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Brain Injury and Addiction: What do we Know?

David M. Ledgerwood, Ph.D.

Department of Psychiatry & Behavioral Neurosciences

Wayne State School of Medicine

dledgerw@med.wayne.edu

Disclosures

•  None

Questions

•  Does traumatic brain injury increase risk for substance use?

•  Does substance use increase risk for traumatic brain injury?

•  How might substance use affect TBI severity? •  What are the implications for TBI recovery

among individuals with substance use problems? •  Are there specific factors that contribute to risk?

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Start with an easy question…

Does pre-TBI Substance Use Disorder Increase Risk for TBI?

Does pre-TBI Substance Use Disorder Increase Risk for TBI?

YES!

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Co-occurrence of TBI and history of SUD

•  Between 44% and 79% of people with TBI have a history of alcohol abuse/dependence

•  Between 21% and 37% of people with TBI have a history of substance abuse/dependence (Taylor et al., 2003)

Intoxication at Time of Injury

•  Out of 1248 TBI patients, 73% had detectable BAL with 53% beyond legal limit (Rimel et al., 1982)

•  Out of 2649 hospitalized or deceased individuals who sustained TBI, 49% had BAL above legal limit including 2/3 of MVA patients, and 60% of assaulted patients

•  Out of 1155 TBI cases, 58% had positive BAL and 84% of those were above 100 mg/dL (Kraus et al., 1981)

•  Additional smaller studies found similar rates of alcohol use and intoxication (Kreutzer et al., 1996; Corrigan et al., 2001)

•  Up to ¾ of TBI patients have positive BAL on admission and about half intoxicated (Taylor et al., 2003)

The BIG Question

Does TBI cause addiction?

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Answer: Mostly, ‘no’

•  Most studies examining the rates of substance abuse following TBI find that rates decline following TBI (See reviews by Bjork & Grant, 2007; Graham & Cardon, 2008; Parry-Jones et al., 2006; Taylor et al., 2003; and many others)

Date of download: 4/23/2014

Copyright © American Psychiatric Association. All rights reserved.

From: Axis I and II Psychiatric Disorders After Traumatic Brain Injury: A 30-Year Follow-Up Study

Am J Psychiatry. 2002;159(8):1315-1321. doi:10.1176/appi.ajp.159.8.1315

Koponen et al., 2002

Brain Injury, 2007

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The BIG Question

•  Does TBI cause addiction?

Wrong Question?

Challenges in Research on TBI as a Cause of SUD

•  Summarized by Bjork & Grant (2009) -  TBI is a heterogeneous diagnosis based on

subjective impression of severity -  Pre-injury history of SUD is suspected in up to 2/3

of cases -  Relationship between TBI, SUD and neurological

problems is not well characterized because of exclusion of substance abusing individuals

-  Predisposition to drug seeking may be masked by intensive monitoring or physical disability after TBI

Decreases may also be caused by…

•  Other factors also caused by the trauma (e.g., PTSD, depression, unemployment, marital discord, financial difficulties) may also contribute to SUDs

•  Recognition of the role played by substance in the accident/injury

•  Narrowing social life post-injury •  Decreased craving because of brain changes

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Heterogeneity of TBI: ���Can TBI Reduce the Severity of

Addiction?

Fig. 2. Patients who quit smoking after lesion onset and patients who underwent a disruption of smoking addiction after lesion onset.

N H Naqvi et al. Science 2007;315:531-534

Published by AAAS

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Fig. 3. Whole-brain region-by-region logistic regression analysis.

N H Naqvi et al. Science 2007;315:531-534

Published by AAAS

On the other hand…

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Mild TBI

•  Research on mTBI sometimes shows significant relationships between injury and addiciton

Date of download: 4/23/2014

Copyright © American Psychiatric Association. All rights reserved.

From: Risk for Addiction-Related Disorders Following Mild Traumatic Brain Injury in a Large Cohort of Active-Duty U.S. Airmen

Am J Psychiatry. 2013;170(4):383-390. doi:10.1176/appi.ajp.2012.12010126

Adjusted Hazard Ratios for Addiction-Related Disorders in Active-Duty U.S. Air Force Airmen With Mild Traumatic Brain Injury (TBI) and Other-Injured Comparison Subjectsaa Results were adjusted for sex, marital status, race/ethnicity, birth year, deployment, education, rank, and career field and for posttraumatic stress disorder, depression, and other mental disorders frequently comorbid with TBI. * Differences are statistically significant at an alpha level of 0.05. † The percentage of outcome in the comparison population was not sufficient to generate a hazard ratio with a 95% confidence interval.

