 95% CI: 0.01-0.75), total major morbidity (OR, 0.30; 95% CI: 0.19-0.47), or overall complications (OR, 0.59; 95% CI: 0.47-0.75) when compared with patients receiving experimental therapy. CONCLUSIONS: Patients with PD in the sham surgery control arm of cell transplantation or gene therapy clinical trials have a low risk of procedure-related adverse events overall and fewer complications than patients in the experimental groups. There were no reported deaths attributed to sham surgery-controlled PD clinical trials. © 2023 International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Complicaciones Cognitivas Postoperatorias , Humanos , Enfermedad de Parkinson/cirugía , Enfermedad de Parkinson/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
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.
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BACKGROUND: 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. OBJECTIVE: Direct comparisons of targeting accuracy and clinical outcomes for awake stereotactic with asleep iMRI-DBS for PD are limited. METHODS: We performed a retrospective review of patients with PD who underwent awake or iMRI-guided DBS surgery targeting the subthalamic nucleus or globus pallidus interna between 2013 and 2019 at our institution. Outcome measures included Unified Parkinson's Disease Rating Scale Part III scores, levodopa equivalent daily dose, radial error between intended and actual lead locations, stimulation parameters, and complications. RESULTS: Of the 218 patients included in the study, the iMRI cohort had smaller radial errors (iMRI: 1.27 ± 0.72 mm, awake: 1.59 ± 0.96 mm, P < .01) and fewer lead passes (iMRI: 1.0 ± 0.16, awake: 1.2 ± 0.41, P < .01). Changes in Unified Parkinson's Disease Rating Scale were similar between modalities, but awake cases had a greater reduction in levodopa equivalent daily dose than iMRI cases ( P < .01), which was attributed to the greater number of awake subthalamic nucleus cases on multivariate analysis. Effective clinical contacts used for stimulation, side effect thresholds, and complication rates were similar between modalities. CONCLUSION: Although iMRI-DBS may result in more accurate lead placement for intended target compared with awake-DBS, clinical outcomes were similar between surgical approaches. Ultimately, patient preference and surgeon experience with a given DBS technique should be the main factors when determining the "best" method for DBS implantation.
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Estimulación Encefálica Profunda , Imagen por Resonancia Magnética Intervencional , Enfermedad de Parkinson , Estimulación Encefálica Profunda/métodos , Humanos , Levodopa/uso terapéutico , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/terapia , San Francisco , Resultado del Tratamiento , VigiliaRESUMEN
Background: 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. Objectives: To compare benefits and risks of bilateral versus unilateral VIM DBS using the largest ET DBS clinical trial dataset available to date. Methods: Participants from the US St. Jude/Abbott pivotal ET DBS trial who underwent staged-bilateral VIM implantation constituted the primary cohort in this sub-analysis. Their assessments "on" DBS at six months after second-side VIM DBS implantation were compared to the assessments six months after unilateral implantation. Two control cohorts of participants with unilateral implantation only were also used for between-group comparisons. Results: The primary cohort consisted of n = 38 ET patients (22M/16F; age of 65.3 ± 9.5 years). The second side VIM-DBS resulted in a 29.6% additional improvement in the total motor CRST score (P < 0.001), with a 64.1% CRST improvement in the contralateral side (P < 0.001). An added improvement was observed in the axial tremor score (21.4%, P = 0.005), and CRST part B (24.8%, P < 0.001) score. Rate of adverse events was slightly higher after bilateral stimulation. Conclusions: In the largest ET DBS study to date, staged-bilateral VIM DBS was a highly effective treatment for ET with bilateral implantation resulting in greater reduction in total motor tremor scores when compared to unilateral stimulation alone.
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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.
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Corteza Auditiva/fisiopatología , Núcleo Caudado/fisiopatología , Cerebelo/fisiopatología , Conectoma , Estimulación Encefálica Profunda , Pérdida Auditiva/fisiopatología , Red Nerviosa/fisiopatología , Acúfeno/fisiopatología , Acúfeno/terapia , Adulto , Anciano , Corteza Auditiva/diagnóstico por imagen , Estudios de Casos y Controles , Núcleo Caudado/diagnóstico por imagen , Cerebelo/diagnóstico por imagen , Estudios Transversales , Femenino , Pérdida Auditiva/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Acúfeno/diagnóstico por imagenRESUMEN
BACKGROUND AND OBJECTIVES: 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. METHODS: PD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5 × 1011 vector genomes (vg); cohort 2, ≤1.5 × 1012 vg; cohort 3, ≤4.7 × 1012 vg. RESULTS: No serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector-related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21%-30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, Unified Parkinson's Disease Rating Scale III "off"-medication and "on"-medication scores), global impressions of improvement (Clinical Global Impression of Improvement, Patient Global Impression of Improvement), and quality of life (39-item Parkinson's Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts. DISCUSSIONS: VY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years. TRIAL REGISTRATION INFORMATION: NCT01973543. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.
