Computational predictive modeling of integrated cerebral metabolism, electrophysiology and hemodynamics

Understanding the energetic requirement of brain cells during resting state and during high neuronal activity is a very active research area where mathematical models have contributed significantly by providing a context for the interpretation of the experimental results. In this thesis, we present three new computational predictive mathematical models to elucidate several dynamics in the brain, comprising electrophysiological activity, cellular metabolism and hemodynamic response. Many computational challenges had to be addressed, mostly due to the very different characteristic times at which the electrical, metabolic and hemodynamic events occur. The first part of the thesis proposes a novel predictive mathematical electro-metabolic model connecting the electrophysiological activity and the metabolism through a double feedback mechanism based on energy demand and production. This model sheds light on the role of the glial potassium cleaning in brain energy metabolism by integrating a four compartment metabolic model with one describing in details the electrical activity. The results of computed experiments performed with this model for different protocols, namely awake resting state, transitions between resting state and neuronal activation and ischemic episodes are in agreement with experimental observations. In the second part of the thesis, the electro-metabolic model is expanded to comprise the brain hemodynamic response. This is attained through a triple feedback mechanism between the electrophysiology, metabolism and a three compartment hemodynamic model tracking the changes of cerebral blood flow and cerebral blood volume through arteries, capillaries and veins. During neuronal activation, the increase in extracellular potassium concentration triggers an increase in the cerebral blood flow and concurrently vasodilation, ensuring the supply of nutrients necessary for the metabolic response to sustain the increased energy demand. The ensuing hemo-electro-metabolic model provides a better insight on the transitions between resting state and neuronal activation. In the third and last part of the thesis, we propose a variant of the electro-metabolic model that adequately describes the changes in the brain in connection with cortical spreading depression (CSD) waves. In addition the dynamics of sodium and potassium, the new model accounts for chloride dynamics, the glutamate-glutamine cycle, as well as neuronal swelling accompanied by shrinkage of extracellular space. As illustrated with computed experiments, with this model it is possible to follow simultaneously the changes in ionic homeostasis, the alterations in the volumes of the cellular compartments and of the extracellular space, and large modifications in brain metabolism during cortical spreading depression waves. The model predictions, in agreement with findings reported in the experimental literature, show a large decrease in glucose and oxygen concentration and a significant increase in lactate concentration during the passing of cortical spreading depression waves.SVP-2014-06872

Synthesis of calculational methods for design and analysis of radiation shields for nuclear rocket systems

Eight computer programs make up a nine volume synthesis containing two design methods for nuclear rocket radiation shields. The first design method is appropriate for parametric and preliminary studies, while the second accomplishes the verification of a final nuclear rocket reactor design

A computational model integrating brain electrophysiology and metabolism highlights the key role of extracellular potassium and oxygen

The human brain is a small organ which uses a disproportional amount of the total metabolic energy pro- duction in the body. While it is well understood that the most significant energy sink is the maintenance of the neuronal membrane potential during the brain signaling activity, the role of astrocytes in the energy balance continues to be the topic of a lot of research. A key function of astrocytes, besides clearing glutamate from the synaptic clefts, is the potassium clearing after neuronal activation. Extracellular potassium plays a significant role in triggering neuronal firing, and elevated concentration of potassium may lead to abnormal firing pattern, e.g., seizures, thus emphasizing the importance of the glial K+ buffering role. The predictive mathematical model proposed in this paper elucidates the role of glial potassium clearing in brain energy metabolism, integrating a detailed model of the ion dynamics which regulates neuronal firing with a three compartment metabolic model. Because of the very different characteristic time scales of electrophysiology and metabolism, care must be taken when coupling the two models to ensure that the predictions, e.g., neuronal firing frequencies and the oxygen- glucose index (OGI) of the brain during activation and rest, are in agreement with empirical observations. The temporal multi-scale nature of the problem requires the design of new computational tools to ensure a stable and accurate numerical treatment of the problem. The model predictions for different protocols, including combinations of elevated activation and ischemic episodes, are in good agreement with experimental observations reported in the literature.This work was supported by the Bizkaia Talent and European Commission through CO- FUND under the grant CIPAS: Computational Inverse Problems Across Scales (AYD-000-278, 2015), by the Basque Government through the BERC 2014-2017 program, and by the Spanish Ministry of Economics and Competitive- ness MINECO through the BCAM Severo Ochoa excellence accreditation SEV-2013-0323 and the Spanish ”Plan Estatal de Investigacio ́n, Desarrollo e Innovacio ́n Orientada a los Retos de la Sociedad” under Grant BELEMET - Brain ELEctro-METabolic modeling and numerical approximation (MTM2015-69992-R). The work of Daniela Cal- vetti was partly supported by Grant Number 246665 from the Simons Foundation, and the work of Erkki Somersalo was partly supported by NSF Grant DMS 1016183. Daniela Calvetti and Erkki Somersalo were partly supported by NIH, grant 1U01GM111251-01

Brain energetics plays a key role in the coordination of electrophysiology, metabolism and hemodynamics: evidence from an integrated computational model