Figure Legend:

Thus…

•  It is possible that the extent to which TBI leads to addictions is determined by a multitude of factors, including severity of injury and possibly specific mechanisms of function

•  Two important areas of function in addictions are the dopamine reward pathways of the limbic/striatal system and the executive function pathways of the frontal lobes

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What about specific mechanisms: Is it possible that SUDs may be caused by injury

to striatal reward pathways?

Striatal Reward Processes

•  A major process in addiction involves a compromising of the reward system through chronic underactivation of natural motivational systems (Koob & LeMoal, 2008).

•  Kalivas and Volkow (2005) - addictive disorders create a dysregulation of cellular and circuitry functions in the brain, such that nondrug motivational stimuli lose salience, decision making abilities are impaired and there is “profound activation of the prefrontal cortex and glutamatergic drive to the nucleus accumbens” when predicting drug availability.

An emergent dominant pattern of affective signaling can modulate activity of several components of the impulsive and reflective systems. These include regions involved in (i) representing patterns of affective states (e.g., the insula and somatosensory cortices); (ii) triggering of affective states (e.g., amygdala (A) and VMPC); (iii) memory, impulse and attention control (e.g., lateral orbitofrontal, inferior frontal gyrus and dorsolateral prefrontal (DLPC), hippocampus (Hip) and anterior cingulate (AC); and (iv) behavioral actions (e.g., striatum and supplementary motor area). 5-HT: serotonin; DA: dopamine. Bechara. (2005). Nature Neuroscience, 8, 1458-1463.

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Parts of the brain

•  Striatum – includes caudate and putamen. Coordinates motivation with body movement. Associated with reward, decision making and executive function

•  Nucleus accumbens – pleasure center. Dopamine levels when drug on board. Cues result in dopamine release to Nacc

•  Prefrontal cortex – executive functions. Regulates overall motivational salience and determines intensity of response

•  Hippocampus – formation of novel memories about experienced events

•  Amygdala – memory and emotional reactions •  Insular cortex – consciousness, self-awareness, autonomic fx,

emotional states related to awareness, drug craving

Reuter et al., Nature Neuroscience 8, 147 - 148 (2005)

Overall é ventral striatum while winning relative to losing PGs ê Ventral striatal and ventromedial prefrontal activation associated with gambling severity

Delay Discounting Task

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PGs with SUD History

PGs without SUD History

Controls

Ledgerwood, Alessi, Phoenix & Petry, 2009, Drug and Alcohol Dependence

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fMRI Pilot Study

•  n = 6 pathological gamblers; n = 6 controls •  Plan to expand •  Participants complete a delay discounting task

in the scanner •  Like delayed gratification •  Extent to which individual selects a smaller

immediate reward over a larger, delayed one

Types of responses

•  Selected immediate reward over delayed reward – Expect activation in striatal/limbic areas associated with reward processing and emotion

•  Select delayed reward over immediate reward – Expect activation in the frontal areas associated with planning and exec function

•  More difficult choices – expect greater activation in all areas

PGs evidenced significant (p<.001, voxel level) amygdala and dorsal prefrontal activity (Amygdala: x=24, y=3, z=-18, t = 7.53, kE=138; dPFC: x=44, y=32, z=40, t = 14.3, kE=650) when they chose delayed reward (relative to immediate).

Amyg

Amyg

dPFC

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•  PGs evidenced significantly striatal (Putamen: x=34, y=4, z=1, t=27.35, kE = 1868, p < 0.001; and Insula: x=-38, y=-4, z=4, t=17.96, kE = 1000, p < 0.001) activity when they chose immediate reward (relative to delayed).

•  PGs evidenced significantly striatal (Putamen: x=34, y=4, z=1, t=27.35, kE = 1868, p < 0.001; and Insula: x=-38, y=-4, z=4, t=17.96, kE = 1000, p < 0.001) activity when they chose immediate reward (relative to delayed).

Putamen

Insula

dPFC

Amyg

Insula

Caudate

•  PGs evidenced increased dorsal anterior aingulate (dACC), orbitofrontal cortex (OFC), striatum, and amygdala activation when faced with difficult choice behavior relative to controls (dACC: x=-14, y=23, z=39, t=3.23, kE= 80, p<0.001; OFC: x=28, y=30, z=-15, t= 4.08, kE=228, p<0.001, Striatum (putamen): x=-32, y=-1, z=-0, t=3.44, kE=282, p<0.004, Amygdala: x=34, y=-1, z=-27, t=3.47, kE=22, p<0.003)

Amyg

OFC

Putamen

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•  TBI may disrupt dopamine pathways •  Several animal studies have studied

neurochemical and behavioral sequelae of controlled injuries

•  But there are no studies of drug-related behavior subsequent to experimentally applied injury (e.g., drug self-administration)

Could SUDs be caused by damage to frontal/executive function areas?