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Carboxiliasas , Enfermedad de Parkinson , Aminoácidos/genética , Aminoácidos/uso terapéutico , Antiparkinsonianos/efectos adversos , Carboxiliasas/uso terapéutico , Terapia Genética/métodos , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Calidad de Vida , Resultado del TratamientoRESUMEN
Objective: 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 de novo implantation of modern and traditional DBS systems in patients with Parkinson's disease (PD) or essential tremor (ET) in the United States. Design: Retrospective, contemporaneous cohort study. Setting: Multicenter data from the United States Centers for Medicare and Medicaid Services administrative claims database between 2016 and 2018. Participants: This population-based sample consisted of 5,998 patients implanted with a DBS system, of which 3,869 patients had a de novo 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. Intervention: Implantation of a modern directional (MD) or traditional omnidirectional (TO) DBS system. Primary and Secondary Outcome Measures: 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. Results: 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. Conclusions: 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.
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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.
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Enfermedad de Parkinson , Barrera Hematoencefálica , Trasplante de Células , Terapia Genética , Humanos , Enfermedad de Parkinson/terapiaRESUMEN
Neural recordings using invasive devices in humans can elucidate the circuits underlying brain disorders, but have so far been limited to short recordings from externalized brain leads in a hospital setting or from implanted sensing devices that provide only intermittent, brief streaming of time series data. Here, we report the use of an implantable two-way neural interface for wireless, multichannel streaming of field potentials in five individuals with Parkinson's disease (PD) for up to 15 months after implantation. Bilateral four-channel motor cortex and basal ganglia field potentials streamed at home for over 2,600 h were paired with behavioral data from wearable monitors for the neural decoding of states of inadequate or excessive movement. We validated individual-specific neurophysiological biomarkers during normal daily activities and used those patterns for adaptive deep brain stimulation (DBS). This technological approach may be widely applicable to brain disorders treatable by invasive neuromodulation.
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Adaptación Fisiológica , Monitorización Neurofisiológica/métodos , Enfermedad de Parkinson/fisiopatología , Tecnología Inalámbrica , Adulto , Estimulación Encefálica Profunda , Femenino , Humanos , Masculino , Persona de Mediana Edad , Corteza Motora/fisiopatología , Movimiento , Enfermedad de Parkinson/terapia , Dispositivos Electrónicos VestiblesRESUMEN
OBJECTIVE: Surgical site infection (SSI) is a complication linked to increased costs and length of hospital stay. Prevention of SSI is important to reduce its burden on individual patients and the healthcare system. The authors aimed to assess the efficacy of preoperative chlorhexidine gluconate (CHG) showers on SSI rates following cranial surgery. METHODS: In November 2013, a preoperative CHG shower protocol was implemented at the authors' institution. A total of 3126 surgical procedures were analyzed, encompassing a time frame from April 2012 to April 2016. Cohorts before and after implementation of the CHG shower protocol were evaluated for differences in SSI rates. RESULTS: The overall SSI rate was 0.6%. No significant differences (p = 0.11) were observed between the rate of SSI of the 892 patients in the preimplementation cohort (0.2%) and that of the 2234 patients in the postimplementation cohort (0.8%). Following multivariable analysis, implementation of preoperative CHG showers was not associated with decreased SSI (adjusted OR 2.96, 95% CI 0.67-13.1; p = 0.15). CONCLUSIONS: This is the largest study, according to sample size, to examine the association between CHG showers and SSI following craniotomy. CHG showers did not significantly alter the risk of SSI after a cranial procedure.
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Objective.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.Approach.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.Main results.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 (R= -0.83) between shift from intended target and intended neural pathway recruitment, where at threshold of â¼2.94 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.Significance.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.
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Estimulación Encefálica Profunda , Encéfalo/cirugía , Estimulación Encefálica Profunda/métodos , Análisis de Elementos Finitos , Humanos , Vías Nerviosas , FísicaRESUMEN
INTRODUCTION: During deep brain stimulation (DBS) surgery, computed tomography (CT) and magnetic resonance imaging (MRI) scans need to be co-registered or fused. Image fusion is associated with the error that can distort the location of anatomical structures. Co-registration in DBS surgery is usually performed automatically by proprietary software; the amount of error during this process is not well understood. Here, our goal is to quantify the error during automated image co-registration with FrameLink™, a commonly used software for DBS planning and clinical research. METHODS: This is a single-center retrospective study at a quaternary care referral center, comparing CT and MR imaging co-registration for a consecutive series of patients over a 12-month period. We collected CT images and MRI scans for 22 patients with Parkinson's disease requiring placement of DBS. Anatomical landmarks were located on CT images and MRI scans using a novel image analysis algorithm that included a method for capturing the potential error inherent in the image standardization step of the analysis. The distance between the anatomical landmarks was measured, and the error was found by averaging the distances across all patients. RESULTS: The average error during co-registration was 1.25 mm. This error was significantly larger than the error resulting from image standardization (0.19 mm) and was worse in the anterior-posterior direction. CONCLUSIONS: The image fusion errors found in this analysis were nontrivial. Although the estimated error may be inflated, it is sig-nificant enough that users must be aware of this potential inaccuracy, and developers of proprietary software should provide details about the magnitude and direction of co-registration errors.
