scholarly journals Alleviating catastrophic forgetting using context-dependent gating and synaptic stabilization

2018 ◽  
Vol 115 (44) ◽  
pp. E10467-E10475 ◽  
Author(s):  
Nicolas Y. Masse ◽  
Gregory D. Grant ◽  
David J. Freedman
Keyword(s):  
High Performance ◽  
Recurrent Network ◽  
Network Architectures ◽  
Complementary Method ◽  
Computational Overhead ◽  
Large Numbers ◽  
Context Dependent ◽  
The Brain ◽  
Synaptic Stabilization

Humans and most animals can learn new tasks without forgetting old ones. However, training artificial neural networks (ANNs) on new tasks typically causes them to forget previously learned tasks. This phenomenon is the result of “catastrophic forgetting,” in which training an ANN disrupts connection weights that were important for solving previous tasks, degrading task performance. Several recent studies have proposed methods to stabilize connection weights of ANNs that are deemed most important for solving a task, which helps alleviate catastrophic forgetting. Here, drawing inspiration from algorithms that are believed to be implemented in vivo, we propose a complementary method: adding a context-dependent gating signal, such that only sparse, mostly nonoverlapping patterns of units are active for any one task. This method is easy to implement, requires little computational overhead, and allows ANNs to maintain high performance across large numbers of sequentially presented tasks, particularly when combined with weight stabilization. We show that this method works for both feedforward and recurrent network architectures, trained using either supervised or reinforcement-based learning. This suggests that using multiple, complementary methods, akin to what is believed to occur in the brain, can be a highly effective strategy to support continual learning.

scholarly journals A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Changpeng Wang ◽  
Siwei Zhang ◽  
Yuefei Zou ◽  
Hongzhao Ma ◽  
Donglang Jiang ◽  
...  
Keyword(s):  
High Performance ◽  
Specific Activity ◽  
High Accumulation ◽  
Metabolic Kinetics ◽  
Thiamine Metabolism ◽  
Pet Tracer ◽  
The Status ◽  
The Brain

Abstract Background Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff–Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high-performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of 18F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, and biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 min after injection as represented by the area under the curve (AUC) and blood thiamine levels was investigated. Results The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61 ± 0.53 in the liver within 1 min, 18.67 ± 7.04 in the kidney within half a minute. The SUV dropped to 0.72 ± 0.05 and 0.77 ± 0.35 after 60 min of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 min after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 min was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = − 0.985, p = 0.015). Conclusion The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

Conversion to renin of exogenously administered recombinant human prorenin in liver and kidney of monkeys

1990 ◽  
Vol 258 (3) ◽  
pp. E451-E458
Author(s):  
S. Kim ◽  
M. Hosoi ◽  
F. Ikemoto ◽  
K. Murakami ◽  
Y. Ishizuka ◽  
...  
Keyword(s):  
Blood Circulation ◽  
High Performance ◽  
Slow Component ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Gel Permeation ◽  
Liver And Kidney ◽  
The Brain ◽  
No Activation

Highly purified recombinant human prorenin, labeled with 125I (125I-prorenin), was intravenously given to monkeys to examine the possible in vivo conversion of this prorenin to renin. 125I-prorenin and 125I-renin were detected using specific anti-prorenin prosegment antibody and anti-renin antibody, respectively. The plasma disappearance of immunoreactive 125I-prorenin in marmosets showed two exponential components with a half-life of 10.4 +/- 0.2 min for the rapid component and 165.7 +/- 12.6 min for the slow component. Fifteen minutes after the injection of 125I-prorenin, 38.7 +/- 2.8 and 3.9 +/- 0.5% of the administered dose accumulated in the liver and kidney, respectively. Less than 1% of the dose injected distributed in the other organs, including the brain, submandibular gland, lung, heart, aorta, adrenal gland, spleen, uterus, ovary, and testis. Thus the labeled prorenin was predominantly taken up by the liver and kidney. Analysis of liver and kidney extracts and plasma, by both gel permeation high-performance liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, demonstrated that 125I-prorenin (Mr = 46,000) taken up by the liver and kidney was significantly converted to 125I-renin (Mr = 42,000), whereas only a negligible amount of 125I-renin (Mr = 42,000) was present in the plasma. Although there seems to be no activation of prorenin in the blood circulation, prorenin does seem to be activated by the liver and kidney.

