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Objective . This study investigated a machine-learning approach to detect the presence of evoked resonant neural activity (ERNA) recorded during deep brain stimulation (DBS) of the subthalamic nucleus (STN) in people with Parkinson's disease. Approach . Seven binary classifiers were trained to distinguish ERNA from the background neural activity using eight different time-domain signal features. Main results . Nested cross-validation revealed a strong classification performance of 99.1% accuracy, with 99.6% specificity and 98.7% sensitivity to detect ERNA. Using a semi-simulated ERNA dataset, the results show that a signal-to-noise ratio of 15 dB is required to maintain a 90% classifier sensitivity. ERNA detection is feasible with an appropriate combination of signal processing, feature extraction and classifier. Future work should consider reducing the computational complexity for use in real-time applications. Significance . The presence of ERNA can be used to indicate the location of a DBS electrode array during implantation surgery. The confidence score of the detector could be useful for assisting clinicians to adjust the position of the DBS electrode array inside/outside the STN., (© 2024 IOP Publishing Ltd.)

Background and Purpose: In deep brain stimulation (DBS), accurate electrode placement is essential for optimizing patient outcomes. Localizing electrodes enables insight into therapeutic outcomes and development of metrics for use in clinical trials. Methods of defining anatomical targets have been described with varying accuracy and objectivity. To assess variability in anatomical targeting, we compare four methods of defining an appropriate target for DBS of the subthalamic nucleus for Parkinson's disease., Methods: The methods compared are direct visualization, red nucleus-based indirect targeting, mid-commissural point-based indirect targeting, and automated template-based targeting. This study assessed 226 hemispheres in 113 DBS recipients (39 females, 73 males, 62.2 ± 7.7 years). We utilized the electrode placement error (the Euclidean distance between the defined target and closest DBS electrode) as a metric for comparative analysis. Pairwise differences in electrode placement error across the four methods were compared using the Kruskal-Wallis H-test and Wilcoxon signed-rank tests., Results: Interquartile ranges of the differences in electrode placement error spanned 1.18-1.56 mm. A Kruskal-Wallis H-test reported a statistically significant difference in the median of at least two groups (H(5) = 41.052, p < .001). Wilcoxon signed-rank tests reported statistically significant difference in two comparisons: direct visualization versus red nucleus-based indirect, and direct visualization versus automated template-based methods (T < 9215, p < .001)., Conclusions: All methods were similarly discordant in their relative accuracy, despite having significant technical differences in their application. The differing protocols and technical aspects of each method, however, have the implication that one may be more practical depending on the clinical or research application at hand., (© 2023 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Objective: The long-term treatment burden, duration of community living, and survival of patients with Parkinson's disease (PD) after deep brain stimulation (DBS) implantation are unclear. This study aims to determine the frequency of programming, repeat hardware surgeries (of the intracranial electrode, implantable pulse generator [IPG], and extension-cable), and the timings of residential care and death in patients with PD treated with DBS., Materials and Methods: In this cross-sectional, population-based study, individual-level data were collected from the Australian government covering a 15-year period (2002-2016) on 1849 patients with PD followed from DBS implantation., Results: The mean DBS implantation age was 62.6 years and mean follow-up 5.0 years. Mean annual programming rates were 6.9 in the first year and 2.8 in subsequent years. 51.4% of patients required repeat hardware surgery. 11.3% of patients had repeat intracranial electrode surgery (including an overall 1.1% of patients who were completely explanted). 47.6% of patients had repeat IPG/extension-cable surgery including for presumed battery depletion. 6.2% of patients had early repeat IPG/extension-cable surgery (within one year of any previous such surgery). Thirty-day postoperative mortality was 0.3% after initial DBS implantation and 0.6% after any repeat hardware surgery. 25.3% of patients were admitted into residential care and 17.4% died. The median interval to residential care and death was 10.2 years and 11.4 years, respectively. Age more than 65 years was associated with fewer repeat hardware surgeries for presumed complications (any repeat surgery of electrodes, extension-cables, and early IPG surgery) and greater rates of residential care admission and death., Conclusions: Data from a large cohort of patients with PD treated with DBS found that the median life span after surgery is ten years. Repeat hardware surgery, including of the intracranial electrodes, is common. These findings support development of technologies to reduce therapy burden such as enhanced surgical navigation, hardware miniaturization, and improved battery efficiency., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Introduction: The efficacy of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) depends on how closely electrodes are implanted relative to an individual's ideal stimulation location. Yet, previous studies have assessed how closely electrodes are implanted relative to the planned location, after homogenizing data to a reference. Thus here, we measured how accurately electrodes are implanted relative to an ideal, dorsal STN stimulation location, assessed on each individual's native imaging. This measure captures not only the technical error of stereotactic implantation but also constraints imposed by planning a suitable trajectory., Methods: This cross-sectional study assessed 226 electrodes in 113 consecutive PD patients implanted with bilateral STN-DBS by experienced clinicians utilizing awake, microelectrode guided, surgery. The error (Euclidean distance) between the actual electrode trajectory versus a nominated ideal, dorsal STN stimulation location was determined in each hemisphere on native imaging and predictive factors sought., Results: The median electrode location error was 1.62 mm (IQR = 1.23 mm). This error exceeded 3 mm in 28/226 electrodes (12.4%). Location error did not differ between hemispheres implanted first or second, suggesting brain shift was minimised. Location error did not differ between electrodes positioned with (48/226), or without, a preceding microelectrode trajectory shift (suggesting such shifts were beneficial). There was no relationship between location error and case order, arguing against a learning effect., Discussion/conclusion: The proximity of STN-DBS electrodes to a nominated ideal, dorsal STN, stimulation location is highly variable, even when implanted by experienced clinicians with brain shift minimized, and without evidence of a learning effect. Using this measure, we found that assessments on awake patients (microelectrode recordings and clinical examination) likely yielded beneficial intraoperative decisions to improve positioning. In many patients the error is likely to have reduced therapeutic efficacy. More accurate methods to implant STN-DBS electrodes relative to the ideal stimulation location are needed., Competing Interests: W.T., K.B. are founders and hold shares and/or options in DBS Technologies Pty Ltd which plans to commercialise the use of neuronal signals to improve DBS. WT, KB, TP are named inventors on Australian patent 2019900808 ‘Systems and methods for monitoring neural activity [ERNA]’ and USA patent 10,463,860 ‘Systems and methods for monitoring neural activity [ERNA]’ which are assigned to DBS Technologies. This does not alter our adherence to PLOS One policies on sharing data and materials. W.T. has received honoraria from Medtronic and Boston Scientific. All other authors report no competing interests.

