Slide 7: This is literally the brain on drugs.   When someone gets “high” on cocaine, where does the cocaine go in the brain? With the help of a radioactive tracer, this PET scan shows us a person’s brain on cocaine and the area of the brain, highlighted in yellow, where cocaine is “binding” or attaching itself. This PET scan shows us minute by minute, in a time-lapsed sequence, just how quickly cocaine begins affecting a particular area of the brain.  We start in the upper left hand corner. You can see that 1 minute after cocaine is administered to this subject nothing much happens. All areas of the brain seem to be functioning normally. But after 3 to 4 minutes [the next scan to the rightl, we see areas highlighted in yellow where cocaine is starting to bind to the striatum [stry-a-tum] of the brain and activate it.  At the 5- to 8-minute interval, we see that cocaine is affecting a large area of the brain. After that, the drug’s effects begin to wear off. At the 9- to 10-minute point, the high feeling is almost gone. Unless the abuser takes more cocaine, the experience is over in about 20 to 30 minutes.  Scientists are doing research to find out if the striatum produces the “high feeling”and controls our feelings of pleasure and motivation. One of the reasons scientists are curious about specific areas of the brain affected by drugs such as cocaine is to develop treatments for people who become addicted to these drugs. Scientists hope to find the most effective way to change an addicted brain back to normal functioning.  Photo courtesy of Nora Volkow, Ph.D. Mapping cocaine binding sites in human and baboon brain in vivo. Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, Macgregor RIR, Hitzemann R, Logan J, Bendreim B, Gatley ST. et al. Synapse 1989;4(4):371-377.

Slide 8: Long-term effects of drug abuse. This PET scan shows us that once addicted to a drug like cocaine, the brain is affected for a long, long time. In other words, once addicted, the brain is literally changed. Let’s see how...  In this slide, the level of brain function is indicated in yellow. The top row shows a normal-functioning brain without drugs. You can see a lot of brain activity. In other words, there is a lot of yellow color.  The middle row shows a cocaine addict’s brain after 10 days without any cocaine use at all. What is happening here? [Pause for response.] Less yellow means less normal activity occurring in the brain—even after the cocaine abuser has abstained from the drug for 10 days.  The third row shows the same addict’s brain after 100 days without any cocaine. We can see a little more yellow, so there is some improvement— more brain activity—at this point. But the addict’s brain is still not back to a normal level of functioning. . . more than 3 months later. Scientists are concerned that there may be areas in the brain that never fully recover from drug abuse and addiction.  Photo courtesy of Nora Volkow, Ph.D. Volkow ND, Hitzemann R, Wang C-I, Fowler IS, Wolf AP, Dewey SL. Long-term frontal brain metabolic changes in cocaine abusers. Synapse 11:184-190, 1992; Volkow ND, Fowler JS, Wang G-J, Hitzemann R, Logan J, Schlyer D, Dewey 5, Wolf AP. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14:169-177, 1993.

