DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
153rd Meeting of the
NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
February 6, 2020
The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened for its 153rd meeting at 9:00 a.m. on Thursday, February 6, 2020, at NIAAA headquarters in Rockville, Maryland. The Council met in closed session from 9:00 a.m. to 9:15 a.m. to review the NIAAA Board of Scientific Counselors (AABSC) intramural review report, and from 9:15 a.m. to 9:44 a.m. to review grant applications and cooperative agreements. Dr. Abraham Bautista, Director, Office of Extramural Activities, presided over the Council’s review session, which, in accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C., and 10(d) of Public Law 92-463, excluded the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds. The closed session recessed at 9:44 a.m.
Council Members Present:
Louis E. Baxter, M.D.
Jill B. Becker, Ph.D.
Daniel J. Calac, M.D.
Christopher S. Carpenter, Ph.D.
Alex M. Dopico, M.D., Ph.D.
Robert J. Hitzemann, Ph.D.
Constance M. Horgan, Sc.D.
Beth Kane-Davidson, LCADC, LCPC
Charles H. Lang, Ph.D.
Mary E. Larimer, Ph.D.
Laura E. Nagy, Ph.D.
Laura Elena Odell, Ph.D.
Scott J. Russo, Ph.D.
Vijay H. Shah, M.D.
Susan M. Smith, Ph.D.
Edith Vioni Sullivan, Ph.D.
Col. Charles S. Milliken, M.D.
NIAAA Director and Chair: George F. Koob, Ph.D.
NIAAA Deputy Director: Patricia Powell, Ph.D.
Executive Secretary: Abraham P. Bautista, Ph.D.
Senior Staff: Vicki Buckley, M.B.A.; Ralph Hingson, Sc.D.; M. Katherine Jung, Ph.D; George Kunos, M.D., Ph.D.; Raye Litten, Ph.D.; Antonio Noronha, Ph.D.; Megan Ryan, M.B.A.; and Bridget Williams-Simmons, Ph.D.
Other Attendees at the Open Session:
Approximately 50 observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.
Call to Order and Introductions
NIAAA Director George Koob, Ph.D., called the open session of the Council meeting to order at 9:58 a.m. on Thursday, February 6, 2020. Council members and senior NIAAA staff introduced themselves.
Introduction of New Members
Dr. Koob introduced the following new Council members: Christopher S. Carpenter, Ph.D., Beth Kane-Davidson, LCADC, LCPC; Mary E. Larimer, Ph.D.; Laura E. Nagy, Ph.D.; and Laura Elena Odell, Ph.D.
Dr. Koob highlighted key recent NIAAA activities, referring to the written Director’s Report, which was distributed to Council members.
• 50th Anniversary Observance: NIAAA celebrates its 50th anniversary in 2020. Information about its founding in 1970 will be posted on the NIAAA website. Special events throughout the year include an Alcohol Research Symposium on campus on March 31 (now postponed for later in the year); screening of the HBO documentary “Risky Drinking” on campus on May 19, and a special presentation at the Research Society on Alcoholism (RSA)/International Society for Biomedical Research on Alcoholism (ISBRA) in New Orleans on June 21.
• Staff Transitions: Dr. Koob announced the recent death of distinguished scientist Richard Veech, M.D., Ph.D., Chief of NIAAA’s Intramural Laboratory of Metabolic Control. He welcomed new NIAAA staff members Emily Brewer, Luis A. Espinoza, Ph.D., and Deborah Langer, and noted Karen Harrington’s transition to Chief, Administrative Services Branch. Dr. Koob also recognized departing staff members, including Anita Bechtholt, Ph.D., Bonnie Ellis, Mehdi Farokhnia, M.D., Bridgette Green, and Minoo McFarland, as well as Dale Hereld, M.D., Ph.D., and Alesia Wilbur who retired.
