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Chapter 12: Neurotransmitter and Cell Death

Pramod Dash, Ph.D., Department of Neurobiology and Anatomy, The UT Medical School at Houston


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Brain tissue is composed of neurons and other supporting cells, such as glia. Neurons in the brain are interconnected to make functional circuits.  If these connections are interrupted as a result of trauma, brain function is impaired.  Neurons are post-mitotic and therefore cannot divide to produce new neurons making neuronal loss as a result of trauma profoundly detrimental to normal brain function. At present, there is no effective therapy available to treat victims of brain trauma.

12.1 Epidemiology and Demographics

Traumatic brain injury (TBI) remains the leading cause of death and disability for those under the age of 44 years.  It has been estimated that nearly 2 million people suffer some degree of head injury every year in the United States alone.  Although the vast majority of these do not seek medical treatment, approximately 400,000 to 500,000 TBI victims require hospitalization.

In the US, the societal cost for TBI has been estimated at between $48 and $83.5 billion per year.  Only 12.5% of the annual financial expense is accounted for by direct cost (e.g. hospitalization, physician costs).  Since most TBI patients are young and in their peak productive years, the indirect costs (reduced or loss of productivity) represent the greatest loss to society.  The behavioral and psychological difficulties experienced by some patients are reported as being devastating not only to the patient but to the family and society as well.

Age: TBI most commonly occurs among infants and children, individuals 15 to 29 years of age, and the elderly (65+).
Sex: The male to female incidence of TBI has been estimated to be 2 to 1.

12.2 Types of Brain Injury

According to the most recent statistics from the National Institutes of Health (NIH), the major cause of TBI is vehicular accidents, violent acts, falls, and sports-related injury.  A head injury is usually a brief event occurring in less than 200 msec.  Traumatic brain damage is a result of (immediate mechanical damage of brain tissue, or primary injury) and indirect (delayed or secondary injury) processes.  The primary injury can be lessened through preventative measures, such as education of potential victims (e.g. don’t drink and drive), use of safety equipment (airbags, helmets) and enforcing laws for individual and public safety.  In contrast, secondary injuries are potentially amenable to therapeutic interventions because of their delayed onset and progression over minutes to months after the initial trauma.  Unfortunately, no effective treatments to abate secondary injuries are currently available
Brain trauma can be broadly divided into three categories.

Inertia injury. (e.g. sudden acceleration or deceleration) Inertial injuries are commonly associated with Diffuse Axonal Injury (DAI).  Axons are highly vulnerable to damage following closed head inertia injury.  Axonal swelling and disconnection can be seen in mild, moderate and sever TBI patients.  A subset of axons undergo axotomy as a result of primary injury, however, the majority undergo progressive changes leading to secondary axotomy.  TBI causes local mechanical and/or biochemical disruption of the axonal cytoskeleton. This causes axonal swelling due to continued delivery of organelles to the site of injury.  This continued swelling results in the disconnection of proximal axon bulb (referred to as retraction bulb) from its distal axonal segment.  Over time the distal axonal segment undergoes Wallerian degeneration, with the downstream deafferentation of the target site. 

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Figure 12.1
Formation of retraction bulb following stretch injury.

Impact injury. (e.g. getting hit with a baseball bat) Impact injuries are often accompanied by the formation of hematomas.

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Figure 12.2
Epidural hematoma following TBI.

Penetrating injury. (e.g. gun shots) Penetrating injuries are commonly associated with post-traumatic epilepsy.

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Figure 12.3
Schematic drawing of Phineas Gage.

12.3 Classification

Table I
Glasgow Coma Scale
Eye Opening
  • Spontaneously
  • To verbal command
  • To pain
  • No response

4
3
2
1

Best motor response
  • To verbal command
  • Localizes pain
  • Flexion - withdrawal
  • Flexion - abnormal
  • Extension
  • No response
6
5
4
3
2
1
Best verbal response
  • Oriented and converses
  • Disoriented and converses
  • Inappropriate words
    Incomprehensible words
  • No response
5
4
3
2
1
Total Glasgow Coma Score (GCS) 3-15

The Glasgow coma scale (GCS) is a means of grading severity in TBI and is based on the patient's response to eye opening, best motor response and best verbal response. 

