The Dark Side of Addiction: The Intersection of TBI, PTSD, and

Alcoholism

George F. Koob, Ph.D.Director

National Institute on Alcohol Abuse and AlcoholismNational Institutes of Health

Conceptual Framework for Neurobiological Basesof the Transition to Excessive Drinking

Brain Arousal-Stress System Modulationin the Extended Amygdala

From: From: Koob, GF 2008 Neuron 59:11-34 and George O, Koob GF. Proc Natl Acad Sci USA, 2013, 110:4165-4166.

Corticotropin-releasing factor

Norepinephrine

Vasopressin

Orexin (hypocretin)

Dynorphin

Neuropeptide Y

Nociceptin (orphanin FQ)

Substance P

Endocannabinoids Dynorphin

From: Mahan AL, Ressler KJ. Trends Neurosci, 2012, 35:24-35.

Brain Circuitry Involvement in PTSD

SENSORIMOTOR CORTEXFunction: Coordination of sensory and motor

functionsIn PTSD: Symptom provocation results in

increased activation

THALAMUSFunction: Sensory relay stationIn PTSD: Decreased cerebral blood flow

PARAHIPPOCAMPAL GYRUSFunction: Important for memory encoding and

retrievalIn PTSD: Show stronger connectivity with

medial prefrontal cortex; decreases in volume

ANTERIOR CINGULATE CORTEXFunction: Autonomic functions, cognitionIn PTSD: Reduced volume, higher resting

metabolic activity

ORBITOFRONTAL CORTEXFunction: Executive functionIn PTSD: Decreases in volume

PREFRONTAL CORTEX

Function: - Emotional regulation

In PTSD: - Decreased gray and white

matter density- Decreased responsiveness to

trauma and emotional stimuli

AMYGDALA

Function: - Conditioned fear- Associative learning

In PTSD: - Increased responsiveness to

traumatic and emotional stimuli

HIPPOCAMPUS

Function: - Conditioned fear- Associative learning

In PTSD: - Increased responsiveness to

traumatic and emotional stimuli

FEAR RESPONSE

Function: - Evolutionary survival

In PTSD: - Stress sensitivity- Generalization of fear response– Impaired extinction

Neural Circuits of the Preoccupation/Anticipation “Craving” Stage

From: George O, Koob GF. Proc Natl Acad Sci USA, 2013, 110:4165-4166.

Executive Dysfunction• impulsivity• compulsivity• sleep disturbances• impaired decision making

Interaction of Traumatic Brain Injury (TBI) and Alcohol Use Disorders

• Studies suggest that both protective and deleterious effects of acute alcohol at the time of TBI.

• A history of alcohol abuse increases the severity of brain damage following TBI and the severity of long term cognitive impairments post TBI.

• A few human epidemiological studies in military personnel suggest that veterans with mTBI do abuse alcohol later in life but such data are complicated by comorbid conditions of PTSD and depression

• Increased post-TBI alcohol drinking is associated with sustained neuroinflammation and neuronal degeneration at the site of injury in animal models.

• Based on retrospective studies in military veterans, mild TBI seems to be a risk factor for developing PTSD

Mild TBI (mTBI) subjects typically remain conscious, and may experience symptoms such as headache, confusion, dizziness, memory impairment but without any physical disability. mTBI (which encompasses but is not limited to concussion) is the most frequent form of TBI among athletes sustaining injuries from contact sports.

Key Findings and Conclusions

Drug Addiction— represents a dysregulation of incentive salience (basal ganglia), reward/stress (extended amygdala) and executive function systems (frontal cortex)

PTSD— produces an activation of CRF, and dynorphin in the extended amygdala that parallels the stress-like responses and a negative emotional states associated with addiction and alcoholism

TBI— produces frontal cortex damage that parallels frontal cortex dysfunction observed in PTSD

Brain Specific Neurochemical Neurocircuitry—encodes stress and unpleasant emotions that when dysregulated form common elements of co-morbidity in addiction, anxiety and TBI disorders