The energetic needs of brain cells at rest and during elevated neuronal activation has been the topic of many investigations where mathematical models have played a significant role providing a context for the interpretation of experimental findings. A recently proposed mathematical model, comprising a double feedback between cellular metabolism and electrophysiology, sheds light on the interconnections between the electrophysiological details associated with changes in the frequency of neuronal firing and the corresponding metabolic activity. We propose a new extended mathematical model comprising a three-way feedback connecting metabolism, electrophysiology and hemodynamics. Upon specifying the time intervals of higher neuronal activation, the model generates a potassium based signal leading to the concomitant increase in cerebral blood flow with associated vasodilation and metabolic changes needed to sustain the increased energy demand. The predictions of the model are in good qualitative and quantitative agreement with experimental findings reported in the literature, even predicting a slow after-hyperpolarization of a duration of approximately 16 s matching experimental observations.The work of Daniela Calvetti was partly support by NSF grants DMS-1522334 and NIH grant 1U01 GM111251-01. The work of Erkki Somersalo was partly support by NSF grants DMS 1714617 and NIH grant 1U01GM111251-01

Spectral changes of brain activity in rat offspring exposed to aluminium during gestation and lactation

Exposure to aluminium during gestation causes changes in mammalian brain development and behavior. Our aim was to perform spectral analysis on electrocortical activity of Sprague Dawley male pups (30±3 days of age) whose mothers were treated with aluminium during gestation and lactation. There was a higher presence of power spectra in the delta range of parietal electrocortical activity, a lower presence in the theta range and increased values of the parameter DT as the ratio of delta to theta range in pups indirectly exposed to aluminium (whose mothers were drinking a 0.5% water solution of aluminium chloride during the gestation and lactation periods), compared to controls

Cognitive functions in repeated glioma surgery

Low-grade gliomas (LGG) are slow-growing brain tumors infiltrating the central nervous system which tend to recur, often with malignant degeneration after primary treatment. Re-operations are not always recommended due to an assumed higher risk of neurological and cognitive deficits. However, this assumption is relatively ungrounded due to a lack of extensive neuropsychological testing. We retrospectively examined a series of 40 patients with recurrent glioma in eloquent areas of the left hemisphere, who all completed comprehensive pre- (T3) and post-surgical (T4) neuropsychological assessments after a second surgery (4-month follow up). The lesions were most frequent in the left insular cortex and the inferior frontal gyrus. Among this series, in 17 patients the cognitive outcomes were compared before the first surgery (T1), 4 months after the first surgery (T2), and at T3 and T4. There was no significant difference either in the number of patients scoring within the normal range between T3 and T4, or in their level of performance. Further addressing the T1\u2013T4 evolution, there was no significant difference in the number of patients scoring within the normal range. As to their level of performance, the only significant change was in phonological fluency. This longitudinal follow-up study showed that repeated glioma surgery is possible without major damage to cognitive functions in the short-term period (4 months) after surgery

Deltaproteobacteria and Spirochaetes-Like Bacteria Are Abundant Putative Mercury Methylators in Oxygen-Deficient Water and Marine Particles in the Baltic Sea

Methylmercury (MeHg), a neurotoxic compound biomagnifying in aquatic food webs, can be a threat to human health via fish consumption. However, the composition and distribution of the microbial communities mediating the methylation of mercury (Hg) to MeHg in marine systems remain largely unknown. In order to fill this knowledge gap, we used the Baltic Sea Reference Metagenome (BARM) dataset to study the abundance and distribution of the genes involved in Hg methylation (thehgcABgene cluster). We determined the relative abundance of thehgcABgenes and their taxonomic identity in 81 brackish metagenomes that cover spatial, seasonal and redox variability in the Baltic Sea water column. ThehgcABgenes were predominantly detected in anoxic water, but somehgcABgenes were also detected in hypoxic and normoxic waters. Phylogenetic analysis identified putative Hg methylators within Deltaproteobacteria, in oxygen-deficient water layers, but also Spirochaetes-like and Kiritimatiellaeota-like bacteria. Higher relative quantities ofhgcABgenes were found in metagenomes from marine particles compared to free-living communities in anoxic water, suggesting that such particles are hotspot habitats for Hg methylators in oxygen-depleted seawater. Altogether, our work unveils the diversity of the microorganisms with the potential to mediate MeHg production in the Baltic Sea and pinpoint the important ecological niches for these microorganisms within the marine water column

A histidine-rich metal binding domain at the N terminus of Cu,Zn-superoxide dismutases from pathogenic bacteria: a novel strategy for metal chaperoning.

