Tbi powerpoint for class 2

Blast-related TBI and Psychopharmacological Treatment

Gerd R. Naydock, MSS, LSWPhiladelphia College of Osteopathic Medicine

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

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.

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.

Rotational Acceleration

Rocket-Propelled Grenades

Video – Blast Injuries

• http://www.youtube.com/watch?feature=player_detailpage&v=4JAHBKe_RAU

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.

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.

Chronic Post-Concussive Symptoms

• These symptoms can be grouped into three categories: somatic (headache, tinnitus, vertigo, insomnia, etc.), cognitive (memory, attention and concentration difficulties and emotional/behavioral (irritability, depression, anxiety, behavioral dyscontrol).

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.

Video – Mild TBI - Magnetoencephalography

• http://www.youtube.com/watch?v=uhlANIGAJXA

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

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.

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.

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.

Diffusion Tensor Imaging

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.

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.

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.

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.

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)

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.).

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

Approach to Cognitive Deficits

• Main target domains:– Memory

• Particularly working memory

– Attention– Executive Functions

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)

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.

MT

FC = Frontal cortex

PC = Parietal cortex

OC = Occipital cortex

H = Hippocampus

M = Medial septal nucleus and diagonal band of Broca

T = Diagonal band of Broca projecting into the olfactory tubercle

B = Nucleus basalis of Meynert

Acetylcholine Pathways

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

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

Neuropathology of Aggression• Hypothalamus

Orchestrates neuroendocrine response to sympathetic arousalMonitors internal status

• Limbic systemAmygdala

Activates and/or suppresses hypothalamusInput from neocortex

Temporal cortexAssociated with aggression on both ictal and interictal status

• Frontal neocortexModulates limbic and hypothalamic activityAssociated with social and judgment aspects of aggression

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.

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)

Why Target Apathy?

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