Radiomic features are potential imaging biomarkers for therapy response assessment in oncology. However, the robustness of features with respect to imaging parameters is not well established. Previously identified potential imaging biomarkers were found to be intrinsically dependent on voxel size and number of gray levels (GLs) in a recent texture phantom investigation. Here, we validate the voxel size and GL in-phantom normalizations in lung tumors. Eighteen patients with non-small cell lung cancer of varying tumor volumes were analyzed. To compare with patient data, phantom scans were acquired on eight different scanners. Twenty four previously identified features were extracted from lung tumors. The Spearman rank (r_s) and interclass correlation coefficient (ICC) were used as metrics. Eight out of 10 features showed high (r_s > 0.9) and low (r_s < 0.5) correlations with number of voxels before and after normalizations, respectively. Likewise, texture features were unstable (ICC < 0.6) and highly stable (ICC > 0.8) before and after GL normalizations, respectively. We conclude that voxel size and GL normalizations derived from a texture phantom study also apply to lung tumors. This study highlights the importance and utility of investigating the robustness of radiomic features with respect to CT imaging parameters in radiomic phantoms.

Cell volume changes are ubiquitous in normal and pathological activity of the brain. Nevertheless, we know little of how cell volume affects neuronal dynamics. We here performed the first detailed study of the effects of cell volume on neuronal dynamics. By incorporating cell swelling together with dynamic ion concentrations and oxygen supply into Hodgkin-Huxley type spiking dynamics, we demonstrate the spontaneous transition between epileptic seizure and spreading depression states as the cell swells and contracts in response to changes in osmotic pressure. Our use of volume as an order parameter further revealed a dynamical definition for the experimentally described physiological ceiling that separates seizure from spreading depression, as well as predicted a second ceiling that demarcates spreading depression from anoxic depolarization. Our model highlights the neuroprotective role of glial K buffering against seizures and spreading depression, and provides novel insights into anoxic depolarization and the relevant cell swelling during ischemia. We argue that the dynamics of seizures, spreading depression, and anoxic depolarization lie along a continuum of the repertoire of the neuron membrane that can be understood only when the dynamic ion concentrations, oxygen homeostasis,and cell swelling in response to osmotic pressure are taken into consideration. Our results demonstrate the feasibility of a unified framework for a wide range of neuronal behaviors that may be of substantial importance in the understanding of and potentially developing universal intervention strategies for these pathological states. Massive rearrangement of ions across the plasma membrane and changes in cellular volume are common features of states such as seizures, spreading depression, and ischemia. In this paper, we focus on how volume itself influences neuronal activity. We build a unified computational framework for a wide range of neuronal behaviors by exploiting their previously unexplored common features. By combining the dynamic ion concentrations and volume, conservation of charge, and the energy requirements of the cell within a Hodgkin-Huxley type framework, we demonstrate the feasibility of a comprehensive framework encompassing a wide range of neuronal behaviors. We show the spontaneous transition of a neuron between seizure and spreading depression when the cell swells and contracts in response to varying osmotic pressure as a result of the rearrangement of different ions. Our model closely reproduces anoxic depolarization and relevant neuronal swelling during ischemia and reveals a dynamical definition for the experimentally described physiological ceilings that demarcate seizure from spreading depression and spreading depression from anoxic depolarization. This study opens up a new way of studying neuronal behavior where different states need not be treated separately but rather as a dynamical continuum of the neuronal membrane potential and its microenvironment.