Partial inhibition of the main energetic pathways and its metabolic consequences after in vivo treatment with benzimidazole derivatives in experimental neurocysticercosis

Parasitology ◽  
2019 ◽  
Vol 146 (12) ◽  
pp. 1578-1582 ◽  
Author(s):  
Guaraciara de Andrade Picanço ◽  
Nayana Ferreira de Lima ◽  
Taynara Cristina Gomes ◽  
Carolina Miguel Fraga ◽  
Daniella de Sousa Moreira Mendes Alves ◽  
...  
Keyword(s):  
Energy Production ◽  
High Performance ◽  
Metabolic Stress ◽  
Benzimidazole Derivatives ◽  
Neglected Tropical Disease ◽  
Promising Alternative ◽  
The World ◽  
Acquired Epilepsy ◽  
The Brain

AbstractBenzimidazole derivatives such as albendazole (ABZ) and mebendazole are important molecules used in helminthic treatment. Neurocysticercosis is the main cause of acquired epilepsy throughout the world and is currently treated with ABZ. New molecules have been studied in order to aid in the treatment of this neglected tropical disease, among them RCB15 and RCB20. The aim of this study was to evaluate the metabolic impact of RCB15 and RCB20 on Taenia crassiceps cysticerci intracranially inoculated in Balb/c mice. Thirty days after the inoculation the mice were treated with 50 mg kg−1 of RCB15, RCB20, ABZ or NaCl 0.9%. The euthanasia and cysticerci removal were performed 24 h after the treatment. The cysticerci were analysed through high performance liquid chromatography. After the treatments, there was an impairment in the main energetic pathways such as glycolytic pathway, homolactic fermentation or in mitochondrion energy production detected through the decrease in pyruvate, lactate, oxaloacetate, malate and fumarate concentrations. This induced the parasite to resort to alternative energetic pathways such as proteins catabolism, propionate fermentation and fatty acids oxidation. Therefore, benzimidazole derivatives are a promising alternative to ABZ use as they also reach the brain tissue and induce a metabolic stress in the cysticerci.

scholarly journals A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

2020 ◽  
Author(s):  
Changpeng Wang ◽  
Siwei Zhang ◽  
Yuefei Zou ◽  
Hongzhao Ma ◽  
Donglang Jiang ◽  
...  
Keyword(s):  
High Performance ◽  
Specific Activity ◽  
High Accumulation ◽  
Metabolic Kinetics ◽  
Thiamine Metabolism ◽  
Pet Tracer ◽  
The Status ◽  
The Brain

Abstract Background: Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff-Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods: A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity, radiochemical purity, radiochemical concentration, were evaluated by high performance liquid chromatography (HPLC). Metabolic kinetics and brain level of 18F-deoxy-thiamine in mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 minutes after injection as represented by the area under the curve (AUC) and blood thiamine levels were investigated. Results: The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61±0.53 in the liver within 1 minute, 18.67±7.04 in the kidney within half a minute. The SUV dropped to 0.72±0.05 and 0.77±0.35 after 60 minutes of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 minutes after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency by thiamine-deprived diet (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 minutes was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = -0.985, p = 0.015).Conclusion: The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

scholarly journals Multimodal magnetic resonance imaging predicts regional amyloid- β burden in the brain

2020 ◽  
Author(s):  
Anusha Rangarajan ◽  
Minjie Wu ◽  
Naomi Joseph ◽  
Helmet T. Karim ◽  
Charles Laymon ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Amyloid Β ◽  
Structural Mri ◽  
In Vivo Detection ◽  
Positron Emission ◽  
Large Numbers ◽  
Early Markers ◽  
Fluid Attenuated Inversion Recovery ◽  
The Brain