A group of Cu,Zn-superoxide dismutases from pathogenic bacteria is characterized by histidine-rich N-terminal extensions that are in a highly exposed and mobile conformation. This feature allows these proteins to be readily purified in a single step by immobilized metal affinity chromatography. The Cu,Zn-superoxide dismutases from both Haemophilus ducreyi and Haemophilus parainfluenzae display anomalous absorption spectra in the visible region due to copper binding at the N-terminal region. Reconstitution experiments of copper-free enzymes demonstrate that, under conditions of limited copper availability, this metal ion is initially bound at the N-terminal region and subsequently transferred to an active site. Evidence is provided for intermolecular pathways of copper transfer from the N-terminal domain of an enzyme subunit to an active site located on a distinct dimeric molecule. Incubation with EDTA rapidly removes copper bound at the N terminus but is much less effective on the copper ion bound at the active site. This indicates that metal binding by the N-terminal histidines is kinetically favored, but the catalytic site binds copper with higher affinity. We suggest that the histidine-rich N-terminal region constitutes a metal binding domain involved in metal uptake under conditions of metal starvation in vivo. Particular biological importance for this domain is inferred by the observation that its presence enhances the protection offered by periplasmic Cu,Zn-superoxide dismutase toward phagocytic killing

Surgical Treatment of Spinal Meningiomas in the Elderly (≥75 Years): Which Factors Affect the Neurological Outcome? An International Multicentric Study of 72 Cases

(1) Background: With the increasing life expectancy in the Western world, an increasing number of old patients presents with spinal meningioma. Considering the benign nature of these tumors, the functional outcome remains of great importance, since more people reach old age in general conditions of well-being and satisfactory autonomy. (2) Methods: We conducted an international multicenter retrospective study to investigate demographic, clinical and radiological data in a population of elderly patients (≥75 years of age) undergoing surgery for SM from January 2000 to December 2020 in four European referral centers. The aim was to identify prognostic and predictive factors for a good postoperative functional outcome. (3) Results: 72 patients were included in the study. Complete tumor resection (Simpson I or II) was achieved in 67 (95.7%) cases. Intraoperative complications were reported in 7 (9.9%) patients while postoperative complications were found in 12 (16.7%). An excellent general postoperative status (McCormick I and II) was achieved in 65.3%. Overall, surgical resection had a good impact on patients’ functional outcome (86.1% either showing an improvement or maintaining a good preoperative status). Uni- and multivariate analyses found that both age and preoperative modified McCormick independently correlated with relative outcome (coeff = −0.058, p = 0.0251; coeff = 0.597, p < 0.0001) and with postoperative status (coeff = 0.058, p = 0.02507; coeff = 0.402, p = 0.00027), respectively. (4) Conclusions: Age and preoperative modified McCormick were found to be independent prognostic factors. Nevertheless, advanced age (≥75), per se, did not seem to contraindicate surgery, even in those with severe preoperative neurological deficits. The functional results sustain the need for surgical resection of SM in the elderly

Olfactory groove meningioma: report of 99 cases surgically treated at the Catholic University School of Medicine, Rome

OBJECTIVE: We reviewed our series of olfactory groove meningiomas (OGMs) with the aim to relate the surgical approach with outcome and to define clinical and pathologic predictors of prognosis. METHODS: Ninety-nine patients who underwent 113 craniotomies at our Institution between 1984 and 2010 were entered this study. The relationship between surgical approach (bifrontal, fronto-orbito-basal, and pterional) and either tumor diameter, extent of tumor resection, complication rate, need of reoperation, and Karnofsky Performance Status (KPS) was analyzed. The impact of age ( 64 70 vs. &gt; 70 years), sex, tumor diameter (&lt; 6 vs. 65 6 cm), pre- and postoperative KPS (&lt; 80 vs. 65 80), Simpson grade (I-II vs. III-IV), and World Health Organization (WHO) histologic grade (I vs. II-III) on survival was assessed. Kaplan-Meier survival curves were plotted and differences in survival between groups of patients were compared. A multivariate analysis adjusted for age, pre- and postoperative KPS, Simpson grade, tumor diameter, and WHO histologic grade also was performed. RESULTS: The fronto-orbito-basal approach (n = 22) allowed a significantly greater percentage of Simpson I-II removals than the bifrontal (n = 70) and pterional approach (n = 21) (P = 0.0354 and P = 0.0485, respectively). The risk of life-threatening complications trended to be lower in patients operated upon either via the fronto-orbito-basal and via the pterional approach than in those treated via the bifrontal approach. Retraction-related brain swelling did not occur in any case after the fronto-orbito-basal approach (P = 0.0384); however, this approach was associated with a greater rate of cerebrospinal fluid leak (P = 0.0011). Among prognostic factors, age 64 70 years (P = 0.0044), tumor diameter &lt;6 cm (P = 0.0455), pre- and postoperative KPS 65 80 (both P &lt; 0.0001), Simpson grade I-II (P = 0.0096), and WHO histologic grade I (P = 0.0112) were significantly associated with longer overall survival. Age (P = 0.0393) and WHO histologic grade (P = 0.0418) emerged as independent prognostic factors for overall survival on multivariate analysis. CONCLUSION: In the largest series of OGMs published to date, the bifrontal approach was associated with a greater risk of life-threatening complications compared with the lateral pterional and fronto-orbito-basal approaches. The fronto-orbito-basal approach provided greater chances of total tumor removal than the bifrontal and pterional approaches. Two independent factors for overall survival of patients with OGM were identified, namely age and WHO grade