The Glasgow coma score is calculated from the scale and ranges from 3 to 15.  Head injured patients are classified as having mild TBI if their GCS score is 13 to 15; a moderate injury if the GCS is 9 to 12, and a severe injury if their GCS score is 3 to 8. 

12.4 Clinical Presentation

Cognitive and behavioral disturbances are the primary contributors to disability in about two thirds of TBI patients.  In the other one third of the patients, motor deficits and other neurophysical sequelae contribute equally or more as compared to neuropsychological sequelae.  Neuropsychological deficits following TBI is related to the region of cerebral damage.  Diffuse cerebral damage to temporal, frontal, orbital and parietal regions result in cognitive impairments, involving memory, attention, information processing speed, intellectual functioning, language, executive functions and visuospatial ability.

Level of consciousness and orientation. Loss of consciousness is the clinical hallmark of head injury and reflects both the amount of brain damage and its distribution.  In its mildest degree, a concussion may be expressed by the subject’s awareness and memory without loss of consciousness (e.g. a football player's "dings").  "Coma" is applied to more profound impairments of consciousness.  An altered level of consciousness may occur in the acute stage following TBI as a result of a diffuse injury to the cerebral hemispheres or damage to the brainstem reticular formation.  Altered consciousness is often accompanied by confusion and disorientation.  Orientation is assessed by asking the patient his name, the date [day of week, month, year] and location [city, name of the hospital, floor number, room number, etc.].

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Figure 12.4
Drawing of a brain showing components of the limbic system.

Memory and temporal lobe damage.  Memory is the most severely affected and most frequently reported symptom by TBI patients and their relatives.  Anterograde amnesia (impairment in ability to recall newly acquired information) as well as retrograde amnesia (impairment in ability to recall old memories) is observed.  Anterograde amnesia is frequently referred to as post-traumatic amnesia (PTA).  In patients with diffused TBI, PTA is thought to be a reliable index of the severity of injury.  PTA is defined as the approximate time post-trauma when the patient establishes memory of day-to-day ongoing events.  If PTA is less than 1 hour, the injury is assumed to be mild; if less than 24 hours, it is moderate; more than 24 hours but less than one month, the injury is severe; and when PTA is greater than 1 month, the injury is thought to be extremely severe.  The longer the duration of PTA, the more likely the patient has significant neurological disability, especially with regard to cognitive function.  Memory impairments may impact a patient's progress in a rehabilitation program, especially if the ability to learn new information is affected.  Damage to the temporal lobe, especially the hippocampus, is associated with memory impairments.  As will be discussed later, neurons in the hippocampus express high levels of glutamate receptors and often die as a result of TBI.

Attention, concentration, executive functions, behavioral disturbance and frontal lobe damage. The frontal lobe comprises a vast expansion of cortex and white matter anterior to the central sulcus.  Humans have a tremendous increase in volume of the prefrontal region compared with other higher primates.  Damage to the frontal lobe can compromise complex decision-making, foresight and social conduct. Attention and concentration difficulties are the second most frequently reported complaint of TBI patients with frontal lobe injuries.  Patients who have mild injury usually recover from attention deficits within three months, in contrast to those with severe injuries, who may have more permanent deficits.  Slowing of cognitive function and distractibility are also common findings.  Mild TBI patients, although they perform well on standard ability tests, report that cognitive tasks demand more effort than prior to the injury.  Attention and concentration may be informally evaluated during the course of the patient examination.  Patients may have difficulty attending to the interview and may be easily distracted by external stimuli such as hallway activity.  Speed of cognitive processing may also be grossly assessed by noting the patient's response time to questions or commands.