Although most of the brain material and size is in place at the start of adolescence, several important developmental processes continue . If all goes well, the brain will be a much more efficient organ at the end of a healthy adolescence. One process is myelination. The axons connecting brain cells across which electrical impulses travel continue to become ensheathed in a fatty substance called myelin. This compound insulates axons and speeds the relay of electric impulses within the brain, helping thinking, decision-making, impulse control, and emotional regulation mature. Another process is synaptic refinement. At the start of adolescence, we have billions of brain cells, each with tens of thousands of connections to other brain cells. Not all these connections are actually needed, and the unnecessary ones become eliminated. This elimination process is shaped by the young person’s activities and experiences, and, as with myelination, it helps the brain work more efficiently. MRI studies reveal ongoing brain maturation during late childhood and early adulthood. Early MRI studies suggest regionally varying volume decreases in gray matter of the cortex and subcortical nuclei (Jernigan, Tallal). More recent studies provide more anatomical detail, emphasize the effects of ongoing myelination and employ mapping methods for visualizing the pattern of age-related change (Sowell, Jernigan). Of particular interest are reported changes between adolescence and young adulthood. A voxel-based comparison of gray matter distribution between two groups of normal young people with mean ages of 14 and 26 showed substantial striatum and thalamus volume reduction, and frontal cortex thinning concurrently with continuing myelination of the underlying white matter in this region. Normal age-effects for volumes of particular brain structures (Jernigan & Gamst, 2005) indicate protracted age-related increases in cerebral white matter, associated with ongoing myelination, as well as volume reductions in nucleus accumbens and thalamus, and continuing volume increase (in young adults) in hippocampal volume. Recently, the ongoing white matter development revealed in these morphometry studies has been studied more closely with DTI. DTI studies focusing specifically on the adolescent age range all show increases in FA in distributed subcortical regions between childhood and young adulthood. Although FA values are lower than in white matter, some of the most robust increases in FA observed across the adolescent age range were in these structures, perhaps reflecting maturation of internal fiber tracts. These FA changes are likely related to the steep reductions in striatal and thalamic gray matter volumes shown in the graphics above. Exposure to alcohol and other drugs during adolescence may alter the function of frontal-striatal and limbic circuits to interact with this pattern of ongoing brain maturation during late adolescence and early adulthood.

Avg. brain is about 3 lb.

Although most of the brain material and size is in place at the start of adolescence, several important developmental processes continue . If all goes well, the brain will be a much more efficient organ at the end of a healthy adolescence. One process is myelination. The axons connecting brain cells across which electrical impulses travel continue to become ensheathed in a fatty substance called myelin. This compound insulates axons and speeds the relay of electric impulses within the brain, helping thinking, decision-making, impulse control, and emotional regulation mature. Another process is synaptic refinement. At the start of adolescence, we have billions of brain cells, each with tens of thousands of connections to other brain cells. Not all these connections are actually needed, and the unnecessary ones become eliminated. This elimination process is shaped by the young person’s activities and experiences, and, as with myelination, it helps the brain work more efficiently. MRI studies reveal ongoing brain maturation during late childhood and early adulthood. Early MRI studies suggest regionally varying volume decreases in gray matter of the cortex and subcortical nuclei (Jernigan, Tallal). More recent studies provide more anatomical detail, emphasize the effects of ongoing myelination and employ mapping methods for visualizing the pattern of age-related change (Sowell, Jernigan). Of particular interest are reported changes between adolescence and young adulthood. A voxel-based comparison of gray matter distribution between two groups of normal young people with mean ages of 14 and 26 showed substantial striatum and thalamus volume reduction, and frontal cortex thinning concurrently with continuing myelination of the underlying white matter in this region. Normal age-effects for volumes of particular brain structures (Jernigan & Gamst, 2005) indicate protracted age-related increases in cerebral white matter, associated with ongoing myelination, as well as volume reductions in nucleus accumbens and thalamus, and continuing volume increase (in young adults) in hippocampal volume. Recently, the ongoing white matter development revealed in these morphometry studies has been studied more closely with DTI. DTI studies focusing specifically on the adolescent age range all show increases in FA in distributed subcortical regions between childhood and young adulthood. Although FA values are lower than in white matter, some of the most robust increases in FA observed across the adolescent age range were in these structures, perhaps reflecting maturation of internal fiber tracts. These FA changes are likely related to the steep reductions in striatal and thalamic gray matter volumes shown in the graphics above. Exposure to alcohol and other drugs during adolescence may alter the function of frontal-striatal and limbic circuits to interact with this pattern of ongoing brain maturation during late adolescence and early adulthood.

The water maze involves rats being put into a small pool of water with a platform that is hidden under water. They then have to swim around and find that platform so they can stand on it, and not have to keep swimming. In the study of alcohol, researchers had a group of adolescent rats and adult rats. They gave half of each group alcohol, and the other half a saline solution. They then put each rat into the water maze and measured things like how fast they swam and how long it took them to find the hidden platform. They then compared the swim speed and maze completion times between the 4 groups of rats (ask what the 4 groups were).