Deep brain stimulation (DBS) is a rapidly expanding treatment for neurological and psychiatric conditions; however, a target-specific biomarker is required to optimize therapy. Here, we show that DBS evokes a large-amplitude resonant neural response focally in the subthalamic nucleus. This response is greatest in the dorsal region (the clinically optimal stimulation target for Parkinson disease), coincides with improved clinical performance, is chronically recordable, and is present under general anesthesia. These features make it a readily utilizable electrophysiological signal that could potentially be used for guiding electrode implantation surgery and tailoring DBS therapy to improve patient outcomes. Ann Neurol 2018;83:1027-1031., (© 2018 American Neurological Association.)

The misfolding of intrinsically disordered proteins such as α-synuclein, tau and the Aβ peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinson's and Alzheimer's diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), that targets α-synuclein, a key protein in Parkinson's disease. We found that this compound has substantial biological activity in cellular models of α-synuclein-mediated dysfunction, including rescue of α-synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of α-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting α-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinson's disease and related conditions.

Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of α-synuclein due to genetic multiplication or point mutations leads to early onset disease. While α-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of α-synuclein over-expression or mutation exist in vivo. Macrophages and microglia isolated from BAC α-synuclein transgenic mice, which overexpress α-synuclein under regulation of its own promoter, express α-synuclein and exhibit impaired cytokine release and phagocytosis. These processes were affected in vivo as well, both in peritoneal macrophages and microglia in the CNS. Extending these findings to humans, we found similar results with monocytes and fibroblasts isolated from idiopathic or familial Parkinson's disease patients compared to age-matched controls. In summary, this paper provides 1) a new animal model to measure α-synuclein dysfunction; 2) a cellular system to measure synchronized mobilization of α-synuclein and its functional interactions; 3) observations regarding a potential role for innate immune cell function in the development and progression of Parkinson's disease and other human synucleinopathies; 4) putative peripheral biomarkers to study and track these processes in human subjects. While altered neuronal function is a primary issue in PD, the widespread consequence of abnormal α-synuclein expression in other cell types, including immune cells, could play an important role in the neurodegenerative progression of PD and other synucleinopathies. Moreover, increased α-synuclein and altered phagocytosis may provide a useful biomarker for human PD.