Executive functions are a type of brain function that motivates self initiated behavior and govern its appropriateness.  Executive functions are needed for problem solving, planning and decision-making and damage to prefrontal cortex can cause deficits in these functions.   Furthermore, verbal fluency, hypothesis generation, use of feedback and shift of strategies are also impaired.

Behavioral disturbances are a common manifestation after severe brain injury, with personality change, slowness, irritability, bad temper, fatigue, rapid mood change and depression.  The orbital frontal regions have been implicated in impulsivity, anger control, aggressiveness, sexual acting out and social judgment.  Damage to orbital frontal region can cause release of previously inhibited behaviors and impair the ability to interpret social signals.

Visual disturbances and occipital lobe damage.  The occipital lobes are the posterior part of hemispheres, and can be divided into the primary visual cortex and visual association cortices.  Damage to these areas will alter visual perception.

Neglect and parietal lobe damage.  Neglect refers to a phenomenon in which a patient fails to attend to a portion of extrapersonal or intrapersonal space.  In the visual modality, in which neglect is most often manifested, the patient may fail to attend to the left hemispace, ignoring objects, persons, and movements that occur in the left side.  Such a presentation is commonly caused by lesion in the right parietal and occipitoparietal region.  Severe neglect often occurs in the acute stage of brain injury, often in the first few days or weeks after the onset of brain damage.  Several months after the onset of the lesion, most patients have recovered substantially, although subtle attentional deficits for the left-sided stimuli may still persist. Focal injury to the dominant parietal lobe may result in impairment of mathematical skills.  Deficits may limit the patient in his ability to manage finances or participate in basic community activities, such as shopping.  Calculation skills can be easily assessed by having the patient perform serial subtraction of sevens from one hundred, although more complex multiplication and division problems can also be administered. However, one must take pre-morbid educational history into account when interpreting the results of these tests.

Speech and language.  Language skills are commonly impaired following TBI that involve the dominant hemisphere.  Difficulty with spoken and written language or problems with language processing can occur.  Language deficits are usually accompanied by other cognitive impairments.  The most common feature of traumatic aphasia is anomia, which is characterized by difficulty in naming, word-finding deficits, and paraphasic errors.  Broca's aphasia is more common in a penetrating-type injury due to a lesion of the dominant frontal lobe. Wernicke's aphasia occurs less frequently following TBI and is caused by focal injury to the dominant temporal lobe.  Higher language skills such as complex auditory processing, spelling, sentence construction, synonyms, antonyms, and abstract language skills, such as picture description, can be impaired. 

Depression.  Depression occurs frequently after brain injury.  TBI patients who experience depression may report worry, hopelessness, suicidal thoughts, and social withdrawal.  It is likely that there are direct and indirect factors related to the development of depression in brain-injured persons.  Brain damage can produce direct neurophysiological and neurochemical changes that may induce depressive symptomatology.  The secondary reaction of the patient to the implications of newly acquired disabilities certainly is a frequent and understandable source of depression.

Cranial nerve damage.  TBI can damage one or more of the cranial nerves resulting in specific deficits. Olfactory dysfunction occurs in approximately 7% of patients with TBI.  This figure approaches 20% in TBI patients who have suffered from loss of consciousness.  Furthermore, the olfactory nerve is the most commonly affected cranial nerve in mild TBI.  Impairment in detection of smell is usually caused by frontal or occipital blows causing direct injury to the olfactory pathways.  Olfactory dysfunction can lead to functional impairment, including diminished pleasure and potential safety problems due to inability to detect dangerous smells such as gas. 

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Figure 12.5
Olfactory nerve damage following TBI.