Alcohol-dependent adolescents (n = 33) with over 100 lifetime alcohol episodes and without dependence on other substances were recruited from alcohol/drug abuse treatment facilities. Comparison (n = 24) adolescents had no histories of alcohol or drug problems and were matched to alcohol-dependent participants on age (15 to 16 years), gender, socioeconomic status, education, and family history of alcohol dependence. NP tests and psychosocial measures were administered to alcohol-dependent participants following 3 weeks of detoxification. Results: Alcohol-dependent and comparison adolescents demonstrated significant differences on sev- eral NP scores. Protracted alcohol use was associated with poorer performance on verbal and nonverbal retention in the context of intact learning and recognition discriminability. Recent alcohol withdrawal among adolescents was associated with poor visuospatial functioning, whereas lifetime alcohol withdrawal was associated with poorer retrieval of verbal and nonverbal information. Conclusions: Deficits in retrieval of verbal and nonverbal information and in visuospatial functioning were evident in youths with histories of heavy drinking during early and middle adolescence.

This picture of the brain depicts the prefrontal regions, critical to planning, organizing information, inhibiting impulses, and regulating emotions. We also see the hippocampus, a structure essential to learning and forming new memories, which is located deeper within the brain (we all have 2: one on the left and one on the right). It too is continuing to develop during adolescence. Studies with rodents have suggested that the hippocampus is particularly sensitive to alcohol, especially during adolescence. This image of the brain is taken face-on, at a slice near the ear. De Bellis and colleagues found smaller left and right hpc volumes in AUD adolescents & young adults. We wanted to extend these findings by comparing AUD with yery limited psych como and other substance use with controls. We replicated study by De Bellis et al., 2001 which found smaller hippcampi in adol & young adults with AUD, but sample included other drug use disorders, PTSD, and other psychiatric disorders. Here, we exclude for other substance use disorders and all other psych disorders except CD Since we previously found learning and memory difficulties in alcohol abusing teens, we looked at the volume a structure critical to memory formation – the hippocampus. 14 adolescents (ages 15 to 17 years) with AUD and 17 healthy comparison teens, all free from psychiatric problems. Those with histories of heavy drinking had smaller left HC volume, even after controlling for conduct disorder.

These are pictures of the brain taken from fMRI. These are examples of two teens from our study: on the right, a non-drinking 16-year-old female, and on the left an alcoholic 16-year-old female. The brain images are a top view looking down, just above ear-level. The warm colors show parts of the brain that were active for the memory task given during the scanning session. Cool colors show parts that were less active than baseline during this task. Both teens have a similar pattern of brain response, but it’s clear that the alcohol-dependent girl has much more activation. Both alcohol-dependent and non-drinking teens performed similarly. This suggests that in early stages of drinking, youth may need to use more brain resources, or “work harder” to maintain performance. These teens have only been drinking about 2 years, and show signs of altered brain activation, even though their performance isn’t suffering now. The bottom pictures are from our study of young adult women. The lower right picture is of a 20-year old woman given this same task. She had been drinking heavily for 5 years, and is now 10% impaired on the task. Compared to her age-mate, she showed substantially less activation. Putting these studies together, it is possible that the brain may compensate by working harder and using different brain areas, but if the neurotoxic insult continues, the brain may not longer be able to compensate as effectively and performance diminishes. Longitudinal studies will be needed to confirm this impression. Perhaps withdrawal, not just drinking, is causing the harm. Parallels NP findings in larger samples The withdrawal symptoms reported here are relatively mild, and represent a spectrum of post-drinking symptom ranging from hangover to withdrawal (e.g., headache, shakes, nausea, orthostatic hypotension, etc.).