AbstractAlzheimer’s disease (AD) is the most common cause of dementia and identifying early markers of this disease is important for prevention and treatment strategies. Amyloid - β protein deposition is one of the earliest detectable pathological changes in AD. But in-vivo detection of amyloid - β using positron emission tomography (PET) is hampered by high cost and limited geographical accessibility. These factors can become limiting when PET is used to screen large numbers of subjects into prevention trials when only a minority are expected to be amyloid- β - positive. Structural MRI is advantageous; as it is relatively inexpensive and more accessible. Thus it could be widely used in large studies, even when frequent or repetitive imaging is necessary. We used a machine learning, pattern recognition, approach using intensity-based features from individual and combination of MR modalities (T1 weighted, T2 weighted, T2 fluid attenuated inversion recovery [FLAIR], susceptibility weighted imaging) to predict voxel-level amyloid- β in the brain. The MR- amyloid β relation was learned within each subject and generalized across subjects using subject–specific features (demographic, clinical, and summary MR features). When compared to other modalities, combination of T1-weighted, T2-weighted FLAIR, and SWI performed best in predicting the amyloid- β status as positive or negative. T2- weighted performed the best in predicting change in amyloid- β over two timepoints. Overall, our results show feasibility of amyloid- β prediction by MRI.

scholarly journals Encoding Time in Feedforward Trajectories of a Recurrent Neural Network Model

2018 ◽  
Vol 30 (2) ◽  
pp. 378-396 ◽  
Author(s):  
N. F. Hardy ◽  
Dean V. Buonomano
Keyword(s):  
Neural Network ◽  
Recurrent Neural Network ◽  
Brain Activity ◽  
Recurrent Network ◽  
In Vivo Studies ◽  
Network Architectures ◽  
Weber’S Law ◽  
Timing Behavior ◽  
Weber's Law

Brain activity evolves through time, creating trajectories of activity that underlie sensorimotor processing, behavior, and learning and memory. Therefore, understanding the temporal nature of neural dynamics is essential to understanding brain function and behavior. In vivo studies have demonstrated that sequential transient activation of neurons can encode time. However, it remains unclear whether these patterns emerge from feedforward network architectures or from recurrent networks and, furthermore, what role network structure plays in timing. We address these issues using a recurrent neural network (RNN) model with distinct populations of excitatory and inhibitory units. Consistent with experimental data, a single RNN could autonomously produce multiple functionally feedforward trajectories, thus potentially encoding multiple timed motor patterns lasting up to several seconds. Importantly, the model accounted for Weber's law, a hallmark of timing behavior. Analysis of network connectivity revealed that efficiency—a measure of network interconnectedness—decreased as the number of stored trajectories increased. Additionally, the balance of excitation (E) and inhibition (I) shifted toward excitation during each unit's activation time, generating the prediction that observed sequential activity relies on dynamic control of the E/I balance. Our results establish for the first time that the same RNN can generate multiple functionally feedforward patterns of activity as a result of dynamic shifts in the E/I balance imposed by the connectome of the RNN. We conclude that recurrent network architectures account for sequential neural activity, as well as for a fundamental signature of timing behavior: Weber's law.

scholarly journals Biodistribution and Anticancer Characteristics of Les-3833, A Novel 4-thiazolidinone-Based Lead Compound

2020 ◽  
Vol 88 (2) ◽  
pp. 18 ◽  
Author(s):  
Lesya Kobylinska ◽  
Andrii Lozynskii ◽  
Roman Lesyk ◽  
Rostyslav Stoika ◽  
Sandor G. Vari
Keyword(s):  
Maximum Concentration ◽  
High Performance ◽  
Maximum Level ◽  
Lead Compound ◽  
Short Period ◽  
Liquid Chromatography Tandem Mass ◽  
Liver And Kidney ◽  
The Brain