An emergent dominant pattern of affective signaling can modulate activity of several components of the impulsive and reflective systems. These include regions involved in (i) representing patterns of affective states (e.g., the insula and somatosensory cortices); (ii) triggering of affective states (e.g., amygdala (A) and VMPC); (iii) memory, impulse and attention control (e.g., lateral orbitofrontal, inferior frontal gyrus and dorsolateral prefrontal (DLPC), hippocampus (Hip) and anterior cingulate (AC); and (iv) behavioral actions (e.g., striatum and supplementary motor area). 5-HT: serotonin; DA: dopamine. Bechara. (2005). Nature Neuroscience, 8, 1458-1463.

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What is executive function and why is it important?"

•  EF involves higher-level cognitive processes implicated in the formation of successful goal-directed behavior, including planning and initiating behaviors, anticipating (positive and negative) consequences of actions, and the ability to adjust behaviors based on environmental feedback.

What is executive function and why is it important?"

1.  Response inhibition - ability to respond to a ‘stop’ signal after being presented with a ‘go’ signal"

2.  Working memory - ability to maintain attention to details essential in planning"

3.  Cognitive flexibility and perseveration - ability to shift one’s thought or action to fit the demands of the situation"

4.  Planning - ability to identify and organize elements needed to carry out a planned act or achieve a goal"

Goudriaan et al., 2006"

•  Studied 49 PG, 48 alcohol dependent, 46 Tourette’s syndrome and 49 control participants."

•  Included measures of response inhibition, time estimation, cognitive flexibility, working memory and planning."

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Goudriaan et al., 2006"

Executive Functioning in Pathological Gamblers

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How is TBI related?

•  TBI to the orbitofrontal cortex can result in organic personality disorders that may be conducive to substance abuse

•  OFC lesions are not easily detected: 1) may not be evident on MRI; 2) do not lead to gross behavioral signs (e.g., speech impairments)

•  TBI survivors often show impairment in DD tasks (Dixon et al., 2005)

•  OFC lesions are associated with decreased sense of “agency” in one’s actions (self as agent of one’s own behaviors; Beer et al., 2006)

What about psychiatric symptoms?

•  Post-traumatic stress disorder (PTSD) frequently occurs in individuals who have sustained TBI

•  PTSD is associated with the development and maintenance of addictive behaviors

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From: Graham & Cardon, 2008, Annals of the New York Academy of Sciences

Bottom Line…

•  Our current studies suggest there are mechanisms through which addictive behaviors are more likely

•  The research findings are limited in terms of whether damage to striatal or frontal areas result in greater chance of addiction

•  Damage to the OFC may result in increased addictive behaviors in some individuals

•  PTSD may increase the risk of addiction as well, but most studies have few subjects and don’t account for TBI severity

How might a substance abuse problem affect recovery from

TBI?

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Outcomes

•  Drinking after TBI is associated with… Slowed recovery Depression (as alcohol is a depressant) Reduced effectiveness of medications Greater impairment of cognition and balance Seizures Aggressive behavior Increased risk for another injury

•  Jorge et al. (2005) Prospective comparison of individuals with TBI who

did (34.8% of 158 participants) and did not have a pre-injury alcohol abuse or dependence on subsequent depression and return to normal productive activity (e.g., employment)

Date of download: 4/17/2014" Copyright © 2014 American Medical Association. All rights reserved."

From: Alcohol Misuse and Mood Disorders Following Traumatic Brain Injury!

Arch Gen Psychiatry. 2005;62(7):742-749. doi:10.1001/archpsyc.62.7.742"

Jorge et al., 2005

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Date of download: 4/17/2014" Copyright © 2014 American Medical Association. All rights reserved."

From: Alcohol Misuse and Mood Disorders Following Traumatic Brain Injury!

Arch Gen Psychiatry. 2005;62(7):742-749. doi:10.1001/archpsyc.62.7.742"

Jorge et al., 2005

Conclusions

•  Pre-TBI addiction certainly increases the risk of TBI •  The question about whether TBI increases the risk of

addiction is not nearly as clear •  Time since TBI, TBI severity, presence of PTSD,

damage to specific areas of the brain may all contribute to relative risk

•  BUT it is clear that addiction prior to TBI and continued substance abuse lead to poorer recovery

Thank You!

Contact: dledgerw@med.wayne.edu

313-993-1380