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Estimulación Encefálica Profunda , Humanos , Imagen por Resonancia Magnética , Estudios Retrospectivos , Programas Informáticos , Tomografía Computarizada por Rayos XRESUMEN
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.
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Cuerpo Estriado , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Imagen por Resonancia Magnética , Procedimientos Neuroquirúrgicos/métodos , Enfermedad de Parkinson/terapia , Sustancia Negra , Animales , Descarboxilasas de Aminoácido-L-Aromático/genética , Ganglios Basales , Dependovirus , Medicina Basada en la Evidencia , GTP Ciclohidrolasa/genética , Glutamato Descarboxilasa/genética , Humanos , Cuidados Intraoperatorios/métodos , Lentivirus , Neurturina/genética , Parvovirinae , Primates , Cirugía Asistida por Computador , Tirosina 3-Monooxigenasa/genéticaRESUMEN
The ability to dynamically change motor outputs, such as stopping an initiated response, is an important aspect of human behavior. A hyperdirect pathway between the inferior frontal gyrus and subthalamic nucleus is hypothesized to mediate movement inhibition, but there is limited evidence for this in humans. We recorded high spatial and temporal resolution field potentials from both the inferior frontal gyrus and subthalamic nucleus in 21 subjects. Cortical potentials evoked by subthalamic stimulation revealed short latency events indicative of monosynaptic connectivity between the inferior frontal gyrus and ventral subthalamic nucleus. During a stop signal task, stopping-related potentials in the cortex preceded stopping-related activity in the subthalamic nucleus, and synchronization between these task-evoked potentials predicted the stop signal reaction time. Thus, we show that a prefrontal-subthalamic hyperdirect pathway is present in humans and mediates rapid stopping. These findings may inform therapies to treat disorders featuring perturbed movement inhibition.
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Inhibición Psicológica , Movimiento/fisiología , Vías Nerviosas/fisiología , Corteza Prefrontal/fisiología , Núcleo Subtalámico/fisiología , Anciano , Electrocorticografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatologíaRESUMEN
BACKGROUND: 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. OBJECTIVES: This substudy aimed to determine whether the timing and magnitude of motor response to intravenous levodopa changed in PD-1101 patients after VY-AADC01 administration. METHODS: Participants received 2-hour threshold (0.6 mg/kg/h) and suprathreshold (1.2 mg/kg/h) levodopa infusions on each of 2 days, both before and approximately 6 months after VY-AADC01. Infusion order was randomized and double blinded. Unified Parkinson's Disease Rating Scale motor scores, finger-tapping speeds, and dyskinesia rating scores were assessed every 30 minutes for 1 hour before and ≥3 hours after start of levodopa infusion. RESULTS: Of 15 PD-1101 patients, 13 participated in the substudy. Unified Parkinson's Disease Rating Scale motor score area under the curve responses to threshold and suprathreshold levodopa infusions increased by 168% and 67%, respectively, after VY-AADC01; finger-tapping speeds improved by 162% and 113%, and dyskinesia scores increased by 208% and 72%, respectively, after VY-AADC01. Adverse events (mild/moderate severity) were reported in 5 participants during levodopa infusions pre-VY-AADC01 and 2 participants post-VY-AADC01 administration. CONCLUSIONS: VY-AADC01 improved motor responses to intravenous levodopa given under controlled conditions. These data and findings from the parent study support further clinical development of AADC gene therapy for people with Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Discinesias , Enfermedad de Parkinson , Antiparkinsonianos/uso terapéutico , Terapia Genética , Humanos , Levodopa , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
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. OBJECTIVE: This study presents a deformation-atlas biomechanical model-based approach to address shift. METHODS: Six patients, who underwent interventional magnetic resonance (iMR) image-guided DBS burr hole surgery, were studied. A patient-specific model was employed under varying surgical conditions, generating a collection of possible intraoperative shift estimations or a 'deformation atlas.' An inverse problem was driven by sparse measurements derived from iMR to determine an optimal fit of solutions of the atlas. This fit was then used to obtain a volumetric deformation field, which was utilized to update preoperative MR and estimate shift at surgical target region localized on iMR. Model performance was examined by quantitatively comparing intraoperative subsurface measurements to their model-predicted counterparts, and qualitatively comparing iMR, preoperative MR, and model updated MR. A nonrigid image registration was introduced as a comparator. RESULTS: Model-based approach reduced general parenchyma shift from 8.2 ± 2.2 to 2.7 ± 1.1 mm (â¼66.8% correction), and produced updated MR with better agreement to iMR than that of preoperative MR. The average model estimated shift at target region was 1.2 mm. CONCLUSIONS: This study demonstrates the feasibility of a model-based shift correction strategy in DBS surgery with only sparse data. SIGNIFICANCE: The developed strategy has the potential to complement and/or enhance current clinical approaches in addressing shift.