• Budget: In the Fiscal Year (FY) 2019 enacted budget, NIH’s total budget was $39.3 billion. NIAAA’s funding increased to $525.6 million, which supported 760 research project grants, 159 competing awards, 182 other research grants, 21 research centers, 326 training positions, and $34 million in research and development contracts. For FY 2020, NIH received $41.6 billion, a $2.3 billion increase. This funding included allocations for the Helping to End Addiction Long-term (HEAL) Initiative, 21st Century Cures Act, BRAIN Initiative, and research on influenza. It also continues support for the Gabriella Miller Kids First Act Pediatric Research Initiative. Under this budget, NIAAA received $545.4 million, a $19.8 M increase from FY19. The FY21 budget is under development.
• Funding Opportunity Announcements (FOAs): NIAAA has released several FOAs, including NADIA Consortium: Neurobiology of Adolescent Drinking in Adulthood (U01 Clinical Trial Not Allowed; U24 Clinical Trial Not Allowed); Impact of Alcohol on the Onset and Progression of Alzheimer’s Disease and Its Related Dementias (R01 - Clinical Trial Optional); and Medications Development for the Treatment of Alcohol Use Disorder (AUD) or Alcohol-Related Organ Damage (AROD), or the Combination of AUD and AROD (U01 Clinical Trial Optional). It has also issued two Notices of Special Interests (NOSI): Administrative Supplements for Regulatory Support for SBIR/STTR Awardees and Neurobehavioral Mechanisms of Social Isolation and Alcohol Use Disorder. NIAAA is currently participating in over 20 FOAs and NOSIs, including: Identification, Validation, and Manipulation of Neural Circuits Related to Mental Illness and Alcohol and Substance Use Disorders in Non-human Primates (R01); Integrative Research on Polysubstance Abuse and Disorder (R61/R33); multiple FOAs in support of career development and diversity in research training: BRAIN Initiative Advanced Postdoctoral Career Transition Award to Promote Diversity (K99/R00); Maximizing Opportunities for Scientific and Academic Independent Careers (MOSAIC) Postdoctoral Career Transition Award to Promote Diversity (K99/R00); Administrative Supplements to Promote Research Continuity and Retention of NIH Mentored Career Development Award Recipients and Scholars (K); NIH Blueprint Program for Enhancing Neuroscience Diversity through Undergraduate Research Education Experiences (R25); and multiple FOAs related to sex and gender influences.
• NIAAA Research in the News: Dr. Koob noted the extensive media attention garnered by a study entitled “Using Death Certificates to Explore Changes in Alcohol-Related Mortality in the United States, 1999-2017,” which was published in Alcoholism Clinical and Experimental Research (January 2020) by Aaron M. White, I-Jen P. Castle, Ralph W. Hingson, and Patricia A. Powell. Their analysis of death certificate data revealed that alcohol-related mortality doubled from 1999 to 2017. Death rates were highest among men and middle-aged and older adults (ages 45-74), and increased over time across all age groups except 16-20 and 75+. The increase in death rate over time was greater in women than in men. These mortality data also linked alcohol use to “deaths of despair” (suicide, drug overdose, liver disease).
• National Drugs and Alcohol Chat Day: Scheduled for April 1, 2020, National Drugs and Alcohol Chat Day is an annual live online chat held between high school students and NIH scientists during National Drug and Alcohol Facts Week®.
• Possible Cultural Shift in Attitudes toward Alcohol Use: Dr. Koob raised the possibility that cultural attitudes toward alcohol use may be shifting in light of the increasing popularity of sober month observances (e.g., Dry January, Sober October) and the emergence of the Sober Curious movement. These trends reduce the stigma associated with not drinking.
• U.S. Dietary Guidelines for Alcohol Consumption: To avoid confusion over what constitutes low risk drinking, going forward NIAAA will promote the 2015-2020 U.S. Dietary Guidelines recommendation for alcohol consumption, as follows. For adults 21 and older: No more than two drinks per day for men; no more than one drink per day for women. For individuals under age 21: No alcohol. Others should avoid alcohol completely, including those who plan to drive or operate machinery, or participate in activities that require skill, coordination, and alertness; have certain medical conditions or take certain medications; are recovering from alcohol use disorder or are unable to control the amount that they drink; and/or are pregnant or trying to become pregnant.
