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BioRxiv : the Preprint Server For... May 2024The functional connectome changes with aging. We systematically evaluated aging related alterations in the functional connectome using a whole-brain connectome network...
The functional connectome changes with aging. We systematically evaluated aging related alterations in the functional connectome using a whole-brain connectome network analysis in 39,675 participants in UK Biobank project. We used adaptive dense network discovery tools to identify networks directly associated with aging from resting-state fMRI data. We replicated our findings in 499 participants from the Lifespan Human Connectome Project in Aging study. The results consistently revealed two motor-related subnetworks (both permutation test p-values <0.001) that showed a decline in resting-state functional connectivity (rsFC) with increasing age. The first network primarily comprises sensorimotor and dorsal/ventral attention regions from precentral gyrus, postcentral gyrus, superior temporal gyrus, and insular gyrus, while the second network is exclusively composed of basal ganglia regions, namely the caudate, putamen, and globus pallidus. Path analysis indicates that white matter fractional anisotropy mediates 19.6% (p<0.001, 95% CI [7.6% 36.0%]) and 11.5% (p<0.001, 95% CI [6.3% 17.0%]) of the age-related decrease in both networks, respectively. The total volume of white matter hyperintensity mediates 32.1% (p<0.001, 95% CI [16.8% 53.0%]) of the aging-related effect on rsFC in the first subnetwork.
PubMed: 38798606
DOI: 10.1101/2024.05.17.594743 -
Cell Death & Disease May 2024Disease models of neurodegeneration with brain iron accumulation (NBIA) offer the possibility to explore the relationship between iron dyshomeostasis and...
Disease models of neurodegeneration with brain iron accumulation (NBIA) offer the possibility to explore the relationship between iron dyshomeostasis and neurodegeneration. We analyzed hiPS-derived astrocytes from PANK2-associated neurodegeneration (PKAN), an NBIA disease characterized by progressive neurodegeneration and high iron accumulation in the globus pallidus. Previous data indicated that PKAN astrocytes exhibit alterations in iron metabolism, general impairment of constitutive endosomal trafficking, mitochondrial dysfunction and acquired neurotoxic features. Here, we performed a more in-depth analysis of the interactions between endocytic vesicles and mitochondria via superresolution microscopy experiments. A significantly lower number of transferrin-enriched vesicles were in contact with mitochondria in PKAN cells than in control cells, confirming the impaired intracellular fate of cargo endosomes. The investigation of cytosolic and mitochondrial iron parameters indicated that mitochondrial iron availability was substantially lower in PKAN cells compared to that in the controls. In addition, PKAN astrocytes exhibited defects in tubulin acetylation/phosphorylation, which might be responsible for unregulated vesicular dynamics and inappropriate iron delivery to mitochondria. Thus, the impairment of iron incorporation into these organelles seems to be the cause of cell iron delocalization, resulting in cytosolic iron overload and mitochondrial iron deficiency, triggering mitochondrial dysfunction. Overall, the data elucidate the mechanism of iron accumulation in CoA deficiency, highlighting the importance of mitochondrial iron deficiency in the pathogenesis of disease.
Topics: Astrocytes; Humans; Mitochondria; Cytosol; Iron; Iron Overload; Tubulin; Phosphorylation; Iron Deficiencies; Acetylation
PubMed: 38796462
DOI: 10.1038/s41419-024-06757-9 -
STAR Protocols May 2024Extracellular recordings in behaving animals are useful for establishing associations between neuronal activity and behavior. Here, we describe how to record in the...
Extracellular recordings in behaving animals are useful for establishing associations between neuronal activity and behavior. Here, we describe how to record in the external globus pallidus (GPe) of monkeys engaged in a behavioral task. We detail the stereotaxic surgery for chamber and head-holder implantation, the post-operative MRI scan to ascertain the GPe coordinates and validate the position of the chamber, and the data collection. This protocol makes it possible to examine the electrophysiological features of GPe neurons in behaving monkeys. For complete details on the use and execution of this protocol, please refer to Katabi et al..
PubMed: 38795352
DOI: 10.1016/j.xpro.2024.103081 -
Cyborg and Bionic Systems (Washington,... 2024The globus pallidus internus (GPi) was considered a common target for stimulation in Parkinson's disease (PD). Located deep in the brain and of small size, pinpointing...
