The Dark Side of Addiction: The Intersection of TBI, PTSD, and Alcoholism George F. Koob, Ph.D. Director National Institute on Alcohol Abuse and Alcoholism National Institutes of Health

Conceptual Framework for Neurobiological Bases of the Transition to Excessive Drinking KoobGCNADdia2c020613jh

Brain Arousal-Stress System Modulation in the Extended Amygdala  Corticotropin-releasing factor  Neuropeptide Y Norepinephrine Nociceptin (orphanin FQ) Dynorphin  Endocannabinoids Vasopressin Orexin (hypocretin) Substance P Dynorphin 101314 Koob NIAAA.pptx 101314 Koob NIAAA brain2.ai See KoobGCNADdia9c012508jh From: From: Koob, GF 2008 Neuron 59:11-34 and George O, Koob GF. Proc Natl Acad Sci USA, 2013, 110:4165-4166.

Brain Circuitry Involvement in PTSD SENSORIMOTOR CORTEX Function: Coordination of sensory and motor functions In PTSD: Symptom provocation results in increased activation ANTERIOR CINGULATE CORTEX Function: Autonomic functions, cognition In PTSD: Reduced volume, higher resting metabolic activity PREFRONTAL CORTEX Function: - Emotional regulation In PTSD: - Decreased gray and white matter density - Decreased responsiveness to trauma and emotional stimuli THALAMUS Function: Sensory relay station In PTSD: Decreased cerebral blood flow PARAHIPPOCAMPAL GYRUS Function: Important for memory encoding and retrieval In PTSD: Show stronger connectivity with medial prefrontal cortex; decreases in volume ORBITOFRONTAL CORTEX Function: Executive function In PTSD: Decreases in volume KoobG/CNAD/sca1/032713jh FEAR RESPONSE Function: - Evolutionary survival In PTSD: - Stress sensitivity - Generalization of fear response – Impaired extinction HIPPOCAMPUS Function: - Conditioned fear - Associative learning In PTSD: - Increased responsiveness to traumatic and emotional stimuli AMYGDALA Function: - Conditioned fear - Associative learning In PTSD: - Increased responsiveness to traumatic and emotional stimuli From: Mahan AL, Ressler KJ. Trends Neurosci, 2012, 35:24-35.

Neural Circuits of the Preoccupation/Anticipation “Craving” Stage In PNAS, Hayashi et al. (1) unveiled some of the neuropsychological mechanisms responsible for self-control by demonstrating that inactivation of the dorsolateral prefrontal cortex (dlPFC) decreases the craving that a smoker experiences when told that he will be able to smoke a cigarette a few minutes later, through inhibition of the process of valuation of drug-related stimuli mediated by the medial orbitofrontal cortex (mOFC), anterior cingulate cortex (ACC), and ventral striatum (VS). A two-stage process of cue reactivity was proposed by Hayashi et al., in which the mOFC tracks the subjective value of the drug, indexed by craving self-reports, and the DLPFC incorporates intertemporal availability and cue information to modulate the presumed mOFC value signal. Executive Dysfunction • impulsivity • compulsivity • sleep disturbances • impaired decision making From: George O, Koob GF. Proc Natl Acad Sci USA, 2013, 110:4165-4166.

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