• Research Highlights: Dr. Koob presented highlights of NIAAA-funded studies, including:
“Cannabinoids Exacerbate Alcohol Teratogenesis by a CB1-Hedgehog” was published in Scientific Reports (2019 Nov 5; 9(1):16057) by EW Fish, LB Murdaugh, C Zhang, KE Boschen, O Boa-Amponsem, HN Mendoza-Romero, M Tarpley, L Chdid, S Mukhopadhyay, G Cole, KP Williams, and SE Parnell. Using animal models of prenatal substance exposure, this study demonstrated that a single exposure to cannabinoids (CB) caused craniofacial and brain malformations similar to those caused by prenatal alcohol exposure. Mechanistic studies in this report indicated that both alcohol and CB converge to inhibit the Sonic Hedgehog (Shh) pathway, an important molecular signal for normal development.
These findings shed light on the mechanism of alcohol and CB-induced birth defects and further highlight the dangers of co-substance use during pregnancy.
“Bacteriophage Targeting of Gut Bacterium Attenuates Alcoholic Liver Disease” was published in Nature (2019 Nov; 575(7783):505-511) by Y Duan, C Llorente, S Lang, K Brandl, H Chu, L Jiang, RC White, TH Clarke, K Nguyen, M Torralba, Y Shao, J Liu, A Hernandez-Morales, L Lessor, IR Rahman, Y Miyamoto, M Ly, B Gao, W Sun, R Kiesel, F Hutmacher, S Lee, M Ventura-Cots, F Bosques-Padilla, EC Verna, JG Abraldes, RS Brown Jr, V Vargas, J Altamirano, J Caballería, DL Shawcross, SB Ho, A Louvet, MR Lucey, P Mathurin, G Garcia-Tsao, R Bataller, XM Tu, L Eckmann, WA van der Donk, R Young, TD Lawley, P Stärkel, Pride, DE Fouts, and B Schnabl. This report demonstrated that the presence of cytolysin-positive E. faecalis, a bacterium that secretes the cell-destroying toxin cytolysin, in the gut correlates with severity of liver disease and mortality in patients with alcoholic hepatitis. Further, using a mouse model of alcohol-associated liver disease, the study also demonstrated that bacteriophages that specifically target cytolysin-positive E. faecalis are effective in reducing liver injury, suggesting a potential therapeutic target for the treatment of alcoholic hepatitis.
“Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis” was published in Cell Metabolism (30 (5), 877-889.e7. 2019 Nov 5) by WM Choi, HH, Kim, MH Kim, R Cinar, HS Yi, HS Eun, SH Kim, YJ Choi, YS Lee, SY Kim, W Seo, JH Lee, YR Shim, YE Kim, K Yang, T Ryu, JH Hwang, CH Lee, HS Choi, B Gao, W Kim, SK Kim, G Kunos, and WI Jeong. Previous research has shown that increased glutamate signaling in the brain plays a role in driving alcohol-seeking behavior through actions at the metabotropic glutamate receptor. This study demonstrated that glutamate signaling via these receptors is also involved in mediating alcohol-associated fatty liver disease. Specifically, the study found that alcohol consumption increases xCT (cystine-glutamate anti-porter) expression in hepatocytes; xCT-derived glutamate release increases expression of mGluR5 in hepatic stellate cells; mGluR5 stimulates 2-AG production in hepatic stellate cells to influence lipogenesis of hepatocytes via CB1; and Inhibition of xCT and mGluR5 blocks alcoholic steatosis in liver. These results suggest that inhibition of a single pharmacological target, mGluRs, may have therapeutic value in the treatment of both alcohol use disorder and alcohol-induced liver damage.