This is Your Brain on Adolescence Ken Winters, Ph.D. Department of Psychiatry University of Minnesota winte001@umn.edu Berkeley, CA May 6, 2010

This work was prepared by Ken Winters, Ph.D. Professor, Dept. of Psychiatry, University of Minnesota Support for this work was provided by the Archie and Bertha Walker Foundation, RKMC Private Foundation, and the Mentor Foundation. The author expresses gratitude to these colleagues whose work and consultation significantly contributed to the development of this presentation: Jay Giedd, National Institute on Mental Health (USA) Jeff Lee, Mentor Foundation (UK) Tom McLellan, Treatment Research Institute (USA) Linda Spear, SUNY at Binghamton (USA) Susan Tapert, University of California – San Diego (USA) Acknowledgements

Emerging Science: Brain Imaging New insights because: 1990’s information explosion due to the development of brain imaging techniques (e.g., CT, PET and MRI).

Addiction as brain disease Brain development Alcohol susceptibility Summary Clinical opportunities

Addiction as brain disease

Dopamine Neurotransmission VTA/SN nucleus accumbens frontal cortex 0 100 200 300 400 500 600 700 800 900 1000 1100 0 1 2 3 4 5 hr Time After Amphetamine % of Basal Release AMPHETAMINE 0 50 100 150 200 0 60 120 180 Time (min) % of Basal Release Empty Box Feeding Di Chiara et al. FOOD

Your Brain on Cocaine PET scan 1-2 Min 3-4 5-6 6-7 7-8 8-9 9-10 10-20 20-30 Yellow = cocaine is binding or attaching itself to areas of the brain

DA D2 Receptor Availability Cocaine Alcohol DA DA DA DA DA DA DA Reward Circuits DA DA DA DA DA Reward Circuits DA DA DA DA DA DA Drug Abuser Non-Drug Abuser Heroin Meth Dopamine D2 Receptors are Lower in Addiction control addicted

What about recovery?

Your Brain After Cocaine Normal Cocaine Addict - 10 days Cocaine Addict - 100 days Yellow = normal brain functioning

Addiction as brain disease Brain development

Cautions Adolescent brain imaging studies are based on small samples gender, ethnic and cultural differences may be significant.

Adolescence is a period of profound brain maturation. We thought brain development was complete by adolescence We now know… maturation is not complete until about age 25!!!

Important ages of majority and privileges 16 - emancipation - driving 18 - gambling (usually age 21 when alcohol served) - smoking (some at age 19 - military 21 -drinking

Allstate ad, NY Times, May, 2007

An Immature Brain = Less Brakes on the “Go” System

Brain Development 1 2 7 16 30 Prenatal Post-birth Age RATE OF CHANGE Tapert & Schweinsburg (2005)

Brain Weight by Age Source: Dekaban, A.S. and Sadowsky, D. Annals of Neurology, 4:345-356, 1978 Newborn I’m adult-size now! Age Slide courtesy Sion Kim Harris, Ph.D.

Brain Development 1 2 7 16 30 Prenatal Post-birth Age RATE OF CHANGE Tapert & Schweinsburg (2005)

When the pruning is complete, the brain is faster and more efficient. But… during the pruning process, the brain is not functioning at full capacity. Construction Ahead

Maturation Occurs from Back to Front of the Brain Images of Brain Development in Healthy Youth (Ages 5 – 20) Source: PHAS USA 2004 May 25; 101(21): 8174-8179. Epub 2004 May 17. Blue represents maturing of brain areas Earlier: Motor Coordination Emotion Motivation Later: Judgment

Preference for …. physical and sensory activities high excitement activities with peers that trigger high intensity/arousal novelty Less than optimal…. balance of emotion and logic when making decisions consideration of negative consequences Greater tendency to… take risks and show impulsiveness Implications of Brain Development: Adolescent Behavior

Preference for …. physical and sensory activities high excitement activities with peers that trigger high intensity/arousal novelty Less than optimal…. balance of emotion and logic when making decisions consideration of negative consequences Greater tendency to… take risks and show impulsiveness Implications of Brain Development: Adolescent Behavior

Taking risks is not always unhealthy. Growth experiences and extending one’s talents may involve risk-taking.