Recently, we identified the promising anticancer potential of the synthetic 4-thiazolidinone-based anticancer lead compound Les-3833 which demonstrated tumor-suppressing action in vitro and in vivo. Based on the results of previous studies, the aim of this research was to investigate the cytotoxicity in vitro and the biodistribution in laboratory mice to support the biotherapeutic drug development of Les-3833. Les-3833 (2.5 mg/kg) was intravenously injected into male Balb/c mice. Measurements were performed at 5 min, 15 min, 1 h, 4 h, and 24 h time points in blood plasma, brain, liver, and kidney using high-performance liquid chromatography/tandem mass spectrometry. After the administration of Les-3833, the maximum level of this compound was observed in plasma at 2.08 min. In the brain, the mean maximum concentration of Les-3833 was 7.17 ng/mL at 5 min, while after 15 min, it was not found. In the liver, at 5 min, the maximum concentration was 1190 ng/g. At 15 min, concentration of Les-3833 in the liver decreased by 14.3%; at 6 h by 22.8%; and after 24 h by 64.7%. Its maximum concentration in kidney was 404 ng/g within 5–15 min, at 1 h it decreased by 36.1%, and after 24 h by 49.3%. Thus, Les-3833 was rapidly taken up by different organs from the bloodstream, partially metabolized in the liver, and excreted mainly through the kidneys, while in the brain, a very low concentration could be observed for only a short period of time.

scholarly journals A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

2020 ◽  
Author(s):  
Changpeng Wang ◽  
Siwei Zhang ◽  
Yuefei Zou ◽  
Hongzhao Ma ◽  
Donglang Jiang ◽  
...  
Keyword(s):  
High Performance ◽  
Specific Activity ◽  
High Accumulation ◽  
Metabolic Kinetics ◽  
Thiamine Metabolism ◽  
Pet Tracer ◽  
The Status ◽  
The Brain

Abstract Background: Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff-Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods: A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of 18F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 minutes after injection as represented by the area under the curve (AUC) and blood thiamine levels were investigated. Results: The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61±0.53 in the liver within 1 minute, 18.67±7.04 in the kidney within half a minute. The SUV dropped to 0.72±0.05 and 0.77±0.35 after 60 minutes of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 minutes after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 minutes was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = - 0.985, p = 0.015).Conclusion: The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

scholarly journals Closed-loop, ultraprecise, automated craniotomies

2015 ◽  
Vol 113 (10) ◽  
pp. 3943-3953 ◽  
Author(s):  
Nikita Pak ◽  
Joshua H. Siegle ◽  
Justin P. Kinney ◽  
Daniel J. Denman ◽  
Timothy J. Blanche ◽  
...  
Keyword(s):  
Closed Loop ◽  
Drill Bit ◽  
Large Array ◽  
Robotic Device ◽  
In Vivo Electrophysiology ◽  
Two Photon ◽  
Aligned Arrays ◽  
Large Numbers ◽  
The Brain

A large array of neuroscientific techniques, including in vivo electrophysiology, two-photon imaging, optogenetics, lesions, and microdialysis, require access to the brain through the skull. Ideally, the necessary craniotomies could be performed in a repeatable and automated fashion, without damaging the underlying brain tissue. Here we report that when drilling through the skull a stereotypical increase in conductance can be observed when the drill bit passes through the skull base. We present an architecture for a robotic device that can perform this algorithm, along with two implementations—one based on homebuilt hardware and one based on commercially available hardware—that can automatically detect such changes and create large numbers of precise craniotomies, even in a single skull. We also show that this technique can be adapted to automatically drill cranial windows several millimeters in diameter. Such robots will not only be useful for helping neuroscientists perform both small and large craniotomies more reliably but can also be used to create precisely aligned arrays of craniotomies with stereotaxic registration to standard brain atlases that would be difficult to drill by hand.

Effect of pH and inhibitors on beta-amyloid fibril assembly

1996 ◽  
Vol 54 ◽  
pp. 752-753
Author(s):  
Beverly E. Maleeff ◽  
Timothy K. Hart ◽  
Stephen J. Wood ◽  
Ronald Wetzel
Keyword(s):  
Amyloid Fibril ◽  
Peptide Fragment ◽  
Hydrophobic Peptides ◽  
Amyloid Fibril Formation ◽  
Effects Of Ph ◽  
Severity Of The Disease ◽  
Kinetics Of ◽  
The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

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