“PCSK9 Inhibition as a Novel Therapeutic Target for Alcoholic Liver Disease” was published in Scientific Reports (9 (1), 17167. 2019 Nov 20) by JS Lee, P Mukhopadhyay, C Matyas, E Trojnar, J Paloczi, YR Yang, BA Blank, C Savage, AV Sorokin, NN Mehta, JCM Vendruscolo, GF Koob, LF Vendruscolo, P Pacher, and FW Lohoff. Proprotein convertase subtilisin/kexin 9 (PCSK9) has been identified as a plausible new target for AUD and alcohol-associated liver disease (ALD). This study tested the PCSK9 inhibitor alirocumab, a monoclonal antibody that robustly reduces low-density lipoprotein (LDL) cholesterol, in a rat model of chronic alcohol exposure. The findings demonstrated that alirocumab significantly reduced alcohol-induced hepatic triglyceride accumulation, hepatocellular injury, and hepatic inflammation. Further research is needed to investigate the therapeutic efficacy and safety of anti-PCSK9 treatment in individuals with AUD and ALD.
“Early Detection and Staging of Chronic Liver Diseases with a Protein MRI Contrast Agent” was published in Nature Communications (2019 Oct 29;10(1):4777) by M Salarian, RC Turaga, S Xue, M Nezafati, K Hekmatyar, J Qiao, Y Zhang, S Tan, OY Ibhagui, Y Hai, J Li, R Mukkavilli, M Sharma, P Mittal, X Min, S Keilholz, L Yu, G Qin, AB Farris, ZR Liu, and JJ Yang. This study reported the development of a sensitive protein-based magnetic resonance imaging (MRI) contrast agent, ProCA32.collagen1, that can detect and accurately quantify early stage fibrosis in mouse models of alcohol-, diet- and chemical-induced liver diseases. With further validation, this contrast agent could potentially be used to noninvasively and accurately detect early stage fibrosis in liver and other organs, allowing for earlier treatment and better patient outcomes.
“Targeting Liver Aldehyde Dehydrogenase-2 Prevents Heavy but Not Moderate Alcohol Drinking” was published in the Proceedings of the National Academy of Sciences of the United States of America (2019 Dec 2. pii: 201908137) by A Guillot, T Ren, T Jourdan, RJ Pawlosky, E Han, SJ Kim, L Zhang, GF Koob, and B Gao. Systemic ALDH2 inhibition by disulfiram has side effects that pose clinical limitations. Using mice with liver-specific Aldh2 gene deletion (compared to global knockout), researchers found that although the liver only contributes to ~half of acetaldehyde clearance, knockdown of Aldh2 in the liver still reduced alcohol intake. These results suggest that liver-specific ALDH2 inhibition may be a potential treatment approach for AUD.
“A Mechanism Linking Two Known Vulnerability Factors for Alcohol Abuse: Heightened Alcohol Stimulation and Low Striatal Dopamine D2 Receptors” was published in Cell Reports (29 (5), 1147-1163.e5. 2019 Oct 29) by MR Bocarsly, D da Silva e Silva, V Kolb, KD Luderman, S Shashikiran, M Rubinstein, DR Sibley, LK Dobbs, and VA Alvarez. Heightened sensitivity to alcohol’s stimulating effects has predictive value for alcohol misuse. Using transgenic mice and other genetic manipulations, this study provided direct evidence that lowering levels of D2 receptors on striatal projection neurons heightens alcohol-related stimulatory effects and escalation of alcohol intake, which continues despite aversive outcomes. The study also demonstrated that upregulation of dopamine D1 receptor functioning is responsible for these effects, suggesting that low striatal D2 receptor levels trigger D1 receptor hypersensitivity, ultimately leading to compulsive-like drinking and other factors related to risk for alcohol use disorder.
“Alcohol and Pain: A Translational Review of Preclinical and Clinical Findings to Inform Future Treatment Strategies“ was published in Alcoholism: Clinical and Experimental Research (2019 Dec 16, doi: 10.1111/acer.14260) by S Edwards, LF Vendruscolo, NW Gilpin, M Wojnar, and K Witkiewitz. AUD and chronic pain are pervasive conditions with a high rate of comorbidity. This review established a broader translational focus on persistent pain and alcohol use that provided updates on recent models and research, described overlapping behavioral, social, and biological mechanisms, and assessed evidence for informing treatment recommendations and future research that intersect pain and AUD.