Background: Within 2 min of severe ischemia, spreading depolarization (SD) propagates like a wave through compromised gray matter of the higher brain. More SDs arise over hours in adjacent tissue, expanding the neuronal damage. This period represents a therapeutic window to inhibit SD and so reduce impending tissue injury. Yet most neuroscientists assume that the course of early brain injury can be explained by glutamate excitotoxicity, the concept that immediate glutamate release promotes early and downstream brain injury. There are many problems with glutamate release being the unseen culprit, the most practical being that the concept has yielded zero therapeutics over the past 30 years. But the basic science is also flawed, arising from dubious foundational observations beginning in the 1950s Methods: Literature pertaining to excitotoxicity and to SD over the past 60 years is critiqued. Results: Excitotoxicity theory centers on the immediate and excessive release of glutamate with resulting neuronal hyperexcitation. This instigates poststroke cascades with subsequent secondary neuronal injury. By contrast, SD theory argues that although SD evokes some brief glutamate release, acute neuronal damage and the subsequent cascade of injury to neurons are elicited by the metabolic stress of SD, not by excessive glutamate release. The challenge we present here is to find new clinical targets based on more informed basic science. This is motivated by the continuing failure by neuroscientists and by industry to develop drugs that can reduce brain injury following ischemic stroke, traumatic brain injury, or sudden cardiac arrest. One important step is to recognize that SD plays a central role in promoting early neuronal damage. We argue that uncovering the molecular biology of SD initiation and propagation is essential because ischemic neurons are usually not acutely injured unless SD propagates through them. The role of glutamate excitotoxicity theory and how it has shaped SD research is then addressed, followed by a critique of its fading relevance to the study of brain injury. Conclusions: Spreading depolarizations better account for the acute neuronal injury arising from brain ischemia than does the early and excessive release of glutamate.

Simultaneous changes in ion concentrations, glutamate, and cell volume together with exchange of matter between cell network and vasculature are ubiquitous in numerous brain pathologies. A complete understanding of pathological conditions as well as normal brain function, therefore, hinges on elucidating the molecular and cellular pathways involved in these mostly interdependent variations. In this paper, we develop the first computational framework that combines the Hodgkin–Huxley type spiking dynamics, dynamic ion concentrations and glutamate homeostasis, neuronal and astroglial volume changes, and ion exchange with vasculature into a comprehensive model to elucidate the role of glutamate uptake in the dynamics of spreading depolarization (SD)—the electrophysiological event underlying numerous pathologies including migraine, ischemic stroke, aneurysmal subarachnoid hemorrhage, intracerebral hematoma, and trauma. We are particularly interested in investigating the role of glutamate in the duration and termination of SD caused by K⁺ perfusion and oxygen-glucose deprivation. Our results demonstrate that glutamate signaling plays a key role in the dynamics of SD, and that impaired glutamate uptake leads to recovery failure of neurons from SD. We confirm predictions from our model experimentally by showing that inhibiting astrocytic glutamate uptake using TFB-TBOA nearly quadruples the duration of SD in layers 2-3 of visual cortical slices from juvenile rats. The model equations are either derived purely from first physical principles of electroneutrality, osmosis, and conservation of particles or a combination of these principles and known physiological facts. Accordingly, we claim that our approach can be used as a future guide to investigate the role of glutamate, ion concentrations, and dynamics cell volume in other brain pathologies and normal brain function. Pathological conditions such as seizure, migraine, traumatic brain injury, and stroke are associated with extreme changes in ion concentrations and glutamate, cell swelling, and heavy exchange of matter between neurons, glia, and vasculature. However, current experimental tools are capable of measuring only a few of these variables, which necessitates the development of biophysically relevant models. This study provides a comprehensive computational framework derived from first physical principles and physiological facts that enables us to investigate a wide range of key variables in SD caused by K⁺ perfusion and oxygen-glucose deprivation. While we use SD as an example, our approach can be extended to other pathological conditions and normal brain function.

Vesicular glutamate transporters accumulate glutamate in synaptic vesicles, where they also function as a major Cl^- efflux pathway. Here we combine heterologous expression and cellular electrophysiology with mathematical modeling to understand the mechanisms underlying this dual function of rat VGLUT1. When glutamate is the main cytoplasmic anion, VGLUT1 functions as H⁺-glutamate exchanger, with a transport rate of around 600 s⁻¹ at −160 mV. Transport of other large anions, including aspartate, is not stoichiometrically coupled to H⁺ transport, and Cl^- permeates VGLUT1 through an aqueous anion channel with unitary transport rates of 1.5 × 10⁵s⁻¹ at −160 mV. Mathematical modeling reveals that H⁺ coupling is sufficient for selective glutamate accumulation in model vesicles and that VGLUT Cl^- channel function increases the transport efficiency by accelerating glutamate accumulation and reducing ATP-driven H⁺ transport. In summary, we provide evidence that VGLUT1 functions as H⁺-glutamate exchanger that is partially or fully uncoupled by other anions.