An Immature Brain = Low Brain Power Source: US News & World Report, 2005

An Immature Brain = Absence of Judgment Source: US News & World Report, 2005

Addiction as brain disease Brain development Alcohol susceptibility

Adolescents may be more susceptible than adults to alcohol (acknowledgement to Linda Spear, Ph.D.) Implications of Brain Development for Drug Abuse Vulnerability Unethical to give human adolescents alcohol in the laboratory; much of the best evidence comes from adolescent rat studies.

Cautions Supporting evidence on alcohol sensitivity from animal models needs to be interpreted with prudence. assumptions of commonality across species pertaining to ….. key characteristics of the adolescent developmental stage acute effects of intoxication lab rats are administered ethanol via injection or directly into the stomach stress - impacts absorption and behavioral effects Other developmental factors, such as hormonal changes, are also biomedical contributors to alcohol sensitivity.

Evidence from epidemiological studies Alcohol use starts early and peaks in the teen years

Prevalence of Past-Year DSM-IV Alcohol Dependence: United States, 2001-2002 (Grant, B.F., et al., Drug and Alcohol Dependence, 74, 223-234, 2004) %

Percentages of Past Year Alcohol Use Disorder (Abuse or Dependence) Among Adults Aged 21 or Older, by Age of First Use (SAMHSA, 2005) Age Started Drinking % Fewer Problems in Those Who Start Later

Are adolescents more susceptible to alcohol than adults? Comparing adolescent and adult rats, both having no prior exposure to alcohol and matched on temperament…. Adolescent rats are less sensitive to the sedative and motor impairment effects of intoxication. more drinking before “signals to stop”

The Water Maze Test Hidden Slide courtesy Sion Kim Harris, Ph.D. Saline vs alcohol Measures Swimming speed Time to find platform

Are adolescents more susceptible to alcohol than adults? Adolescent rats are more sensitive to the social disinhibition effects of alcohol. greater social comfort from intoxication

Wanna look for some cheese with me? Sure!

Are adolescents more susceptible to alcohol than adults? Adolescent rats are less sensitive to the sedative and motor impairment effects of intoxication. Adolescent rats are more sensitive to the social disinhibition effects of alcohol. #2 and #3 : May contribute to binge drinking and increased risk to alcohol dependence.

Are adolescents more susceptible to alcohol than adults? Alcohol may produce greater cognitive disruptions in adolescents.

Human Data: Alcohol’s Effects Verbal information Nonverbal information Retention Rate % Source: Brown et al., 2000

MRI: Hippocampal Size Nagel, Schweinsburg, Pham, & Tapert, 2005 Hippocampus Encodes new info Left smaller in AUD teens (p<.01) But no relationship with cognitive functioning (due to less severe alcohol group than Brown et al. sample?) 10% smaller volume

Teen Drinking & Brain Activation Non-Drinkers Heavy Drinkers Activation De-activation Age 16 Age 20 Tapert et al., 2001, 2004 Slide courtesy of Susan Tapert, PhD. 2 yrs drinking 5 yrs drinking

Addiction as brain disease Brain development Alcohol susceptibility Summary

Summary Adolescence is an extended period of transition from reliance on adults to independence Normal adolescence is characterized by…. increase in conflicts with family members desire to be with one’s friends resistance to messages from authority irritability risk taking proclamations of sheer boredom

Adolescents may be highly susceptible to the effects of drugs (particularly alcohol) and to gambling.