Parkinson disease (PD) is a neurodegenerative disease characterized by death of dopaminergic neurons in the substantia nigra region of the brain. Iron content is also elevated in this region in PD and is implicated in the pathobiology of the disease. Desferrioxamine B (DFOB) is a high-affinity iron chelator and has shown efficacy in animal models of Parkinson disease. The high water solubility of DFOB, however, attenuates its ability to enter the brain. In this study, we have conjugated DFOB to derivatives of adamantane or the clinical iron chelator deferasirox to produce lipophilic compounds designed to increase the bioavailability of DFOB to brain cells. We found that the novel compounds are highly effective in preventing iron-mediated paraquat and hydrogen peroxide toxicity in neuronal-like BE2-M17 dopaminergic cells, primary neurons, and iron-loaded or glutathione-depleted primary astrocytes. The compounds also alleviated paraquat toxicity in BE2-M17 cells that express the PD-causing A30P mutation of α-synuclein. This protection was ∼66-fold more potent than DFOB alone and also more effective than other cell-permeative metal chelators, clioquinol and phenanthroline. These results demonstrate that increasing the bioavailability of DFOB through the conjugation of lipophilic fragments greatly enhances its protective capacity. These novel compounds have potential as therapeutics for the treatment of PD and other conditions of Fe dyshomeostasis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Mutations in PTEN-induced kinase 1 (PINK1) gene cause PARK6 familial Parkinsonism. To decipher the role of PINK1 in pathogenesis of Parkinson's disease (PD), researchers need to identify protein substrates of PINK1 kinase activity that govern neuronal survival, and establish whether aberrant regulation and inactivation of PINK1 contribute to both familial Parkinsonism and idiopathic PD. These studies should take into account the several unique structural and functional features of PINK1. First PINK1 is a rare example of a protein kinase with a predicted mitochondrial-targeting sequence and a possible resident mitochondrial function. Second, bioinformatic analysis reveals unique insert regions within the kinase domain that are potentially involved in regulation of kinase activity, substrate selectivity and stability of PINK1. Third, the C-terminal region contains functional motifs governing kinase activity and substrate selectivity. Fourth, accumulating evidence suggests that PINK1 interacts with other signaling proteins implicated in PD pathogenesis and mitochondrial dysfunction. The most prominent examples are the E3 ubiquitin ligase Parkin, the mitochondrial protease high temperature requirement serine protease 2 and the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1. How PINK1 may regulate these proteins to maintain neuronal survival is unclear. This review describes the unique structural features of PINK1 and their possible roles in governing mitochondrial import, processing, kinase activity, substrate selectivity and stability of PINK1. Based upon the findings of previous studies of PINK1 function in cell lines and animal models, we propose a model on the neuroprotective mechanism of PINK1. This model may serve as a conceptual framework for future investigation into the molecular basis of PD pathogenesis.

Alpha-synuclein (alphaSN) is implicated in Parkinson's disease (PD) and is the major component of Lewy bodies (LBs). Although alphaSN is mainly expressed in neuronal cells and exists as a cytoplasmic protein, it has been found in body fluids including cerebrospinal fluid and blood. This study explored plasma alphaSN as a diagnostic marker for PD. Western blot analysis was used to characterize plasma alphaSN compared to brain alphaSN. Plasma alphaSN of 16 kDa migrates with the same mobility as its brain counterpart and recombinant alphaSN on denatured polyacrylamide gels and reacted with three different antibodies against the C-terminal and NAC regions of the alphaSN protein. The alphaSN levels in plasma from PD subjects are significantly lower than that in age-matched controls (p=0.001), and the alphaSN levels in patients with early-onset PD are lower than that in both late-onset PD and controls. This initial study indicates that measurement of alphaSN in plasma can provide support for a clinical diagnosis of Parkinson's disease and warrants further study in a larger population.

The Parkinson's disease (PD) causative PINK1 gene encodes a mitochondrial protein kinase called PTEN-induced kinase 1 (PINK1). The autosomal recessive pattern of inheritance of PINK1 mutations suggests that PINK1 is neuroprotective and therefore loss of PINK1 function causes PD. Indeed, overexpression of PINK1 protects neuroblastoma cells from undergoing neurotoxin-induced apoptosis. As a protein kinase, PINK1 presumably exerts its neuroprotective effect by phosphorylating specific mitochondrial proteins and in turn modulating their functions. Towards elucidation of the neuroprotective mechanism of PINK1, we employed the baculovirus-infected insect cell system to express the recombinant protein consisting of the PINK1 kinase domain either alone [PINK1(KD)] or with the PINK1 C-terminal tail [PINK1(KD+T)]. Both recombinant enzymes preferentially phosphorylate the artificial substrate histone H1 exclusively at serine and threonine residues, demonstrating that PINK1 is indeed a protein serine/threonine kinase. Introduction of the PD-associated mutations, G386A and G409V significantly reduces PINK1(KD) kinase activity. Since Gly-386 and Gly-409 reside in the conserved activation segment of the kinase domain, the results suggest that the activation segment is a regulatory switch governing PINK1 kinase activity. We also demonstrate that PINK1(KD+T) is approximately 6-fold more active than PINK1(KD). Thus, in addition to the activation segment, the C-terminal tail also contains regulatory motifs capable of governing PINK1 kinase activity. Finally, the availability of active recombinant PINK1 proteins permits future studies to search for mitochondrial proteins that are preferentially phosphorylated by PINK1. As these proteins are likely physiological substrates of PINK1, their identification will shed light on the mechanism of pathogenesis of PD.