Precision targeting in the globus pallidus interna: insights from the multicenter, prospective, blinded VA/NINDS CSP 468 study.

OBJECTIVE: Deep brain stimulation (DBS) targeting the globus pallidus interna (GPi) has been shown to significantly improve motor symptoms for the treatment of medication-refractory Parkinson's disease. Yet, heterogeneity in clinical outcomes persists, possibly due to suboptimal target identification within the GPi. By leveraging robust sampling of the GPi and 6-month postsurgical outcomes, this study aims to determine optimal symptom-specific GPi DBS targets. METHODS: In this study, the authors analyzed the anatomical lead location and 6-month postsurgical, double-blinded outcome measures of 86 patients who underwent bilateral GPi DBS. These patients were selected from the multicenter Veterans Affairs (VA)/National Institutes of Neurological Disorders and Stroke (NINDS) Cooperative Studies Program (CSP) 468 study to identify the optimal target zones ("sweet spots") for the control of overall motor (United Parkinson's Disease Rating Scale [UPDRS]-III), axial, tremor, rigidity, and bradykinesia symptoms. Lead coordinates were normalized to Montreal Neurological Institute space and the optimal target zones were identified and validated using a leave-one-patient-out approach. RESULTS: The authors' findings revealed statistically significant optimal target zones for UPDRS-III (R = 0.37, p < 0.001), axial (R = 0.22, p = 0.042), rigidity (R = 0.20, p = 0.021), and bradykinesia (R = 0.23, p = 0.004) symptoms. These zones were localized within the primary motor and premotor subdivisions of the GPi. Interestingly, these zones extended beyond the GPi lateral border into the GPi-globus pallidus externa (GPe) lamina and into the GPe, but they did not reach the GPi ventral border, challenging traditional surgical approaches based on pallidotomies. CONCLUSIONS: Drawing upon a robust dataset, this research effectively delineates specific optimal target zones for not only overall motor improvement but also symptom subscores. These insights hold the potential to enhance the precision of targeting in subsequent bilateral GPi DBS surgical procedures.

Management of rare atlantoaxial synovial cyst case with extension to the cerebellopontine angle: illustrative case.

BACKGROUND: Synovial cysts are a common finding in degenerative spine disease, most frequently involving the facet joints of the lumbar spine. Synovial cysts are less common in the cervical spine and rarely involve the atlantoaxial junction. OBSERVATIONS: In this case report, the authors detail a unique presentation of a left atlantoaxial synovial cyst with large intracranial extension into the cerebellopontine angle causing progressive cranial nerve palsies resulting in tinnitus, vertigo, diminished hearing, gait imbalance, left trigeminal hypesthesia, left facial weakness, and dysarthria. The patient underwent a retromastoid craniectomy for resection of the synovial cyst, resulting in improvement and resolution of symptoms. Follow-up occurred at 6 weeks, 3 months, and 5 months postoperatively without recurrence on imaging. LESSONS: The authors describe acute and long-term management of a unique presentation of an atlantoaxial synovial cyst including retromastoid craniectomy, intervals for follow-up for recurrence, and possible treatment options in cases of recurrence. A systematic literature review was also performed to explore all reported cases of craniocervical junction synovial cysts and subsequent surgical management.

Microglial activation persists beyond clinical recovery following sport concussion in collegiate athletes.

Introduction: In concussion, clinical and physiological recovery are increasingly recognized as diverging definitions. This study investigated whether central microglial activation persisted in participants with concussion after receiving an unrestricted return-to-play (uRTP) designation using [18F]DPA-714 PET, an in vivo marker of microglia activation. Methods: Eight (5 M, 3 F) current athletes with concussion (Group 1) and 10 (5 M, 5 F) healthy collegiate students (Group 2) were enrolled. Group 1 completed a pre-injury (Visit1) screen, follow-up Visit2 within 24 h of a concussion diagnosis, and Visit3 at the time of uRTP. Healthy participants only completed assessments at Visit2 and Visit3. At Visit2, all participants completed a multidimensional battery of tests followed by a blood draw to determine genotype and study inclusion. At Visit3, participants completed a clinical battery of tests, brain MRI, and brain PET; no imaging tests were performed outside of Visit3. Results: For Group 1, significant differences were observed between Visits 1 and 2 (p < 0.05) in ImPACT, SCAT5 and SOT performance, but not between Visit1 and Visit3 for standard clinical measures (all p > 0.05), reflecting clinical recovery. Despite achieving clinical recovery, PET imaging at Visit3 revealed consistently higher [18F]DPA-714 tracer distribution volume (VT) of Group 1 compared to Group 2 in 10 brain regions (p < 0.001) analyzed from 164 regions of the whole brain, most notably within the limbic system, dorsal striatum, and medial temporal lobe. No notable differences were observed between clinical measures and VT between Group 1 and Group 2 at Visit3. Discussion: Our study is the first to demonstrate persisting microglial activation in active collegiate athletes who were diagnosed with a sport concussion and cleared for uRTP based on a clinical recovery.

Phagocytosis in the retina promotes local insulin production in the eye.

The retina is highly metabolically active, relying on glucose uptake and aerobic glycolysis. Situated in close contact to photoreceptors, a key function of cells in the retinal pigment epithelium (RPE) is phagocytosis of damaged photoreceptor outer segments (POS). Here we identify RPE as a local source of insulin in the eye that is stimulated by POS phagocytosis. We show that Ins2 messenger RNA and insulin protein are produced by RPE cells and that this production correlates with RPE phagocytosis of POS. Genetic deletion of phagocytic receptors ('loss of function') reduces Ins2, whereas increasing the levels of the phagocytic receptor MerTK ('gain of function') increases Ins2 production in male mice. Contrary to pancreas-derived systemic insulin, RPE-derived local insulin is stimulated during starvation, which also increases RPE phagocytosis. Global or RPE-specific Ins2 gene deletion decreases retinal glucose uptake in starved male mice, dysregulates retinal physiology, causes defects in phototransduction and exacerbates photoreceptor loss in a mouse model of retinitis pigmentosa. Collectively, these data identify RPE cells as a phagocytosis-induced local source of insulin in the retina, with the potential to influence retinal physiology and disease.