“Trait Self-Control Predicts Drinking Patterns During Treatment for Alcohol Use Disorder and Recovery Up to Three Years Following Treatment” was published in Addictive Behaviors (99, 106083. Dec 2019) by E Stein and K Witkiewitz. Previous research has identified demographic and clinical indicators related to recovery outcomes, but behavioral traits such as self-control have received less attention. Using latent class analysis, this study confirmed seven classes of drinking patterns among participants in treatment identified in previous research and compared baseline self-control across classes. The researchers established that the consistent low-risk drinking group had significantly higher self-control than both persistent heavy drinking and consistent abstinence groups. This finding has important clinical implications, suggesting that achieving low-risk drinking throughout treatment may require even more self-control than achieving abstinence.
“Association of Prior Convictions for Driving Under the Influence with Risk of Subsequent Arrest for Violent Crimes Among Handgun Purchasers” was published in JAMA Internal Medicine (2019 Sep 30, doi: 10.1001/jamainternmed.2019.4491) by RMC Kagawa, S Stewart, MA Wright, AB Shev, VA Pear, CD McCort, R Pallin, R Asif-Sattar, S Sohl, PH Kass, M Cerdá, P Gruenewald, DM Studdert, and GJ Wintemute. In this study of authorized handgun purchasers in California, history of driving under the influence (DUI) conviction at the time of purchase was associated with a significant increase in the risk of subsequent arrest for a violent crime, independent of a range of individual and community-level measures. Purchasers with a previous DUI conviction and other non-DUI arrests or convictions were at greatest risk of subsequent arrest for a violent crime. This finding extends previous links between alcohol use and violence specifically to legal purchasers of handguns, suggesting that alcohol-related prohibitions on firearms purchase based on DUI convictions may reduce firearm-related injury and death.
Sex Differences in Addiction—Lessons from Animal Models
Dr. Koob introduced Jill B. Becker, Ph.D., University of Michigan, whose presentation addressed the findings of preclinical research on sex differences in addiction.
Sex Differences in the Brain: Chromosomal sex determines gonadal sex that determines most sex differences in the brain and behavior. The developing male testes produce testosterone, which is converted in the brain to estradiol, and causes the brain to become masculinized. There are also developmental effects that occur in utero and at puberty that permanently change the brain and the body. When estradiol is given to males and females, it produces different effects in the sexes because their substrates (brain and body) give different responses to the hormone. As a result, there is not a bimodal distribution of sex differences. Rarely are there specific differences (other than basic reproductive ones) between males and females; most are nuanced. In some areas, their brains are the same but there is a quantitative difference in behavior in response to the same dose of drug. There are also “population differences” as a result of influences that happens during development that act on males and females in different ways, e.g., females tend to escalate drug taking more rapidly than most males. There are also examples where a trait is identical in males and females but where the mechanisms are different. Therefore, it’s important to think about sex differences as being more nuanced than “all girls do this, all boys do that.”
The Reward System in the Brain: Neural systems that mediate motivation and addiction are dependent on the reward system in the brain. Dr. Becker’s work has primarily addressed dopamine and her presentation focused on the striatum and nucleus accumbens (NAc). Her research has demonstrated that dopamine in the NAc and the dorsal striatum is dramatically and rapidly influenced by estradiol. Receptors for estradiol in the cell nucleus are slow-acting while there are rapidly activating estradiol receptors (ER) on neuronal membranes. Thus, there are both rapid effects of estradiol as well as long-term, slower-acting effects that interact to produce changes in neural activity. In one experiment, Dr. Becker inserted estradiol directly into the brains of rats and then administered amphetamine about an hour later. She observed that the estradiol acted rapidly and locally within the dorsal striatum to increase dopamine release. When estradiol was administered, thirty minutes later there was a down-regulation of D2 dopamine receptors was observed (D2 dopamine receptor activation is thought to be related to increased drug taking behavior). There is also a simultaneous decrease in gamma aminobutyric acid (GABA) release that results in enhanced dopamine release. Thus, there is simultaneously enhanced dopamine release and decreased D2 dopamine receptors, resulting in greater D1 activation that leads to enhanced drug-taking behavior. These effects are specific to females. The researchers believe that these are females-specific effects are differentiated during critical periods of development, and they influence motivation and drug-taking behavior.
