1. Blast-related TBI and Psychopharmacological Treatment
Gerd R. Naydock, MSS, LSW
Philadelphia College of Osteopathic Medicine

2. Traumatic Brain Injury
• Generally defined as a physiologically significant
disruption of brain functioning subsequent to
the application of external forces, including
acceleration/deceleration forces which cause
damage to brain structures.
• American Congress of Rehabilitation Medicine, 1993

3. Blast –related TBIs in OEF/OIF
Veterans
• Increased frequency of blast-related TBI
compared to previous military conflicts.
• Use of Improvised Explosive Devices (IEDs)
and Rocket-Propelled Grenades (RPGs) by
enemy combatants.
• TBI s account for one-fourth of the medical
evacuations in Iraq and Afghanistan.
• Improved equipment and post-trauma medical
treatment enhance survivability.

4. Types of Blast Injuries
• Primary – Occur as rapid changes in
atmospheric pressure force rotational
acceleration of the brain within the cranium.
• Secondary – Occurs from fast-moving ballistic
objects which as a result of an explosion strike
and often penetrate skull.
• Tertiary – Individuals are picked up and thrown
by the blast.

6. Rotational Acceleration

7. Rocket-Propelled Grenades

9. Video – Blast Injuries
• http://www.youtube.com/watch?feature=
player_detailpage&v=4JAHBKe_RAU

10. Mild TBI
• Mild traumatic brain injury is defined as a loss or
alteration of consciousness < 30 minutes, post-
traumatic amnesia < 24 hours, focal neurologic deficits
that may or may not be transient, and/or Glasgow
Coma Score (GCS) of 13-15.
• By definition, a mild traumatic brain injury typically
involves symptoms of brain damage but no sign of
damage based on a neurological exam.
• Controversy over whether primary blast injuries
damage brain. Animal models suggest they do.

11. Mild TBI - Symptoms
• Headache, dizziness, insomnia, impaired
memory and/or lowered tolerance for noise and
light. In most cases of mTBI the patient returns
to their previous level of function within 3 to 6
months
• 10-15% of patients may go on to develop
chronic post-concussive symptoms.

12. Chronic Post-Concussive
Symptoms
• These symptoms can be grouped into three
categories: somatic
(headache, tinnitus, vertigo, insomnia, etc.), cogn
itive (memory, attention and concentration
difficulties and emotional/behavioral
(irritability, depression, anxiety, behavioral
dyscontrol).

13. Comorbid Psychiatric Disorders
• Patients who have experienced mTBI are also at
increased risk for psychiatric disorders compared
to the general population, including depression
and PTSD.

14. Video – Mild TBI - Magnetoencephalography
• http://www.youtube.com/watch?v=uhlANIGA
JXA

15. Neurobiological Changes after TBI
• The principal neurobiological consequences of TBI are:
– cortical contusions (mostly in severe TBI)
• results in a loss of function served by that area
– white matter lesions
• results in interruption of information processing between cortical
areas
– diffuse axonal injury
• results in slowed and inefficient information processing
• disproportionately affects glutamatergic and cholinergic projections
– results in problems with attention, memory, and various aspects of
frontally-mediated cognition (ie, working memory, executive function)
• may affect serotonergic systems
• dysfunction in these systems may secondarily affect the efficiency of
function in dopaminergic or noradrenergic systems

16. Diffuse Axonal Injuries
• Damage to the pathways (axons) that connect
the different areas of the brain. This occurs
when there is twisting and turning of the brain
tissue secondary to unrestricted head movement
at the time of blast.
• Affects white matter of the cerebrum, corpus
callosum, deep gray matter, internal capsule,
upper brainstem and the cortico-meullary (gray-
white matter) junctions of cerebral cortex.

17. Diffuse Axonal Injuries
• Damage to rats’ axonal cytoskeleton results in
loss of their elasticity and impaired transport
and accumulation of axonal transport proteins
within axonal swellings.
• Axonal swellings are caused by damage to
sodium and calcium ion channels and can lead
to dysfunction of the mitochondria.

18. Secondary Neurological Injury
• With the progression of time, axons can become
disconnected within the white matter of the
brain which will lead to chronic neurological
impairment for the individual affected.

21. Diffusion Tensor Imaging

22. Secondary & Tertiary Blast
Injuries
• Responsible for the majority of
macroscopic, focal, brain injuries.
• Include, cerebral contusions, edema and
hematomas.
• Significant axonal damage when compressed
within brainstem. Leads to coma.

23. Symptoms of Secondary and
Tertiary Blast Injuries
• Cranial Nerve Dysfunction –
opthalmopareses, olfactory and gustatory
problems, dysphagia and vestibulopathy.
• Psychomotor – Involuntary
movements, spastisity, tremors and dyspraxia.

