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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
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
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
OBJECTIVE: 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. METHODS: Fifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY-AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 1011 vg/ml and ≤450 µl per putamen (total dose, ≤7.5 × 1011 vg); cohort 2 received the same concentration (8.3 × 1011 vg/ml) and ≤900 µl per putamen (total dose, ≤1.5 × 1012 vg); and cohort 3 received 2.6 × 1012 vg/ml and ≤900 µl per putamen (total dose, ≤4.7 × 1012 vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes. RESULTS: MRI-guided administration of ascending VY-AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of -15%, -33%, and -42%, respectively, at 6 months. At 12 months, there were dose-related improvements in clinical outcomes, including increases in patient-reported ON-time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life. INTERPRETATION: Novel intraoperative monitoring of administration facilitated targeted delivery of VY-AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704-714.
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Descarboxilasas de Aminoácido-L-Aromático/genética , Terapia Genética/métodos , Imagen por Resonancia Magnética/métodos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/genética , Putamen/diagnóstico por imagen , Adulto , Anciano , Descarboxilasas de Aminoácido-L-Aromático/administración & dosificación , Femenino , Técnicas de Transferencia de Gen , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/terapiaRESUMEN
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
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
Patients with Parkinson disease (PD) often experience nonmotor symptoms including cognitive deficits, depression, and anxiety. Cognitive and affective processes are thought to be mediated by prefrontal cortico-basal ganglia circuitry. However, the topography and neurophysiology of prefrontal cortical activity during complex tasks are not well characterized. We used high-resolution electrocorticography in pFC of patients with PD and essential tremor, during implantation of deep brain stimulator leads in the awake state, to understand disease-specific changes in prefrontal activity during an emotional face processing task. We found that patients with PD had less task-related theta-alpha power and greater task-related gamma power in the dorsolateral pFC, inferior frontal cortex, and lateral OFC. These findings support a model of prefrontal neurophysiological changes in the dopamine-depleted state, in which focal areas of hyperactivity in prefrontal cortical regions may compensate for impaired long-range interactions mediated by low-frequency rhythms. These distinct neurophysiological changes suggest that nonmotor circuits undergo characteristic changes in PD.
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Electrocorticografía , Emociones/fisiología , Reconocimiento Facial/fisiología , Ritmo Gamma/fisiología , Enfermedad de Parkinson/fisiopatología , Corteza Prefrontal/fisiopatología , Ritmo Teta/fisiología , Anciano , Temblor Esencial/etiología , Temblor Esencial/fisiopatología , Femenino , Humanos , Neuroestimuladores Implantables , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicacionesRESUMEN
BACKGROUND/AIMS: 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. METHODS: Medical records and operative times of patients were retrospectively reviewed. Patient demographics and mean surgical durations were reported with statistical comparisons via ANOVA and the 2-tailed Student t test, an α of 0.05, and the Bonferroni correction. Patients experiencing postoperative VTE underwent an in-depth chart review. RESULTS: Two out of two hundred ten (0.95%) iMRI procedures resulted in postoperative VTE events. There were statistically significant differences in procedure times between unilateral electrode (157.5 ± 5.7 min), bilateral electrode (193.6 ± 2.9 min), and bilateral gene therapy procedures (467.3 ± 26.5 min). Both patients had longer-than-average operative times for their respective procedures. CONCLUSIONS: The incidence of postoperative VTE is low following iMRI procedures, even without the use of PCD during surgery.
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Complicaciones Intraoperatorias/diagnóstico por imagen , Complicaciones Intraoperatorias/etiología , Imagen por Resonancia Magnética Intervencional/efectos adversos , Técnicas Estereotáxicas/efectos adversos , Tromboembolia Venosa/diagnóstico por imagen , Tromboembolia Venosa/etiología , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Imagenología Tridimensional/métodos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND/AIMS: 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. METHODS: Hemorrhage incidence was assessed in a series of 231 iMRI procedures (374 electrodes implanted). All patients had movement disorders and the subthalamic nucleus or the globus pallidus internus was typically targeted. Hemorrhage was detected with intra- or postoperative MRI or postoperative computed tomography. Hemorrhage was classified based on its point of origin and clinical impact. RESULTS: Hemorrhage and symptomatic hemorrhage were detected during 2.4 and 1.1% of electrode implantations, respectively. The hemorrhage origin was subdural/subarachnoid (n = 3), subcortical (n = 5), or deep (n = 1). Factors that contributed to hemorrhage included unintentional crossing of a sulcus and resistance at the pial membrane, which produced cortical depression and a rebound hemorrhage. Delayed hemorrhage occurred in 2 patients and was attributed to premature reintroduction of anticoagulation therapy or air intrusion into the cranial cavity. CONCLUSIONS: Hemorrhage was readily apparent on intraoperative imaging, and hemorrhage rates for iMRI-guided DBS implantations were comparable to those for conventional implantation approaches.