Post-traumatic epilepsy.  Epileptic seizures occur in 2.5 to 5% of patients with traumatic brain injury.  In 1930, Foerester and Penfield induced seizure activity by electrical stimulation of areas surrounding a gunshot lesion of cerebral cortex.  These findings suggested the presence of an epileptic zone or penumbra surrounding the site of injury.  Furthermore, retraction of dura that had become adherent to the damaged cortex also triggered seizures.  This hypothesis is supported by clinical findings that head injuries associated with dural penetration are associated with the highest incidence of post-traumatic epilepsy (27 to 43%).  An intriguing hypothesis of post- traumatic epilepsy has been the implication of blood breakdown products in the cellular events that lead to epileptogenesis.  An important role for iron deposition has been supported by experimental studies in animals.  Another possibility is that TBI can create imbalances between neuronal excitation and inhibition that can lead to post-traumatic epileptogenesis. 

TBI is a risk factor for Alzheimer’s disease.  Epidemiological studies have suggested that head injury may be a risk factor for Alzheimer’s disease.  Histopathological examination of brains from patients who died as a consequence of head trauma has shown amyloid beta (Ab) deposition.  It is also interesting to note that demential pugilistica (punch-drunk syndrome) is also associated with memory loss and diffuse Ab deposition.  Carriers of the apolipoprotein E4 (apoE4) allele, which may play a direct role in Ab deposition in vivo, have been shown to be an increase risk factor for developing Alzheimer’s disease.  Head-injured patients with apoE4 are more than twice as likely as those without apoE4 to have an unfavorable outcome.

12.5 Molecular Mechanisms of Secondary Injury

As indicate above, traumatic injury to the central nervous system is a progressive disorder with two distinct components.  The initial, immediate biomechanical damage (referred to as primary injury) is defined as structural damage to neurons, their supporting cells and vasculature.  Secondary injury consists of progressive cellular damage resulting from degradative biochemical processes that occur as a response to the primary injury.  The recognition of secondary injury as a progressive biochemical disorder implies that a window of time exists in which effective pharmacotherapy could be administered.

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Figure 12.6
Transport of ions through a NMDA receptor

Excitatory amino acid receptors.  Levels of extracellular excitatory amino acids (e.g. glutamate and aspartate) are increased following brain trauma.  These neurotransmitters activate specific cell surface receptors causing influx of sodium and calcium ions into the cytosol.  Glutamate is the most abundant excitatory neurotransmitter in the central nervous system.  Binding of glutamate to NMDA receptors allows influx of sodium and calcium ions into neurons.  Influx of sodium leads to neuronal swelling and increase intracellular calcium causes cell death.  Antagonists for NMDA and non-NMDA receptors have been shown to be neuroprotective in experimental TBI. Clinical trials using excitatory amino acid blockers, however, have shown discouraging results and unwanted side effects, namely psychotropic problems. 

Calcium ions.  Among ions, calcium has drawn the most attention.  This ion has been implicated in cerebral edema, vasospasm and cell death following injury to the CNS.  Increases in intracellular calcium can occur via multiple pathways including, NMDA receptors, calcium channels and release of calcium from intracellular stores.  Sustained elevations of intracellular calcium are toxic.  The molecular events triggered by elevated calcium include activation of proteases, lipases, generation of free radicals and impairment of mitochondrial function leading to energy failure. 

Proteolytic mechanisms of cell death.  The calpain family of proteases are activated by elevated intracellular calcium.  Calpains proteolyze many cellular proteins including cytoskeletal proteins, excitatory amino acid receptors, cell adhesion molecules and enzymes.  Breakdown of these proteins causes irreversible structural and functional alterations leading to cellular necrosis.  Another family of proteases, the caspases, also cause cell death following CNS injury.  Caspases are involved in neuronal apoptosis.  Apoptosis differs from necrosis in that cell lysis does not occur and is a relatively slower process of cell death.

Phospholipases. Elevated intracellular calcium phospholipases, enzymes that degrade membrane lipids, increase following TBI.  Breakdown of membrane lipids (notably by phospholipase A2) result in loss of cellular integrity, ionic imbalance and cell death. 

