What is the true discharge rate and pattern of the striatal projection neurons in Parkinson's disease and Dystonia?
- The Hebrew University - Hadassah Medical School, Israel
- Hadassah University Hospital, Israel
- University of Bordeaux, France
Abstract
Dopamine and striatal dysfunctions play a key role in the pathophysiology of Parkinson's disease (PD) and Dystonia, but our understanding of the changes in the discharge rate and pattern of striatal projection neurons (SPNs) remains limited. Here, we recorded and examined multi-unit signals from the striatum of PD and dystonic patients undergoing deep brain stimulation surgeries. Contrary to earlier human findings, we found no drastic changes in the spontaneous discharge of the well-isolated and stationary SPNs of the PD patients compared to the dystonic patients or to the normal levels of striatal activity reported in healthy animals. Moreover, cluster analysis using SPN discharge properties did not characterize two well-separated SPN subpopulations, indicating no SPN subpopulation-specific (D1 or D2 SPNs) discharge alterations in the pathological state. Our results imply that small to moderate changes in spontaneous SPN discharge related to PD and Dystonia are likely amplified by basal ganglia downstream structures.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 3 and 9.
Article and author information
Author details
Funding
European Research Council
- Hagai Bergman
Rosetrees
- Hagai Bergman
Israel Science Foundation
- Hagai Bergman
Israel Authority for Innovation
- Hagai Bergman
French National Research Agency
- Marc Deffains
French National Center for Scientific Research
- Marc Deffains
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: All patients met the criteria for DBS and signed a written informed consent for surgery that involved microelectrode recording. This study was authorized and approved by the Institutional Review Board of Hadassah Hospital in accordance with the Helsinki Declaration (reference code: 0168-10-HMO)
Copyright
© 2020, Valsky et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Download links
Further reading
-
- Medicine
Background:
Approximately one-third of patients with HER2-positive breast cancer experienced recurrence within 10 years after receiving 1 year of adjuvant trastuzumab. The ExteNET study showed that 1 year of extended adjuvant neratinib after trastuzumab-based adjuvant therapy could reduce invasive disease-free survival (iDFS) events compared with placebo. This study investigated the efficacy and safety of pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy in patients with high-risk, HER2-positive early or locally advanced breast cancer.
Methods:
This multicenter phase II trial was conducted at 23 centers in China. After enrollment, patients received 1 year of extended adjuvant pyrotinib (400 mg/day), which should be initiated within 6 months after the completion of 1-year adjuvant therapy (trastuzumab alone or plus pertuzumab). The primary endpoint was 2-year iDFS rate.
Results:
Between January 2019 and February 2022, 141 eligible women were enrolled and treated. As of October 10, 2022, the median follow-up was 24 (interquartile range, 18.0–34.0) months. The 2-year iDFS rate was 94.59% (95% confidence interval [CI]: 88.97–97.38) in all patients, 94.90% (95% CI: 86.97–98.06) in patients who completed 1-year treatment, 90.32% (95% CI: 72.93–96.77) in patients who completed only 6-month treatment, 96.74% (95% CI: 87.57–99.18) in the hormone receptor (HR)-positive subgroup, 92.77% (95% CI: 83.48–96.93) in the HR-negative subgroup, 96.88% (95% CI: 79.82–99.55) in the lymph node-negative subgroup, 93.85% (95% CI: 86.81–97.20) in the lymph node-positive subgroup, 97.30% (95% CI: 82.32–99.61) in patients with adjuvant trastuzumab plus pertuzumab, and 93.48% (95% CI: 86.06–97.02) in patients with adjuvant trastuzumab. The most common adverse events were diarrhea (79.4%), fatigue (36.9%), lymphocyte count decreased (36.9%), nausea (33.3%), and hand-foot syndrome (33.3%).
Conclusions:
Extended adjuvant pyrotinib administrated after trastuzumab-based adjuvant therapy showed promising efficacy in patients with high-risk HER2-positive breast cancer. The follow-up is ongoing to determine the long-term benefit.
Funding:
No external funding was received for this work.
Clinical trial number:
ClinicalTrials.gov: NCT05880927
-
- Immunology and Inflammation
- Medicine
Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RA−CCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3−CCR7+Helios−CD127−CD8+) and pro-inflam Macs (CD206−CD163−CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163−CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206− pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.