Sex Differences in Addiction: Research on motivation indicates that sex differences in the neural system that are important for maternal motivation result in sex differences in motivated behaviors in general. Sex differences in the role of hormones in modulation of energy intake also play a role in sex differences in motivation: in females, estradiol decreases feeding behavior, whereas males eat more than females due to sexual differentiation of the hypothalamus. Dr. Becker believes that the same hormonal events that affect drug-taking behavior also influence the onset of maternal behavior. After estradiol priming, female rats become attached to their infants immediately upon giving birth.
Epidemiological studies of humans have established that the time from first exposure to drugs (including alcohol) to chronic drug use is shorter for women than for men. Females who present for treatment consume more cocaine than men, even though their time of use is shorter. Women’s reports on the reasons they initiated drug use include self-medication for depression, stress and anxiety most often; men and boys report they engage in risky behaviors that include taking drugs to be part of the group.
At all stages of the addiction cycle, there are sex differences in alcohol and drug use. Some of these differences are quantitative, some are qualitative, and some are population differences. The same trends are observed in rodent research. Thus, rodents are a good model for studying substance misuse in humans and for studying sex differences in addiction.
Dr. Becker described some of the experiments conducted in her laboratory to investigate such sex differences. In one study, researchers offered rats a choice between tasty banana-flavored pellets or cocaine that the rats obtained via nose pokes. At the beginning, when given a choice, the rats preferred the pellets. Seven weeks later, some rats chose cocaine over pellets. About 50 percent of the females chose cocaine and they chose it more rapidly than the males did, although some males (about 20 percent) also chose cocaine. An examination of the rats’ brains during the choice for cocaine revealed that the cocaine-preferring animals had a decrease in dopamine release in the NAc while the animals who chose pellets had the same amount of dopamine release throughout their drug taking. No sex difference was observed so this appeared to be a population difference: more females chose cocaine but the neural systems that were mediating it, at least in terms of dopamine release, appeared to be the same for males and females.
In another experiment using conditioned place preference, the researchers examined the NAc and the ventral tegmental area (VTA) of the rats’ brains to investigate how the receptors for estradiol present in these areas were affecting the rats’ preference for cocaine. They included males in this study, but were really expecting the effect to be in females. The investigators gave an antagonist (ICI 182, 780) to ER-alpha and ER-beta. The rats were then placed for 30 minutes in one compartment paired with cocaine and in another compartment paired with saline.The researchers observed where the rats preferred to spend the most time following multiple exposures. Surprisingly, there was no effect whatsoever in females. In the dorsal lateral striatum, ICI blocked conditioned place preference in the males. That was curious since the researchers had never seen an effect of estradiol on behavioral response to cocaine or amphetamine in the males. Finally, the research team realized that ICI is also an agonist to a new receptor, GPER-1. Next, they gave an agonist to GPER-1 to males and females. It had no effect in females but it blocked preference for cocaine in males. Thus, GPER-1 activation inhibits cocaine-preference in males; GPER-1 inhibition enhances preference for cocaine in males only.