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Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/epidemiología , Estimulación Encefálica Profunda/efectos adversos , Imagen por Resonancia Magnética/efectos adversos , Adulto , Anciano , Estimulación Encefálica Profunda/métodos , Electrodos Implantados/efectos adversos , Femenino , Humanos , Incidencia , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/diagnóstico por imagen , Trastornos del Movimiento/epidemiología , Trastornos del Movimiento/terapia , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: 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. METHODS: We classified 235 subjects by motor subtype: tremor dominant (TD), intermediate (I), or postural instability gait difficulty (PIGD), based on pre-DBS baseline Unified Parkinson's Disease Rating Scale (UPDRS) scores off-medication. The primary outcome was change in UPDRS part III (UPDRS-III) off-medication scores from baseline to 24 months post-DBS, compared among subjects with particular PD motor subtypes and by DBS target (STN vs GPi). Changes in tremor, rigidity, akinesia, and gait scores were also assessed using the UPDRS. RESULTS: TD patients had greater mean overall motor improvement, measured by UPDRS-III, after GPi DBS, compared to STN DBS (17.5 ± 13.0 vs 14.6 ± 14.9, p = 0.02), with improvement in gait accounting for this difference. Regardless of stimulation target, PIGD subjects had lower mean overall improvement in UPDRS-III scores compared with I or TD subjects (8.7 ± 12.2 vs 21.7 ± 11.2 vs 16.3 ± 13.8, p = 0.001). INTERPRETATION: Our results suggest that responsiveness to both GPi and STN DBS is similar among different PD motor subtypes, although the TD motor subtype may have a greater response to GPi DBS with respect to gait. PIGD patients obtained less overall benefit from stimulation.
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Estimulación Encefálica Profunda/métodos , Globo Pálido , Enfermedad de Parkinson/clasificación , Enfermedad de Parkinson/terapia , Núcleo Subtalámico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Método Simple Ciego , Resultado del TratamientoRESUMEN
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.
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Trasplante de Células , Imagen por Resonancia Magnética Intervencional/métodos , Técnicas Estereotáxicas/instrumentación , Animales , Cadáver , Cateterismo , Cuerpo Estriado/cirugía , Femenino , Humanos , Imagen por Resonancia Magnética Intervencional/instrumentación , Putamen/cirugía , PorcinosRESUMEN
BACKGROUND: 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. OBJECTIVE: To compare targeting accuracy, the number of lead targeting attempts, and surgical duration between procedures performed on 1.5- and 3-tesla iMRI systems. METHODS: Radial targeting error, the number of targeting attempts, and procedure duration were compared between surgeries performed on 1.5- and 3-tesla iMRI systems (SmartFrame and ClearPoint systems). RESULTS: During the first year of operation of each system, 26 consecutive leads were implanted using the 1.5-tesla system, and 23 consecutive leads were implanted using the 3-tesla system. There was no significant difference in radial error (Mann-Whitney test, p = 0.26), number of lead placements that required multiple targeting attempts (Fisher's exact test, p = 0.59), or bilateral procedure durations between surgeries performed with the two systems (p = 0.15). CONCLUSIONS: Accurate DBS lead targeting can be achieved with iMRI systems utilizing either 1.5- or 3-tesla magnets. The use of a 3-tesla magnet, however, offers improved visualization of the target structures and allows comparable accuracy and efficiency of placement at the selected targets.
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Estimulación Encefálica Profunda/normas , Distonía/cirugía , Monitorización Neurofisiológica Intraoperatoria/normas , Imagen por Resonancia Magnética Intervencional/normas , Tempo Operativo , Enfermedad de Parkinson/cirugía , Adulto , Estimulación Encefálica Profunda/métodos , Distonía/diagnóstico por imagen , Femenino , Humanos , Monitorización Neurofisiológica Intraoperatoria/métodos , Imagen por Resonancia Magnética Intervencional/métodos , Masculino , Enfermedad de Parkinson/diagnóstico por imagen , Factores de TiempoRESUMEN
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.
