A mechanistic model of calcium homeostasis leading to occurrence and propagation of secondary brain injury.

Secondary brain injury (SBI) refers to new or worsening brain insult after primary brain injury (PBI). Neurophysiological experiments show that calcium (Ca2+) is one of the major culprits that contribute to neuronal damage and death following PBI. However, mechanistic details about how alterations of Ca2+ levels contribute to SBI are not well characterized. In this paper, we first build a biophysical model for SBI related to calcium homeostasis (SBI-CH) to study the mechanistic details of PBI-induced disruption of CH, and how these disruptions affect the occurrence of SBI. Then, we construct a coupled SBI-CH model by formulating synaptic interactions to investigate how disruption of CH affects synaptic function and further promotes the propagation of SBI between neurons. Our model shows how the opening of voltage-gated calcium channels (VGCCs), decreasing of plasma membrane calcium pump (PMCA), and reversal of the Na+/Ca2+ exchanger (NCX) during and following PBI, could induce disruption of CH and further promote SBI. We also show that disruption of CH causes synaptic dysfunction, which further induces loss of excitatory-inhibitory balance in the system, and this might promote the propagation of SBI and cause neighboring tissue to be injured. Our findings offer a more comprehensive understanding of the complex interrelationship between CH and SBI.NEW & NOTEWORTHY We build a mechanistic model SBI-CH for calcium homeostasis (CH) to study how alterations of Ca2+ levels following PBI affect the occurrence and propagation of SBI. Specifically, we investigate how the opening of VGCCs, decreasing of PMCA, and reversal of NCX disrupt CH, and further induce the occurrence of SBI. We also present a coupled SBI-CH model to show how disrupted CH causes synaptic dysfunction, and further promotes the propagation of SBI between neurons.

A model of metabolic supply-demand mismatch leading to secondary brain injury.

Secondary brain injury (SBI) is defined as new or worsening injury to the brain after an initial neurologic insult, such as hemorrhage, trauma, ischemic stroke, or infection. It is a common and potentially preventable complication following many types of primary brain injury (PBI). However, mechanistic details about how PBI leads to additional brain injury and evolves into SBI are poorly characterized. In this work, we propose a mechanistic model for the metabolic supply demand mismatch hypothesis (MSDMH) of SBI. Our model, based on the Hodgkin-Huxley model, supplemented with additional dynamics for extracellular potassium, oxygen concentration, and excitotoxity, provides a high-level unified explanation for why patients with acute brain injury frequently develop SBI. We investigate how decreased oxygen, increased extracellular potassium, excitotoxicity, and seizures can induce SBI and suggest three underlying paths for how events following PBI may lead to SBI. The proposed model also helps explain several important empirical observations, including the common association of acute brain injury with seizures, the association of seizures with tissue hypoxia and so on. In contrast to current practices which assume that ischemia plays the predominant role in SBI, our model suggests that metabolic crisis involved in SBI can also be nonischemic. Our findings offer a more comprehensive understanding of the complex interrelationship among potassium, oxygen, excitotoxicity, seizures, and SBI.NEW & NOTEWORTHY We present a novel mechanistic model for the metabolic supply demand mismatch hypothesis (MSDMH), which attempts to explain why patients with acute brain injury frequently develop seizure activity and secondary brain injury (SBI). Specifically, we investigate how decreased oxygen, increased extracellular potassium, excitotoxicity, seizures, all common sequalae of primary brain injury (PBI), can induce SBI and suggest three underlying paths for how events following PBI may lead to SBI.

A New Neural Mass Model Driven Method and Its Application in Early Epileptic Seizure Detection.

OBJECTIVE: Despite numerous neural computational models proposed to explain physiological and pathological mechanisms of brain activity, a large gap remains between theory and application of the models. Building on the successful application of data-driven methods in epileptic seizure detection, we aim to build a bridge between data and models in this paper. METHODS: We first propose a novel model-driven seizure detection method based on dynamic features in epileptic EEGs, where the rationale for dynamic features in epileptic EEGs can be clarified in theory by characterizing the variation of parameters of the model. Then we apply the proposed D&F-model-driven method to the problem of early epileptic seizure detection, where the evolution of model parameters selected and optimized by the proposed method is measured and used to detect the starting point of the seizure. RESULTS: Numerical results on two open EEG databases demonstrate that our proposed method does a good job of early epileptic seizure detection. The average detection sensitivity, false positive rate and early detection period attain 100%, 0.1/h, and 7.1 s respectively. CONCLUSION: This paper provides a strategy to characterize EEG signals using a NMM-related method and the model parameters optimized by real EEG may then serve as features in their own right for early seizure detection. SIGNIFICANCE: An useful attempt to early detect epileptic seizures by combining the neural mass model with data analysis.

