Parkinson’s disease is characterized by degeneration of nigral dopaminergic neurons, leading to a wide variety of psychomotor dysfunctions. Accumulated evidence suggests that abnormally synchronized ...oscillations in the basal ganglia contribute to the expression of parkinsonian motor symptoms. However, the mechanism that generates abnormal oscillations in a dopamine‐depleted state remains poorly understood. We addressed this question by examining basal ganglia neuronal activity in two 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐treated parkinsonian monkeys. We found that systemic administration of l‐3,4‐dihydroxyphenylalanine (l‐DOPA; dopamine precursor) decreased abnormal neuronal oscillations (8–15 Hz) in the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) during the ON state when parkinsonian signs were alleviated and during l‐DOPA‐induced dyskinesia. GPi oscillations and parkinsonian signs were suppressed by silencing of the STN with infusion of muscimol (GABAA receptor agonist). Intrapallidal microinjection of a mixture of 3‐(2‐carboxypiperazin‐4‐yl)‐propyl‐1‐phosphonic acid (CPP; N‐methyl‐d‐aspartate receptor antagonist) and 1,2,3,4‐tetrahydro‐6‐nitro‐2,3‐dioxo‐benzofquinoxaline‐7‐sulfonamide (NBQX; AMPA/kainate receptor antagonist) also decreased the oscillations in the GPi and the external segment of the globus pallidus (GPe). Neuronal oscillations in the STN were suppressed after intrasubthalamic microinjection of CPP/NBQX to block glutamatergic afferents of the STN. The STN oscillations were further reduced by muscimol inactivation of the GPe to block GABAergic inputs from the GPe. These results suggest that, in the dopamine‐depleted state, glutamatergic inputs to the STN and reciprocal GPe–STN interconnections are both important for the generation and amplification of the oscillatory activity of STN neurons, which is subsequently transmitted to the GPi, thus contributing to the symptomatic expression of Parkinson’s disease.
Parkinson’s disease is characterized by degeneration of nigral dopaminergic neurons, leading to a wide variety of psychomotor dysfunctions. Accumulated evidence suggests that abnormally synchronized oscillations in the basal ganglia contribute to the expression of parkinsonian motor symptoms.
Summary Background Parkinson's disease is typically treated with oral dopamine replacement therapies; however, long-term treatment leads to motor complications and, occasionally, impulse control ...disorders caused by intermittent stimulation of dopamine receptors and off-target effects, respectively. We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and continuous dopamine production in patients with advanced Parkinson's disease. Methods We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinson's disease. All patients were then enrolled in a separate open-label follow-up study of long-term safety. Three doses were assessed in separate cohorts: low dose (1·9×107 transducing units TU); mid dose (4·0×107 TU); and high dose (1×108 TU). Inclusion criteria were age 48–65 years, disease duration 5 years or longer, motor fluctuations, and 50% or higher motor response to oral dopaminergic therapy. The primary endpoints of the phase 1/2 study were the number and severity of adverse events associated with ProSavin and motor responses as assessed with Unified Parkinson's Disease Rating Scale (UPDRS) part III (off medication) scores, at 6 months after vector administration. Both trials are registered at ClinicalTrials.gov , NCT00627588 and NCT01856439. Findings 15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on–off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 SD 9 vs 26 8, n=15, p=0·0001) and 12 months (38 vs 27 8; n=15, p=0·0001) compared with baseline. Interpretation ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients. Funding Oxford BioMedica.
Deep brain stimulation (DBS) is an established treatment for Parkinson's disease (PD). Clinicians face various challenges in adjusting stimulation parameters and configurations in clinical DBS ...settings owing to inexperience, time constraints, and recent advances in DBS technology that have expanded the number of possible contact configurations. We aimed to assess the efficacy of a closed-loop algorithm (CLA) for the DBS-programming method using external motion sensor-based motor assessments in patients with PD.
In this randomized, double-blind, crossover study, we enrolled 12 patients who underwent eight-ring-contact DBS lead implantations bilaterally in the subthalamic nucleus. The DBS settings of the participants were programmed using a standard of care (SOC) and CLA method. The clinical effects of both programming methods were assessed in a randomized crossover fashion. The outcomes were evaluated using the Unified Parkinson's Disease Scale part III (UPDRS-III) and sensor-based scores for baseline (medication-off/stimulation-off) and both programming methods. The number of programming steps required for each programming method was also recorded.
The UPDRS-III scores and sensor-based scores were significantly improved by SOC and CLA settings compared to the baseline. No statistical difference was observed between SOC and CLA. The programming steps were significantly reduced in the CLA settings compared to those in the SOC. No serious adverse events were observed.
CLA can optimize DBS settings prospectively with similar therapeutic benefits as that of the SOC and reduce the number of programming steps. Automated optimization of DBS settings would reduce the burden of programming for both clinicians and patients.