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Trasplante de Células , Terapia Genética , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/efectos de los fármacos , Núcleo Subtalámico/cirugía , Animales , Terapia por Estimulación Eléctrica , Humanos , Resultado del TratamientoRESUMEN
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: 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. OBJECTIVE: To develop a stereotactic device that effectively distributes viable cells to the human brain. Our primary aims were to (1) minimize the number of transcortical penetrations required for transplantation, (2) reduce variability in cell dosing and (3) increase cell survival. METHODS: We developed a modular cannula system capable of radially branched deployment (RBD) of a cell delivery catheter at variable angles from the longitudinal device axis. We also developed an integrated catheter-plunger system, eliminating the need for a separate syringe delivery mechanism. The RBD prototype was evaluated in vitro and in vivo with subcortical injections into the swine brain. Performance was compared to a 20G straight cannula with dual side ports, a device used in current clinical trials. RESULTS: RBD enabled therapeutic delivery in a precise 'tree-like' pattern branched from a single initial trajectory, thereby facilitating delivery to a volumetrically large target region. RBD could transplant materials in a radial pattern up to 2.0 cm from the initial penetration tract. The novel integrated catheter-plunger system facilitated manual delivery of small and precise volumes of injection (1.36 ± 0.13 µl per cm of plunger travel). Both dilute and highly concentrated neural precursor cell populations tolerated transit through the device with high viability and unaffected developmental potential. While reflux of infusate along the penetration tract was problematic with the use of the 20G cannula, RBD was resistant to this source of cell dose variability in agarose. RBD enabled radial injections to the swine brain when used with a modern clinical stereotactic system. CONCLUSIONS: By increasing the total delivery volume through a single transcortical penetration in agarose models, RBD strategy may provide a new approach for cell transplantation to the human brain. Incorporation of RBD or selected aspects of its design into future clinical trials may increase the likelihood of successful translation of cell-based therapy to the human patient.
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Encéfalo/citología , Encéfalo/cirugía , Células-Madre Neurales/trasplante , Trasplante de Células Madre/instrumentación , Trasplante de Células Madre/métodos , Animales , Células Cultivadas , Diseño de Equipo/instrumentación , Diseño de Equipo/métodos , Humanos , Ratones , PorcinosRESUMEN
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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Clinical trials involving direct infusion of neurotrophic therapies for Parkinson's disease (PD) have suffered from poor coverage of the putamen. The planned use of a novel interventional-magnetic resonance imaging (iMRI) targeting system for achieving precise, real-time convection-enhanced delivery in a planned clinical trial of adeno-associated virus serotype 2 (AAV2)-glial-derived neurotrophic factor (GDNF) in PD patients was modeled in nonhuman primates (NHP). NHP received bilateral coinfusions of gadoteridol (Gd)/AAV2-GDNF into two sites in each putamen, and three NHP received larger infusion volumes in the thalamus. The average targeting error for cannula tip placement in the putamen was <1 mm, and adjacent putamenal infusions were distributed in a uniform manner. GDNF expression patterns in the putamen were highly correlated with areas of Gd distribution seen on MRI. The distribution volume to infusion volume ratio in the putamen was similar to that in the thalamus, where larger infusions were achieved. Modeling the placement of adjacent 150 and 300 µl thalamic infusions into the three-dimensional space of the human putamen demonstrated coverage of the postcommissural putamen, containment within the striatum and expected anterograde transport to globus pallidus and substantia nigra pars reticulata. The results elucidate the necessary parameters for achieving widespread GDNF expression in the putamenal motor area and afferent substantia nigra of PD patients.
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Dependovirus/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Enfermedad de Parkinson/terapia , Putamen/metabolismo , Animales , Ensayos Clínicos como Asunto , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Macaca mulatta , Imagen por Resonancia Magnética , Enfermedad de Parkinson/patologíaRESUMEN
Deep brain stimulation (DBS) surgery typically involves placement of a single lead through a burr hole, either unilaterally or bilaterally. Rare indications, however, call for placement of 2 ipsilateral leads. To date, there have been no technical descriptions of how best to secure dual ipsilateral leads to the skull. We describe a method of placing and securing 2 ipsilateral DBS leads through a single burr hole using standard cranial plating equipment and a simple modification to a burr hole-mounted anchoring ring. This method has been used safely in 6 patients without detectable displacement of the first lead during implantation of the second lead.
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Craneotomía/métodos , Estimulación Encefálica Profunda/instrumentación , Estimulación Encefálica Profunda/métodos , Temblor Esencial/cirugía , Temblor Esencial/terapia , Cráneo/cirugía , Placas Óseas , Electrodos Implantados , Humanos , Esclerosis Múltiple/cirugía , Esclerosis Múltiple/terapia , Procedimientos Neuroquirúrgicos/instrumentación , Procedimientos Neuroquirúrgicos/métodos , Complicaciones Posoperatorias/prevención & control , Técnicas Estereotáxicas/instrumentación , Tálamo/fisiología , Tálamo/cirugíaRESUMEN
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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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.