Seizure tracking of epileptic EEGs using a model-driven approach.

OBJECTIVE: As a chronic neurological disorder, epilepsy is characterized by recurrent and unprovoked epileptic seizures that can disrupt the normal neuro-biologic, cognitive, psychological conditions of patients. Therefore, it is worthwhile to give a detailed account of how the epileptic EEG evolves during a period of seizure so that an effective control can be guided for epileptic patients in clinics. APPROACH: Considering the successful application of the neural mass model (NMM) in exploring the insights into brain activities for epilepsy, in this paper, we aim to construct a model-driven approach to track the development of seizures using epileptic EEGs. We first propose a new time-delay Wendling model with sub-populations (TD-W-SP model) with respect to three aspects of improvements. Then we introduce a model-driven seizure tracking approach, where a model training method is designed based on extracted features from epileptic EEGs and a tracking index is defined as a function of the trained model parameters. MAIN RESULTS: Numerical results on eight patients on CHB-MIT database demonstrate that our proposed method performs well in simulating epileptic-like EEGs as well as tracking the evolution of three stages (that is, from pre-ictal to ictal and from ictal to post-ictal) during a period of epileptic seizure. SIGNIFICANCE: A useful attempt to track epileptic seizures by combining the NMM with the data analysis.

A novel neural computational model of generalized periodic discharges in acute hepatic encephalopathy.

Acute hepatic encephalopathy (AHE) due to acute liver failure is a common form of delirium, a state of confusion, impaired attention, and decreased arousal. The electroencephalogram (EEG) in AHE often exhibits a striking abnormal pattern of brain activity, which epileptiform discharges repeat in a regular repeating pattern. This pattern is known as generalized periodic discharges, or triphasic-waves (TPWs). While much is known about the neurophysiological mechanisms underlying AHE, how these mechanisms relate to TPWs is poorly understood. In order to develop hypotheses how TPWs arise, our work builds a computational model of AHE (AHE-CM), based on three modifications of the well-studied Liley model which emulate mechanisms believed central to brain dysfunction in AHE: increased neuronal excitability, impaired synaptic transmission, and enhanced postsynaptic inhibition. To relate our AHE-CM to clinical EEG data from patients with AHE, we design a model parameter optimization method based on particle filtering (PF-POM). Based on results from 7 AHE patients, we find that the proposed AHE-CM not only performs well in reproducing important aspects of the EEG, namely the periodicity of triphasic waves (TPWs), but is also helpful in suggesting mechanisms underlying variation in EEG patterns seen in AHE. In particular, our model helps explain what conditions lead to increased frequency of TPWs. In this way, our model represents a starting point for exploring the underlying mechanisms of brain dynamics in delirium by relating microscopic mechanisms to EEG patterns.

Effects of Cholinergic Neuromodulation on Thalamocortical Rhythms During NREM Sleep: A Model Study.

It has been suggested that cholinergic neurons shape the oscillatory activity of the thalamocortical (TC) network in behavioral and electrophysiological experiments. However, theoretical modeling demonstrating how cholinergic neuromodulation of thalamocortical rhythms during non-rapid eye movement (NREM) sleep might occur has been lacking. In this paper, we first develop a novel computational model (TC-ACH) by incorporating a cholinergic neuron population (CH) into the classical thalamo-cortical circuitry, where connections between populations are modeled in accordance with existing knowledge. The neurotransmitter acetylcholine (ACH) released by neurons in CH, which is able to change the discharge activity of thalamocortical neurons, is the primary focus of our work. Simulation results with our TC-ACH model reveal that the cholinergic projection activity is a key factor in modulating oscillation patterns in three ways: (1) transitions between different patterns of thalamocortical oscillations are dramatically modulated through diverse projection pathways; (2) the model expresses a stable spindle oscillation state with certain parameter settings for the cholinergic projection from CH to thalamus, and more spindles appear when the strength of cholinergic input from CH to thalamocortical neurons increases; (3) the duration of oscillation patterns during NREM sleep including K-complexes, spindles, and slow oscillations is longer when cholinergic input from CH to thalamocortical neurons becomes stronger. Our modeling results provide insights into the mechanisms by which the sleep state is controlled, and provide a theoretical basis for future experimental and clinical studies.