Stress, Social Support, and Sex Differences: Dr. Becker’s lab has also been looking at the effects of social support and the role of oxytocin. In humans, oxytocin is considered a potential treatment for alcohol abuse in severely alcoholic individuals. In one study with female rats only, the researchers measured how much the rats liked methamphetamine by how willing they were to continue increasing thenumber of nose pokes required to obtain it. The rat reached a breaking point when she was no longer willing to work to obtain the drug. The researchers observed that If the rats were individually housed, they worked harder than if they had a friend in their home cage. Next, the researchers observed the behavior of the same animals after they received oxytocin peripherally or via vehicle. Those given the vehicle, whether socially housed or individually housed, continued to work harder than the other animals. Thus, over a period of two weeks, there was a decrease in drug-seeking after treatment with oxytocin. Looking at individual variability in the animals and their response to oxytocin, the researchers observed that social housing increased the proportion of animals who had very low motivation for methamphetamine, making social housing a good treatment upfront. After seven weeks, the animals who were responding to the oxytocin were those with the greatest motivation for methamphetamine, suggesting an interaction between the ability of oxytocin to decrease motivation and its effectiveness.
In summary, there are a number of different ways of thinking about sex differences in animals and humans. For one, estradiol makes a qualitative difference in that it acts in females and not in males. But there are also quantitative differences in initial response to cocaine or methamphetamine that is greater in females than in males. There are also population differences reflected in the vulnerability to addiction. Finally, there are different underlying neural mechanisms, as well as population differences in the response to drugs of abuse. By studying females, researchers may discover important insights that are relevant for both females and males, keeping in mind that sex differences in the brain are fundamental. Understanding sex differences and similarities will improve understanding of neural function of both sexes.
Discussion: Robert Hitzemann, Ph.D., noted that his laboratory is going to publish a paper that shows the escalation of alcohol use is much stronger in heterogenous stock mice than it is in in-bred mice. Thus, there is a genetic role that also needs to be considered. Dr. Becker acknowledged that a number of factors contribute to differences; sex is one important factor. Louis Baxter, M.D., commented that those in addiction medicine have observed many sex differences clinically, but providers who are not addiction specialists are often unaware of them. He noted that Dr. Becker’s work provides a foundation for explaining such differences to these providers. Dr. Koob inquired about oxytocin’s natural role for males, other than being a transmitter in the brain. Dr. Becker responded that it’s important for ejaculation. In the brain, it’s important for pair-bonding, but pair-bonding in most males is less structured than the mother-infant bond. She would predict, if a sex difference were observed, that oxytocin would be slightly less efficacious in males because it’s primarily acting on the ventral pallidum in males rather than in the NAc, and the projections are less robust there in males. In regard to social interaction among rodents, Dr. Koob asked how male and females rats are housed compared to male and female mice. Dr. Becker said that male mice tend to fight when housed together. Her laboratory co-houses post-pubertal male rats who bond together, but the social behavior of the males is different from that of the females. Males play together and try to dominate, whereas females tend to huddle together. Edith V. Sullivan, Ph.D., inquired if post-partum females differ from other females in their responses to drugs and alcohol. Dr. Becker responded that researchers in her laboratory examined that issue and were surprised at the results. They expected that post-partum females would be less vulnerable to cocaine taking. It turned out that there wasn’t much of an effect until you stressed the animals (with a foot shock), then the post-partum females escalated much more rapidly than the nulliparous females. Also, their dopamine release in the NAc induced by cocaine was greater in the post-partum females than in the nulliparous females.. Susan Smith, Ph.D., commented that there’s now a culture of mothers self-medicating. Women aren’t rewarded for taking care of themselves; perhaps this is not a social construct but biological. Dr. Becker responded that scientists know the brain is totally changed when a rat has a litter of pups, so it seems that this is a topic that needs to be studied. In the human literature, there’s little attention paid to the differences between mothers and non-mothers; it could be an important consideration.
Council Member Presentation: Using Health Services Research to Improve the Delivery of Alcohol Services
Dr. Koob introduced Constance Horgan, Sc.D., Brandeis University, who discussed how health services research can be used to improve the delivery of alcohol services.
An Overview of Health Services Research: Health services research examines people’s access to health care; quality of care; health care costs; and outcomes. Its goals are to study the most effective ways to organize, manage, and finance high quality care based on evidence. It addresses health services within a full continuum of care framework, including prevention/education, recognition, treatment, and maintenance.