Preference for …. physical and sensory activities high excitement activities with peers that trigger high intensity/arousal novelty Less than optimal…. balance of emotion and logic when making decisions consideration of negative consequences Greater tendency to… take risks and show impulsiveness

Addiction as brain disease Brain development Alcohol susceptibility Summary Clinical opportunities

Brain Development and Drug Treatment Treatment is vital. Youth is a particularly vulnerable period for developing a substance use disorder. Not treating it during youth… probably increases the likelihood that the adolescent will have a drug problem as an adult may contribute to learning and memory problems

Treatment Continuum Adapted from Broadening the Base of Alcohol Treatment (IOM) Primary Prevention Abstinence Recreational use moderate severe Brief Intervention Intensive Tx Drug Use Severity Thresholds for Action

Brain Development and Drug Treatment Sobriety is vital. All addicted brains need to become drug – free so that neurological repair can occur. Restoration may be even more critical for youth due to concerns of drug toxicity on the developing brain.

Screen target groups for gambling Drug-abusing youth Youth with ADHD Brain Development and Problem Gambling

Lie/Bet Screen (Johnson et al., 1997) 2-question version of the DSM-IV criteria: 1. Have you ever had to lie to people important to you about how much you gambled? 2. Ever felt the need to bet more and more money? Score of 1+ is a red flag.

Brain Development and Problem Gambling Treatment issues for youth with drug abuse or ADHD raise insights that gambling is a source of excitement teach limits, if the person gambles

Some Resources

www.drugfree.org/teenbrain

Working with Parents P = Promote activities that capitalize on the strengths of the developing brain. A = Assist children with challenges that require planning. R = Reinforce their seeking advice from adults; teach decision making. E = Encourage lifestyle that promotes good brain development. N = Never underestimate the effects of drugs on the developing brain; emphasize the importance of drug-free lifestyle. T = Tolerate the “oops” behaviors due to an immature brain.

Hazelden’s Brain Development Curriculum for High School Science Classes

THANK YOU! winte001@umn.edu

Suggested Readings Dahl, R.E. & Spear, L.P. (Eds.) (2004). Adolescent brain development: vulnerabilities and opportunities. NY, NY: Annals of the New York Academy of Sciences, Volume 1021. Dubuc, B. (n.d.). The brain from top to bottom. Retrieved September 1, 2004, from McGill University Web site: http://www.thebrain.mcgill.ca/flash/index_d.html# Nestler, E. J., & Malenka, R. C. (2004, March). The addicted brain. Scientific American, 290 (3), 78-85. Wallis, C. (2004, May 10). What makes teens tick? Time, 163, 57-65. U.S. News & World Report. (Special Issue, 2005). Mysteries of the teen years. Author.

Brown, S.A., Tapert, S.F., Granholm, E., & Delis, D.C. (2000). Neurocognitive functioning of adolescents: Effects of protracted alcohol use. Alcoholism: Clinical and Experimental Research, 242, 164-171. Deary et al. (2004). Journal of Personality and Social Psychology, 86, 130-147. Giedd. J. N. (2004). Structural magnetic resonance imaging of the adolescent brain. Annals of the New York Academy of Sciences, 1021, 77-85. Gogtay, N., Giedd, J.N., et al. (2004). Dynamic mapping of human cortical development during childhood through early adulthood. Proceedings of the National Academy of Sciences, 101 (21), 8174 – 8179. Grant, B.F., Dawson, D., et al. (2004). The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991-1992 and 2001-2002. Drug and Alcohol Dependence, 74, 223-234. Nagel, B.J., Schweinsburg, A.D., Phan, V., & Tapert, S.F. (2005). Reduced hippocampal volume among adolescents with alcohol use disorders without psychiatric comorbidity. Neuroimaging, 139, 181 –190. Spear, L. P. (2002). Alcohol’s effects on adolescents. Alcohol Health and Research World, 26(4), 287-291. Tapert, S. & Schweinsburg, A.D. (2005). The human adolescent brain and alcohol use disorders (pp 177-197). In M. Galanter (Ed.), Recent developments in alcoholism: Vol XVII. Washington D.C.: American Psychiatric Press. Winters, K.C., & Lee, S. (2008). Likelihood of developing an alcohol and cannabis use disorder during youth: Association with recent use and age. Drug and Alcohol Dependence, 92, 239-247. References