Free radicals.  Free radicals are highly reactive molecules that damage neuronal, glial and vascular membrane phospholipids and cause oxidation of cellular proteins and nucleic acids.  The brain appears to be particularly vulnerable to such oxidative injury.  It contains relatively high concentrations of readily peroxidizable fatty acids.  Furthermore, the brain is poorly supplied with protective antioxidant enzymes and endogenous antioxidant compounds.  Free radicals cause widespread cellular and vascular damage.  Potential sources of oxygen free radicals within the injured brain include mitochondrial leakage, arachidonic acid metabolism, xanthine oxidase pathway and catecholamine oxidation.  Several drugs have been tested for their ability to protect free radical-mediated damage.  Superoxide dismutase (SOD) and its polyethylene glycol-conjugate (PEG-SOD), which has a longer biological half life, has been shown to be neuroprotective in experimental models.  However, a multi-center study did not show a significantly improved outcome in patients who received PEG-SOD compared to those who received placebo. 

Secondary Injury. The pathology of TBI reflects the initial insult, resulting from mechanical damage to neural and vascular structures (the primary injury), and the evolution of a cascade of secondary events that impair function, damage structures, and promote further cell death collectively referred to as secondary injury. Secondary injury encompasses a number of pathological processes that can continue to evolve over a period of days, weeks or even months, after the primary insult.  For example, neurons in the CNS that are synaptically connected not only release neurotransmitters but also neurotrophic factors (e.g. BDNF) that are critical for their survival.  Damage to the axon of a neuron as a result of primary injury leads to its degeneration disconnection from the post-synaptic neuron.  This results in reduced availability of neurotrophic factors leading to eventual degeneration (via apoptosis or programmed cell death) of the post-synaptic neuron.  Since secondary injuries evolve over time after the primary injury, they may provide a window of opportunity for therapeutic intervention.

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Figure 12.7
Delayed cell death following TBI.

12.6 Spinal Cord Inujry (SCI)

Traumatic injury to the spinal cord causes loss of sensory and motor function distal to the point of injury.  There are approximately 400,000 patients with SCI in the US.  The leading causes of SCI are motor vehicle accidents, violent acts and sports-related injuries, especially diving accidents.  The majority of the victims are typically between the ages of 16 and 25 years. 

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Figure 12.8
Biomechanics of cervical SCI.

 

Figure 12.9
Myotome chart.

Pathophysiology of SCI. The pathophysiology of SCI can be divided into three phases: Primary, secondary and chronic processes.  Primary injury results mainly from mechanical damage, while secondary process involves apoptotic cell death, release of growth inhibitory molecules and glial scar formation.  Chronic pain syndrome develops usually within several months to years following injury.  This pain profoundly affects the quality of life.

Targets for Intervention. The most immediate intervention in SCI treatment is patient stabilization and decompression of the vertebral columns to prevent further trauma.  An acute treatment recommended by the National Acute Spinal Cord Injury Study is administration of a high dose of methylprednisolone (MP), a steroid, within eight hours of injury.  MP is thought to decrease edema, inflammatory response and/or free radical production.  Many axons are demyelinated as result of secondary injury.  Voltage-gated potassium channel blocker 4-aminopyridine (4-AP) looks extremely promising in clinical trials.  Application of 4-AP blocks potassium channels and partially restores action potential conduction properties. 

12.7 Future Directions

Molecular and genetic strategies may represent new avenues for future clinical trials.  The following processes have to succeed for recovery of neuronal functions following brain trauma.

  1. Survival of injured neurons
  2. Growth of severed axons through the glial scar
  3. Guidance of regenerating axons towards their targets
  4. Reinnervation of appropriate targets

 

Test Your Knowledge

  • Question 1
  • A
  • B
  • C
  • D
  • E

An elderly person suffered relatively mild head trauma, but subsequently developed a progressive dementia over the course of several weeks, is most likely to have sustained which of the following?