24. Symptoms of Secondary &
Tertiary Blast Injuries
• Cognitive – gross memory loss and orientation.
• Behavioral – Agitation, aggression and other
inappropriate and extreme bxs which stem from
disinihibition. Usually caused by damage in the
hippocampus, prefrontal cortex, frontolimbic
pathways. Abnormal serotonergic modulation
contributes to this.

25. Cognition
• Cognitive Impairments constitute the most
common chronic sequelae of blast-related
TBI.
• Cognitive functioning is highly dopamine
dependent and TBI is usually associated
with decreased dopaminergic activities in
the striatum, large areas of the cerebral
cortex to include the caudate nucleus and
mediofrontal cortex.

26. Cognition
• Many neurotransmitters are involved in the
regulation of cognition
• Several neurotransmitters are particularly
relevant to the regulation of frontal and
frontotemporal structures involved in cognition:
– dopamine
– norepinephrine
– serotonin
– acetylcholine
– glutamate gamma-aminobutyric acid (GABA)

27. Psychopharmacology
• At present, there are no FDA approved
treatments for cognitive, emotional, or
behavioral impairment due to TBI
• Pharmacotherapies are generally modeled
after those for patients with
phenomenologically similar but
etiologically distinct disorders (i.e.,
attention-deficit hyperactivity disorder,
Alzheimer’s disease, etc.).

28. Psychopharmacology Issues
• Medication approaches generally take
three broad approaches:
– amelioration of psychiatric complications
– amelioration of specific somatic symptoms
(e.g., headache, dizziness, sleep
disturbances)
– augmentation of cognition

29. Approach to Cognitive Deficits
• Main target domains:
– Memory
• Particularly working memory
– Attention
– Executive Functions

30. Dopamine Agonists
• A variety of agonists have been shown
effective in animal models and are used
clinically:
– Methylphenidate (most widely studied)
(stimulant)
– Amantadine ( >pre- & post-synaptic dopamine
in striatum) (non-stimulant)
– Bromocriptine (presynaptic D2 agonist) (non-
stimulant)

33. Cholinergic Augmentation
• Multiple studies demonstrate that cholinergic
augmentation, generally using one of several
cholinesterase inhibitors (e.g., physostigmine,
donepezil) can improve arousal, processing
speed, and sustained attention/vigilance even
in the late post-injury period (>1 year) in
some TBI survivors
• Hypocholinergic activity results in learning and
memory impairments and decreased arousal.

34. Acetylcholine Pathways
FC = Frontal cortex
PC = Parietal cortex
OC = Occipital cortex
H = Hippocampus M
T
M = Medial septal nucleus and
diagonal band of Broca
T = Diagonal band of Broca
projecting into the olfactory
tubercle
B = Nucleus basalis of Meynert

35. Aggression & TBI
• Acute phase: 35% - 96% of patients exhibit
agitated behaviors
– 89 patients assessed during the first six months after
TBI, aggressive behavior found in 33.7% of TBI
patients, compared to 11.5% of patients with multiple
trauma but without TBI (Tateno et al)
• Recovery phase: 31% - 71% of patients with
severe TBI and 5% - 70% of patients with mild
TBI are agitated or irritable
• Irritability increases with more TBI’s

36. Aggression & TBI
• Reactive: Triggered by modest or trivial stimuli
• Nonreflective: Usually does not involve
premeditation or planning
• Nonpurposeful: Aggression serves no obvious
long-term aims or goals
• Explosive: Buildup is NOT gradual
• Periodic: Brief outbursts of rage and aggression,
punctuated by long periods of relative calm
• Ego-dystonic: After outbursts, patients are
upset, concerned, and/or embarrassed, as
opposed to blaming others or justifying behavior

37. Neuropathology of Aggression
• Hypothalamus
Orchestrates neuroendocrine response to sympathetic arousal
Monitors internal status
• Limbic system
Amygdala
Activates and/or suppresses hypothalamus
Input from neocortex
Temporal cortex
Associated with aggression on both ictal and interictal status
• Frontal neocortex
Modulates limbic and hypothalamic activity
Associated with social and judgment aspects of aggression

38. Beta Blockers
• Increases in norepinephrine, dopamine and
acetylcholine also increase violent behaviors in
animal models.
• Propranalol, pindolol etc. serve as antagonists
and block the action of epinephrine and
norepinephrine on beta 1 and beta 2 andrenergic
receptors exerting effects on the locus coerulus
– primary norandrenergic system in CNS.

39. Apathy
• Believed to be caused by cholinergic dysfunction
in the frontal lobe, particularly the nucleus
basalis, anterior cingulated gyrus as well as
subregions of the basal ganglia.
• Dysfunction of these pathways is linked to <
ability to discern emotional significance to
environmental stimuli.
• MAO B inhibitors raise dopamine levels in the striatal cortex.
(Rasagaline & Selegiline)

40. Why Target Apathy?

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