The globus pallidus internus (GPi) was considered a common target for stimulation in Parkinson's disease (PD). Located deep in the brain and of small size, pinpointing it during surgery is challenging. Multi-channel microelectrode arrays (MEAs) can provide micrometer-level precision functional localization, which can maximize the surgical outcome. In this paper, a 64-channel MEA modified by platinum nanoparticles with a detection site impedance of 61.1 kΩ was designed and prepared, and multiple channels could be synchronized to cover the target brain region and its neighboring regions so that the GPi could be identified quickly and accurately. The results of the implant trajectory indicate that, compared to the control side, there is a reduction in local field potential (LFP) power in multiple subregions of the upper central thalamus on the PD-induced side, while the remaining brain regions exhibit an increasing trend. When the MEA tip was positioned at 8,700 μm deep in the brain, the various characterizations of the spike signals, combined with the electrophysiological characteristics of the β-segmental oscillations in PD, enabled MEAs to localize the GPi at the single-cell level. More precise localization could be achieved by utilizing the distinct characteristics of the internal capsule (ic), the thalamic reticular nucleus (Rt), and the peduncular part of the lateral hypothalamus (PLH) brain regions, as well as the relative positions of these brain structures. The MEAs designed in this study provide a new detection method and tool for functional localization of PD targets and PD pathogenesis at the cellular level.
PubMed: 38784125
DOI: 10.34133/cbsystems.0123 -
Neurological Research and Practice May 2024Pallidal deep brain stimulation (GPi-DBS) has been considered as an effective treatment option for medication-refractory Huntington's disease (HD).
BACKGROUND
Pallidal deep brain stimulation (GPi-DBS) has been considered as an effective treatment option for medication-refractory Huntington's disease (HD).
OBJECTIVES
To identify stimulation-dependent effects on motor symptoms and to determine if these alterations are associated with the local impact of DBS on different pallidal parcellations.
METHODS
We prospectively evaluated the effects of bilateral GPi-DBS within one year in 5 HD patients. We evaluated the effects of GPi-DBS on choreatic symptoms and UHDRS. Electrode placement in the pallidum was localized, and the local impact of DBS was estimated.
RESULTS
The chorea subscore (p < 0.001) and UHDRS total motor score was significantly reduced postoperatively (p = 0.019). Pallidal DBS did not improve other motor symptoms. Activation of the lateral GPi/GPe was associated with improvement in choreatic symptoms (p = 0.048; r = 0.90).
CONCLUSIONS
Our findings indicate that stimulation of the lateral GPi has a stable effect on choreatic symptoms. The modulation of the electrical field is relevant for motor outcome.
PubMed: 38778367
DOI: 10.1186/s42466-024-00316-5 -
Neurobiology of Disease May 2024Multiple system atrophy (MSA) is a primary oligodendroglial synucleinopathy, characterized by elevated iron burden in early-affected subcortical nuclei. Although...
BACKGROUND
Multiple system atrophy (MSA) is a primary oligodendroglial synucleinopathy, characterized by elevated iron burden in early-affected subcortical nuclei. Although neurotoxic effects of brain iron deposition and its relationship with α-synuclein pathology have been demonstrated, the exact role of iron dysregulation in MSA pathogenesis is unknown. Therefore, advancing the understanding of iron dysregulation at the cellular level is critical, especially in relation to α-synuclein cytopathology.
METHODS
Iron burden in subcortical and brainstem regions were histologically mapped in human post-mortem brains of 4 MSA-parkinsonian (MSA-P), 4 MSA-cerebellar (MSA-C), and 1 MSA case with both parkinsonian and cerebellar features. We then performed the first cell type-specific evaluation of pathological iron deposition in α-synuclein-affected and -unaffected cells of the globus pallidus, putamen, and the substantia nigra, regions of highest iron concentration, using a combination of iron staining with immunolabelling. Selective regional and cellular vulnerability patterns of iron deposition were compared between disease subtypes. In 7 MSA cases, expression of key iron- and closely related oxygen-homeostatic genes were examined.
RESULTS
MSA-P and MSA-C showed different patterns of regional iron burden across the pathology-related systems. We identified subcortical microglia to predominantly accumulate iron, which was more distinct in MSA-P. MSA-C showed relatively heterogenous iron accumulation, with greater or similar deposition in astroglia. Iron deposition was also found outside cellular bodies. Cellular iron burden associated with oligodendrocytic, and not neuronal, α-synuclein cytopathology. Gene expression analysis revealed dysregulation of oxygen homeostatic genes, rather than of cellular iron. Importantly, hierarchal cluster analysis revealed the pattern of cellular vulnerability to iron accumulation, distinctly to α-synuclein pathology load in the subtype-related systems, to distinguish MSA subtypes.