•A randomized, double-blind, crossover study was performed to investigate a novel closed loop-deep brain stimulation programming algorithm.•A novel closed-loop algorithm using external motion sensor provided similar therapeutic benefit as that of the standard of care programming method.•Am novel closed-loop algorithm reduced the number of programming steps.
We describe the case of a 51-year-old man with Parkinson's disease (PD) presenting with motor fluctuations, who received bilateral subthalamic deep brain stimulation (DBS) with an adaptive DBS (aDBS) ...device, Percept™ PC (Medtronic, Inc. , Minneapolis, MN). This device can deliver electrical stimulations based on fluctuations of neural oscillations of the local field potential (LFP) at the target structure. We observed that the LFP fluctuations were less evident inside the hospital than outside, while the stimulation successfully adapted to beta oscillation fluctuations during the aDBS phase without any stimulation-induced side effects. Thus, this new device facilitates condition-dependent stimulation; this new stimulation method is feasible and provides new insights into the pathophysiological mechanisms of PD.
Holmes tremor (HT) is a refractory tremor associated with cortico-basal ganglia loops and cerebellothalamic tract abnormalities. Various drug treatments have been attempted; however, no treatment ...method has yet been established. Historically, thalamic deep brain stimulation (DBS) has been performed in medically refractory cases. Recently, the posterior subthalamic area (PSA) has been used for HT. Here, we report cases of HT and review the effectiveness and safety of PSA-DBS for HT.
We conducted a retrospective chart review of two patients with HT who underwent PSA-DBS. Improvement in tremors was observed 1 year after surgery without apparent complications.
We identified 12 patients who underwent PSA-DBS for HT, including our cases. In six patients, PSA was targeted alone; for the rest, the ventralis intermediate nucleus (Vim) of the thalamus and PSA were simultaneously targeted. The Fahn-Tolosa-Marin Tremor Rating Scale improvement rates were 56.8% (range, 33.9-82.1%;
= 6) and 77.8% (range, 42.6-100%;
= 5) for the PSA-DBS and PSA+Vim-DBS, respectively.
Reasonable improvements in HT were observed after PSA-DBS. PSA might be an appropriate target for improving the symptoms of HT. Long-term observations, accumulation of cases, and randomized studies are required in future.
Atlantoaxial transarticular screw fixation (TASF) is a procedure that involves inserting screws vertically into the articular processes of C1 and C2. However, this procedure is associated with a risk ...of injury to surrounding structures including the vertebral artery, carotid artery, pharynx, and spinal cord by misinserting K-wires or screws. This study was performed to evaluate the risk of TASF using 3-dimensional navigation-guided drilling and screw insertion tract creation.
Three patients underwent the surgical procedure using a navigation system guided by intraoperative computed tomography. The insertion tract of the screw was created using the navigation system to avoid penetration of the C1 anterior arch or damage to the vertebral artery. A blunt-tipped guide wire was used, which was safe to advance to the cortex of the anterior arch of C1.
There were no complications or instrument failures in any of the surgeries. In each case, the total radiation dose delivered was 5.31–7.02 mGy, and total radiation exposure time was 55.6–106.8 seconds. Bone fusion was achieved in all cases.
TASF using a navigation system for drilling is useful for accurate placement of K-wire and preventing damage of the vital structures, lowering the risk of the procedure.
Abstract
Multiple system atrophy (MSA) is classified into two main types: parkinsonian and cerebellar ataxia with oligodendrogliopathy. We examined microstructural alterations in the white matter and ...the substantia nigra pars compacta (SNc) of patients with MSA of parkinsonian type (MSA-P) using multishell diffusion magnetic resonance imaging (dMRI) and myelin sensitive imaging techniques. Age- and sex-matched patients with MSA-P (
n
= 21,
n
= 10 first and second cohorts, respectively), Parkinson’s disease patients (
n
= 19, 17), and healthy controls (
n
= 20, 24) were enrolled. Magnetization transfer saturation imaging (MT-sat) and dMRI were obtained using 3-T MRI. Measurements obtained from diffusion tensor imaging (DTI), free-water elimination DTI, neurite orientation dispersion and density imaging (NODDI), and MT-sat were compared between groups. Tract-based spatial statistics analysis revealed differences in diffuse white matter alterations in the free-water fractional volume, myelin volume fraction, and intracellular volume fraction between the patients with MSA-P and healthy controls, whereas free-water and MT-sat differences were limited to the middle cerebellar peduncle in comparison with those with Parkinson’s disease. Region-of-interest analysis of white matter and SNc revealed significant differences in the middle and inferior cerebellar peduncle, pontine crossing tract, corticospinal tract, and SNc between the MSA-P and healthy controls and/or Parkinson’s disease patients. Our results shed light on alterations to brain microstructure in MSA.
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