Dynamic FDG-PET in localization of focal epilepsy: A pilot study.

Epilepsy surgery remains underutilized, in part because non-invasive methods of potential seizure foci localization are inadequate. We used high-resolution, parametric quantification from dynamic 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography (dFDG-PET) imaging to locate hypometabolic foci in patients whose standard clinical static PET images were normal. We obtained dFDG-PET brain images with simultaneous EEG in a one-hour acquisition on seven patients with no MRI evidence of focal epilepsy to record uptake and focal radiation decay. Images were attenuation- and motion-corrected and co-registered with high-resolution T1-weighted patient MRI and segmented into 18 regions of interest (ROI) per hemisphere. Tracer uptake was calibrated with a model corrected blood input function with partial volume (PV) corrections to generate tracer parametric maps compared between mean radiation values between hemispheres with z-scores. We identified ROI with the lowest negative z scores (<-1.65 SD) as hypometabolic. Dynamic 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography ( found focal regions of altered metabolism in all cases in which standard clinical FDG-PET found no abnormalities. This pilot study of dynamic FDG-PET suggests that further research is merited to evaluate whether glucose dynamics offer improved clinical utility for localization of epileptic foci over standard static techniques.

Model Corrected Blood Input Function to Compute Cerebral FDG Uptake Rates From Dynamic Total-Body PET Images of Rats in vivo.

Recently, we developed a three-compartment dual-output model that incorporates spillover (SP) and partial volume (PV) corrections to simultaneously estimate the kinetic parameters and model-corrected blood input function (MCIF) from dynamic 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) images of mouse heart in vivo. In this study, we further optimized this model and utilized the estimated MCIF to compute cerebral FDG uptake rates, K i , from dynamic total-body FDG PET images of control Wistar-Kyoto (WKY) rats and compared to those derived from arterial blood sampling in vivo. Dynamic FDG PET scans of WKY rats (n = 5), fasted for 6 h, were performed using the Albira Si Trimodal PET/SPECT/CT imager for 60 min. Arterial blood samples were collected for the entire imaging duration and then fitted to a seven-parameter function. The 60-min list mode PET data, corrected for attenuation, scatter, randoms, and decay, were reconstructed into 23 time bins. A 15-parameter dual-output model with SP and PV corrections was optimized with two cost functions to compute MCIF. A four-parameter compartment model was then used to compute cerebral Ki. The computed area under the curve (AUC) and K i were compared to that derived from arterial blood samples. Experimental and computed AUCs were 1,893.53 ± 195.39 kBq min/cc and 1,792.65 ± 155.84 kBq min/cc, respectively (p = 0.76). Bland-Altman analysis of experimental vs. computed K i for 35 cerebral regions in WKY rats revealed a mean difference of 0.0029 min-1 (~13.5%). Direct (AUC) and indirect (Ki) comparisons of model computations with arterial blood sampling were performed in WKY rats. AUC and the downstream cerebral FDG uptake rates compared well with that obtained using arterial blood samples. Experimental vs. computed cerebral K i for the four super regions including cerebellum, frontal cortex, hippocampus, and striatum indicated no significant differences.

S-nitrosylation of cytoskeletal proteins.

Nitric oxide has pronounced effects on cellular functions normally associated with the cytoskeleton, including cell motility, shape, contraction, and mitosis. Protein S-nitrosylation, the covalent addition of a NO group to a cysteine sulfur, is a signaling pathway for nitric oxide that acts in parallel to cyclic guanosine monophosphate (cGMP), but is poorly studied compared to the latter. There is growing evidence that S-nitrosylation of cytoskeletal proteins selectively alters their function. We review that evidence, and find that S-nitrosylation of cytoskeletal targets has complementary but distinct effects to cyclic-GMP in motile and contractile cells-promoting cell migration, and biasing muscle contraction toward relaxation. However, the effects of S-nitrosylation on a host of cytoskeletal proteins and functions remains to be explored.

Concerted reactions and mechanism of glucose pyrolysis and implications for cellulose kinetics.

Concerted reactions are proposed to be keys to understanding thermal decomposition of glucose in the absence of ionic chemistry, including molecular catalysis by ROH molecules such as H(2)O, other glucose molecules, and most of the intermediates and products. Concerted transition states, elementary-reaction pathways, and rate coefficients are computed for pyrolysis of ß-D-glucose (ß-D-glucopyranose), the monomer of cellulose, and for related molecules, giving an improved and elementary-reaction interpretation of the reaction network proposed by Sanders et al. (J. Anal. Appl. Pyrolysis, 2003, 66, 29-50). Reactions for ring-opening and formation, ring contraction, retro-aldol condensation, keto-enol tautomerization, and dehydration are included. The dehydration reactions are focused on bicyclic ring formations that lead to levoglucosan and 1,6-ß-D-anhydrousglucofuranose. The bimolecular ROH-assisted reactions are found to have lower activation energy compared to the unimolecular reactions. The same dehydration reaction to levoglucosan should occur for cellulose going to cellosan (e.g., cellotriosan) plus a shortened cellulose chain, a hypothesis supported by the very similar activation energies computed when alternate groups were substituted at the C1 glycosidic oxygen. The principles of Sanders et al. that distinguish D-glucose, D-fructose, sucrose, and cellulose pyrolysis prove useful in providing qualitative insights into cellulose pyrolysis.