CONCLUSIONS
Our comprehensive evaluation of iron deposition in MSA brains identified distinct regional, and for the first time, cellular distribution of iron deposition in MSA-P and MSA-C and revealed cellular vulnerability patterns to iron deposition as a novel neuropathological characteristic that predicts MSA clinical subtypes. Our findings suggest distinct iron-related pathomechanisms in MSA clinical subtypes that are therefore not a consequence of a uniform down-stream pathway to α-synuclein pathology, and inform current efforts in iron chelation therapies at the disease and cellular-specific levels.
PubMed: 38761956
DOI: 10.1016/j.nbd.2024.106535 -
Cell Reports. Medicine May 2024Levodopa-induced dyskinesia (LID) is an intractable motor complication arising in Parkinson's disease with the progression of disease and chronic treatment of levodopa....
Levodopa-induced dyskinesia (LID) is an intractable motor complication arising in Parkinson's disease with the progression of disease and chronic treatment of levodopa. However, the specific cell assemblies mediating dyskinesia have not been fully elucidated. Here, we utilize the activity-dependent tool to identify three brain regions (globus pallidus external segment [GPe], parafascicular thalamic nucleus, and subthalamic nucleus) that specifically contain dyskinesia-activated ensembles. An intensity-dependent hyperactivity in the dyskinesia-activated subpopulation in GPe (GPe) is observed during dyskinesia. Optogenetic inhibition of GPe significantly ameliorates LID, whereas reactivation of GPe evokes dyskinetic behavior in the levodopa-off state. Simultaneous chemogenetic reactivation of GPe and another previously reported ensemble in striatum fully reproduces the dyskinesia induced by high-dose levodopa. Finally, we characterize GPe as a subset of prototypic neurons in GPe. These findings provide theoretical foundations for precision medication and modulation of LID in the future.
PubMed: 38759649
DOI: 10.1016/j.xcrm.2024.101566 -
ENeuro May 2024A hallmark of Parkinson's disease is the appearance of correlated oscillatory discharge throughout the cortico-basal ganglia (BG) circuits. In the primate globus...
A hallmark of Parkinson's disease is the appearance of correlated oscillatory discharge throughout the cortico-basal ganglia (BG) circuits. In the primate globus pallidus (GP), where the discharge of GP neurons is normally uncorrelated, pairs of GP neurons exhibit oscillatory spike correlations with a broad distribution of pairwise phase delays in experimental parkinsonism. The transition to oscillatory correlations is thought to indicate the collapse of the normally segregated information channels traversing the BG. The large phase delays are thought to reflect pathological changes in synaptic connectivity in the BG. Here we study the structure and phase delays of spike correlations measured from neurons in the mouse external GP (GPe) subjected to identical 1-100 Hz sinusoidal drive but recorded in separate experiments. First, we found that spectral modes of a GPe neuron's empirical instantaneous phase response curve (iPRC) elucidate at what phases of the oscillatory drive the GPe neuron locks when it is entrained and the distribution of phases at which it spikes when it is not. Then, we show that in this case the pairwise spike cross-correlation equals the cross-correlation function of these spike phase distributions. Finally, we show that the distribution of GPe phase delays arises from the diversity of iPRCs and is broadened when the neurons become entrained. Modeling GPe networks with realistic intranuclear connectivity demonstrates that the connectivity decorrelates GPe neurons without affecting phase delays. Thus, common oscillatory input gives rise to GPe correlations whose structure and pairwise phase delays reflect their intrinsic properties captured by their iPRCs.
Topics: Animals; Globus Pallidus; Neurons; Action Potentials; Mice; Mice, Inbred C57BL; Male; Electric Stimulation; Models, Neurological
PubMed: 38755012
DOI: 10.1523/ENEURO.0187-24.2024 -
Acta Neurochirurgica May 2024To assess whether diffusion tensor imaging (DTI) and generalized q-sampling imaging (GQI) metrics could preoperatively predict the clinical outcome of deep brain...
PURPOSE
To assess whether diffusion tensor imaging (DTI) and generalized q-sampling imaging (GQI) metrics could preoperatively predict the clinical outcome of deep brain stimulation (DBS) in patients with Parkinson's disease (PD).
