Synopsis

TBI is devastating yet currently without a cure. Investigators are seeking therapeutic strategies through the preclinical animal model to elucidate changes occurring after brain injury and identify potential neuroprotective therapies for brain-injured patients. The choice of animal model depends on the research goal and underlying objectives. This lecture will introduce the animal models of TBI commonly used for MRI study and explain their biomechanical, pathological and neurological differences in characteristics. Recent advances of MRI in probing the pathophysiology responses in experimental TBI will also be reviewed.

Preface

Traumatic brain injury (TBI) is one of the leading causes of death and disability in young adults.¹ Falls and unintentional blunt trauma are the leading causes of TBI and disproportionately affect the youngest and oldest age groups accounting for more than 60% of TBIs in the United States for 2006–2010.² The mortality rates in the USA ranges between 15 and 20 per 100,000 each year and currently at least 5.³ million Americans, 2% of the U.S. population, live with disabilities resulting from TBI. Investigations conducted on the animal models of TBI have generated an ample amount of data in the past decades providing critical insights into the trauma events that could never been observed in the clinical data Many different types of animal TBI models have been developed to generate the injury mimicking the heterogeneous nature of the clinical situation in TBI. This lecture will introduce the animal models of TBI commonly used for MRI study and explain their biomechanical, pathological and neurological differences in characteristics, as well as the recent advances of MRI in probing the pathophysiology responses in experimental TBI.

Biomechanical concerns of an experimental TBI model

Characterization of the biomechanics of injury may necessitate a different model than evaluation of molecular mechanisms of tissue loss, or testing the efficacy of novel therapeutic treatments. A suitable experimental model should satisfy these criteria: 1) the mechanical force used to induce injury is controlled, reproducible, and quantifiable; 2) the inflicted injury is reproducible, quantifiable, and mimics components of human conditions; 3) the injury outcome, measured by morphological, physiological, biochemical, or behavioral parameters, is related to the mechanical force causing the injury; and 4) the intensity of the mechanical force used to inflict injury should predict the outcome severity.³

The Mechanical force inflicts either static or dynamic brain trauma, depending on its amplitude, duration, velocity and acceleration.³ The mechanical force in static models possesses defined amplitude and duration, whereas the velocity and acceleration are irrelevant. Inherently, the static models usually focus on morphological and functional processes involved in injury, such as the cranial nerve injury with forceps. On the other hand, mechanical force, with well-characterized amplitude, duration, velocity, and/or acceleration, inflicts dynamic brain injury that can be divided into three main categories: 1) focal impact TBI; 2) diffuse impact TBI; and 3) non-impact TBI, as detailed in the following section.

Animal models of TBI

Focal Impact TBI

1. Feeney's weight-drop model: A free weight is released directly onto the exposed dura.⁴
2. Controlled cortical impact (CCI) injury model: An air or electromagnetic driven piston penetrates the brain at a known distance and velocity.⁵
3. The penetrating ballistic-like brain injury (PBBI): Transmission of projectiles (a metal rod or expansion of the probe's elastic balloon) with high energy to the exposed dura to cause damage in the brain.⁶
4. Lateral fluid percussion (LFP) injury: A pendulum strikes a fluid reservoir which creates a fluid pressure pulse to the exposed dura and causes a deformation of the underlying brain.⁷
5. Central fluid percussion injury: Similar to the LFP model, a fluid percussion device uses rapid injection of a fluid pulse into the epidural space.⁸

Diffuse Impact TBI

1. Impact-Acceleration (Marmarou's weight-drop) model: A free weight is released from a set distance onto a metal disk placed over the skull (to prevent bone fracture) to induce diffuse type of brain damage.⁹
2. Pneumatic impact acceleration model: Similar to the Marmarou’s model, but uses a pneumatic impactor to generate hits to a steel disc centered onto the skull.¹⁰
3. CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration): Non- surgical procedure using a sophisticated device to precisely deliver impacts of prescribed dynamic characteristics to a closed skull while enabling kinematic analysis of unconstrained head movement.¹¹

Non-Impact TBI

1. Inertial Acceleration Injury: Inertial loading is generated through a biphasic centroidal rotation for 110° within 20ms to produce injury by a sudden halt of the device.¹²
2. Rotational Injury: Diffuse brain injuries are produced by sagittal plane rearward rotational acceleration.¹³
3. Blast brain injury: Primary injury is caused by explosives or compressed air related to the blast and other mechanisms.¹⁴