A. An acute subdural hematoma

B. An acute epidural hematoma

C. A chronic subdural hematoma

D. An intracerebral hematoma

E. An intracerebellar hematoma

An elderly person suffered relatively mild head trauma, but subsequently developed a progressive dementia over the course of several weeks, is most likely to have sustained which of the following?

A. An acute subdural hematoma This answer is INCORRECT.

B. An acute epidural hematoma

C. A chronic subdural hematoma

D. An intracerebral hematoma

E. An intracerebellar hematoma

An elderly person suffered relatively mild head trauma, but subsequently developed a progressive dementia over the course of several weeks, is most likely to have sustained which of the following?

A. An acute subdural hematoma

B. An acute epidural hematoma This answer is INCORRECT.

C. A chronic subdural hematoma

D. An intracerebral hematoma

E. An intracerebellar hematoma

An elderly person suffered relatively mild head trauma, but subsequently developed a progressive dementia over the course of several weeks, is most likely to have sustained which of the following?

A. An acute subdural hematoma

B. An acute epidural hematoma

C. A chronic subdural hematoma This answer is CORRECT!

Chronic subdural hematoma is relatively common in elderly and in patients receiving renal dialysis. Subdural hematoma can be identified on CT scanning or by MRI.

D. An intracerebral hematoma

E. An intracerebellar hematoma

An elderly person suffered relatively mild head trauma, but subsequently developed a progressive dementia over the course of several weeks, is most likely to have sustained which of the following?

A. An acute subdural hematoma

B. An acute epidural hematoma

C. A chronic subdural hematoma

D. An intracerebral hematoma This answer is INCORRECT.

E. An intracerebellar hematoma

An elderly person suffered relatively mild head trauma, but subsequently developed a progressive dementia over the course of several weeks, is most likely to have sustained which of the following?

A. An acute subdural hematoma

B. An acute epidural hematoma

C. A chronic subdural hematoma

D. An intracerebral hematoma

E. An intracerebellar hematoma This answer is INCORRECT.

 

 

 

 

 

 

 

 

 

  • Question 2
  • A
  • B
  • C
  • D
  • E

In automobile accidents, collision with the windshield at high speed is highly likely to produce an intracranial hemorrhage in which one of the following structures?

A. Occipital

B. Thalamus

C. Putamen

D. Parietal lobe

E. Temporal lobe

In automobile accidents, collision with the windshield at high speed is highly likely to produce an intracranial hemorrhage in which one of the following structures?

A. Occipital This answer is INCORRECT.

B. Thalamus

C. Putamen

D. Parietal lobe

E. Temporal lobe

In automobile accidents, collision with the windshield at high speed is highly likely to produce an intracranial hemorrhage in which one of the following structures?

A. Occipital

B. Thalamus This answer is INCORRECT.

C. Putamen

D. Parietal lobe

E. Temporal lobe

In automobile accidents, collision with the windshield at high speed is highly likely to produce an intracranial hemorrhage in which one of the following structures?

A. Occipital

B. Thalamus

C. Putamen This answer is INCORRECT.

D. Parietal lobe

E. Temporal lobe

In automobile accidents, collision with the windshield at high speed is highly likely to produce an intracranial hemorrhage in which one of the following structures?

A. Occipital

B. Thalamus

C. Putamen

D. Parietal lobe This answer is INCORRECT.

E. Temporal lobe

In automobile accidents, collision with the windshield at high speed is highly likely to produce an intracranial hemorrhage in which one of the following structures?

A. Occipital

B. Thalamus

C. Putamen

D. Parietal lobe

E. Temporal lobe This answer is CORRECT!

The temporal lobes and the inferior frontal lobes are frequently involved in traumatic brain injury. The continued forward movement of the brain within the bony cranial vault which has suddenly decelerated at impact leads to these anterior brain structures striking the inside of the skull with great force creating contusion in these areas.

 

 

 

 

 

 

 

 

 

 

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