METHODS
In this single-center retrospective study, from September 2021 to March 2023, preoperative DTI and GQI examinations of 44 patients who underwent DBS surgery, were analyzed. To evaluate motor functions, the Unified Parkinson's Disease Rating Scale (UPDRS) during on- and off-medication and Parkinson's Disease Questionnaire-39 (PDQ-39) scales were used before and three months after DBS surgery. The study population was divided into two groups according to the improvement rate of scales: ≥ 50% and < 50%. Five target regions, reported to be affected in PD, were investigated. The parameters having statistically significant difference were subjected to a receiver operating characteristic (ROC) analysis.
RESULTS
Quantitative anisotropy (qa) values from globus pallidus externus, globus pallidus internus (qa_Gpi), and substantia nigra exhibited significant distributional difference between groups in terms of the improvement rate of UPDRS-3 scale during on-medication (p = 0.003, p = 0.0003, and p = 0.0008, respectively). In ROC analysis, the best parameter in predicting DBS response included qa_Gpi with a cut-off value of 0.01370 achieved an area under the ROC curve, accuracy, sensitivity, and specificity of 0.810, 73%, 62.5%, and 85%, respectively. Optimal cut-off values of ≥ 0.01864 and ≤ 0.01162 yielded a sensitivity and specificity of 100%, respectively.
CONCLUSION
The imaging parameters acquired from GQI, particularly qa_Gpi, may have the ability to non-invasively predict the clinical outcome of DBS surgery.
Topics: Humans; Deep Brain Stimulation; Parkinson Disease; Diffusion Tensor Imaging; Female; Male; Middle Aged; Retrospective Studies; Aged; Treatment Outcome; Globus Pallidus; Predictive Value of Tests
PubMed: 38748304
DOI: 10.1007/s00701-024-06096-w -
Journal of Neurosciences in Rural... 2024Liver cirrhosis patients commonly progress to minimal hepatic encephalopathy (MHE) with cognitive impairment and raised blood ammonia and proinflammatory cytokines...
OBJECTIVES
Liver cirrhosis patients commonly progress to minimal hepatic encephalopathy (MHE) with cognitive impairment and raised blood ammonia and proinflammatory cytokines levels. This study aims to identify the subjects of MHE in patients with liver cirrhosis by hydrogen 1 magnetic resonance (1H-MR) spectroscopy of the brain, serum proinflammatory cytokines, and neuropsychiatric tests.
MATERIALS AND METHODS
This prospective was carried out on 100 patients of liver cirrhosis without overt hepatic encephalopathy (HE) and compared with 100 healthy controls in a tertiary care hospital in Northeast India between September 2017 and October 2019. The psychometric hepatic encephalopathy score (PHES) neuropsychological tests, cranial MRIwith H-MR spectroscopy, and estimation of serum interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were done. The PHES scores and serum proinflammatory markers levels were correlated with the conventional and H-MR spectroscopy findings of the brain.
RESULTS
The mean PHES score in the case group was -7.58±3.43 (standard deviation [SD]) and the control group was -3.41 ± 3.87 (SD). Patients with Child-Pugh class A ( = 8) had a PHES score of -8.7 ± 2.5 (SD), class B ( = 42) -7.62 ± 3.7 (SD), and class C ( = 50) had a score of -7.36 ± 3.3 (SD). The mean value of IL-6 and TNF-α in the case group was 219 ± 180 (SD) pg/mL and 99 ± 118 (SD) pg/mL and the control group was 67.4 ± 77 (SD) pg/mL and 57.5 ± 76 (SD) pg/mL. Globus pallidus T1-weighted hyperintensities on the visibility scale with a visibility score of 0 were observed in 39 cases, a score of 1 in 38 cases, and a score of 2 in 23 cases. Increased glutamate/glutamine/creatine (Glx/Cr) ratio was identified in the case group on MR spectroscopy as compared to the control (0.95 ± 0.24 vs. 0.31 ± 0.19, < 0.0005), a decrease of myoinositol/creatine (mI/Cr) ratio (0.11 ± 0.13 vs. 0.30 ± 0.12, < 0.0005), and increase choline/creatine (Cho/Cr) ratio (0.69 ± 0.26 vs. 0.61 ± 0.20, < 0.0005). There was a statistically significant difference in Glx/Cr, mI/Cr and Cho/Cr ratio between the case and control groups with < 0.0005.
CONCLUSION
Predicting the development of MHE in established cases of liver cirrhosis using non-invasive modalities like PHES, IL-6, TNF-α levels, and H-MR spectroscopy plays an important role in further progression to overt HE and coma.
PubMed: 38746531
DOI: 10.25259/JNRP_460_2023