Pathophysiology in the animal models of experimental TBI

The purpose of experimental models of TBI is to replicate certain pathological components or phases of clinical trauma in experimental animals aiming to address pathology and/or treatment. In brain trauma, the primary injurious event is followed by secondary pathological processes that can exacerbate damage, and are thus targets for therapy.^15,16

Primarily Injury

• Tissue level

1. Mechanical tissue deformation
2. Shearing and tearing of blood vessels, glia, neurons and axons
3. Hemorrhage
4. Vasospasm
5. Subdural hematoma
6. Edema

• Cellular/Molecular level

1. Necrotic cells death
2. Initiation of secondary injury

Secondary Injury

• Tissue level

1. Blood-brain barrier damage
2. Edema
3. Increased intracranial pressure
4. Altered cerebral blood flow
5. Ischemia and hypoxia
6. Demyelination
7. Tissue loss
8. Brain atrophy

• Cellular/Molecular level

1. Inflammation
2. Excitatory amino acid release
3. Calcium influx
4. Increased cytokines and chemokines
5. Increased free radicals
6. Increase in lactate
7. Mitochondria damage
8. Apoptosis
9. Cell death
10. Energy deficits

In TBI, the primary injury, which is the direct result of the external force, involves mechanical tissue deformation and causes diffuse neuronal depolarization and release of excitatory neurotransmitters including glutamate and aspartate, which bind to glutamate receptors and induce a massive influx of calcium.¹⁵ Calcium activates calcium-dependent phospholipases, proteases and endonucleases that degrade lipids, proteins and nucleic acids. Calcium sequestration in mitochondria leads to calcium disturbance, energy deficits, free radical formation, and initiation of apoptosis. Increased formation of oxygen and nitrogen reactive species oxidizes lipids, proteins and nuclei acids after TBI.¹⁵

Following injury, there is an urgent demand for more cellular energy to reestablish ionic equilibrium for brain cells to restore nerve function.¹⁷ Increasingly recognized are the cellular perturbations and impaired regulation of cerebral blood flow that challenge energy metabolism to an ischemic state and induce transient cell membrane disruptions that lead to redistribution of ions and neurotransmitters, altering the membrane potential.

TBI up-regulates many transcription factors, inflammatory mediators, and neuroprotective genes but down-regulates neurotransmitter receptors and release mechanisms.¹⁸ Increased expression of detrimental cytokines and chemokines induces brain edema, blood–brain barrier damage, and cell death. The result of these complex cascades after TBI eventually leads to cell damage and death, which causes functional deficits.¹⁹ Substantial experimental and clinical data have accumulated over the past decade indicating that the adult brain is capable of substantial structural and functional reorganization after injury, which may contribute to spontaneous functional recovery. Interventions targeting secondary injury mechanisms and modulating neuroplasticity promote functional recovery in animal models of TBI.

Radiological-pathological-behavioral correlation in experimental TBI

Advanced MRI techniques, such as diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), perfusion MRI and chemical exchange saturation transfer (CEST) have been shown sensitive to investigate diffuse axonal injury, inflammation, astrogliosis, metabolic disorder, cortical neuronal swelling and loss in the brain parenchyma.^20-23 The relation between the observed changes of radiological metrics and the underlying diffuse pathophysiology in TBI is crucial for the clinical translation of these imaging technique. However, the heterogeneity of diffuse injury patterns in the TBI patient complicates the detection of the MRI data with pathological findings, thus requires extensive investigations using animal model of TBI for radiological-pathological-behavioral validation.

Radiological-pathological-behavioral correlations of MRI measures are needed to characterize the injury natural history and substantiate the sensitivity and specificity of these MRI metrics in relationship to subtle abnormalities in TBI.20 Most studies of the relationship between radiological metrics and pathology or behavior have been characterized in moderate-to-severe focal TBI animal models, such as controlled cortical impact (CCI)^24,25 or lateral fluid percussion (LFP).^26,27 In milder forms of experimental brain trauma (e.g. impact-acceleration model), the radiological-pathological-behavioral correlation has been difficult and required more sensitive imaging modality and exquisite analysis to observe the subtle morphological changes.^20,28 These animal models provide a useful platform for pathological or behavioral correlation with imaging results facilitating the interpretation of the changes of radiological data for TBI.

Acknowledgements

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