Changes in the Healthcare System: Recent imperatives in health care are causing profound change in the system, including: 1) health care reform and parity, which together have been two major forces for coverage expansion and new delivery models and alternative payment approaches; 2) measuring and rewarding performance, i.e., increasing effective health care delivery through incentives for accountability and quality improvement; 3) information technology, such as greater use of Electronic Health Records (EHRs), automated databases and computer-based information technology (e.g., clinical decision-making, patient monitoring/reminders); and 4) a movement toward integrated care, i.e., “no wrong door.” Payment and delivery system reform has altered key relationships among payers, provider organizations, providers, and patients with a focus on improving system performance.
Key Issues for Alcohol Services: The delivery of alcohol services has also changed. For example, alcohol was largely ignored in primary care in the past; in the future, alcohol use will be screened and monitored in primary care practices. With the increased use of EHRs, clinical services can now be coordinated, whereas in the past, there was little contact between alcohol services and primary care. Increasingly, the focus is on the “whole person” rather than specific body parts. Finally, fee-for-service is falling by the wayside as alternative payment models emerge. In general, changes in behavioral health services have lagged behind other areas of care.
Dr. Horgan illustrated these trends by citing two examples. The first is the integration of behavioral health and physical health care services. In an integrated system, substance use can be screened in primary care and monitored (if moderate in nature) or referred to specialty care. If referred, the individual can then return to primary care for continued monitoring. Integration may be viewed as a continuum, ranging from coordinated to co-located (on-site) to partially/fully integrated. To support full clinical integration, there must be an infrastructure that supports clinical integration, as well as financial and payment policies that support structural and clinical integration. Payment plans can either thwart clinical integration (e.g., by not paying for coordination activities outside face-to-face visits) or support it (e.g., by paying for communication and team-based care). These are important issues because clinical integration has been found to improve treatment outcomes, improve patient experiences, and reduce costs and service utilization for certain populations. There is not yet clear evidence about which care processes, models of integration, and payment structures are most effective.
Dr. Horgan’s second example addressed using payment strategies to improve quality. Pay for Performance (P4P) is “The systematic and deliberate use of payment incentives that recognize and reward high levels of quality and quality improvement can serve as a powerful stimulus to drive institutional and provider behavior toward better quality” (Institute of Medicine, 2007). Historically, both low and high quality providers earned the same income at the same volume levels. P4P or Results-based Financing (RBF) offers financial incentives to improve quality, care, access and efficiency. To adopt P4P, one must have measures and determine how to pay for them. There are well established performance measures in the addiction area, addressing, for example, Screening, Brief Intervention, and Referral to Treatment (SBIRT), identification and treatment, to determine whether high quality services are being delivered. There are concerns with P4P, such as design of the payment system, providers gaming the system, etc., and resolving them is an area where health services research can be helpful. There has been a lot of research in this area, particularly in mental health and addiction, largely done at the state level. The results indicate that improvements do happen in many areas of healthcare, e.g., waiting time and utilization, among others, but there is also evidence of unintended consequences in many areas. In summary, P4P initiatives are well established in the medical arena, but less well developed for addiction and mental health services. There are few rigorous studies and the evidence thus far is mixed. The field is still learning how to use P4P effectively.
The Future: Dr. Horgan identified the following key issues for the alcohol field moving forward: Adapting to the “whole person” concept (e.g., co-occurring medical, mental health and other substance use disorders [SUD]); identifying opportunities in a “less siloed” medical environment and the community (e.g., criminal justice, housing, workplace); and offering services across the full continuum of prevention, identification, treatment, and recovery.
Discussion: Dr. Koob highlighted the importance of parity, asking Dr. Horgan if she believes these issues will be resolved. She replied that there are many lawsuits regarding access to services, but other key issues involve getting the delivery system and clinicians to put the system into practice, i.e., the knowledge is not being implemented systematically. Daniel Calac, M.D., interjected that the system is right on the cusp of change with the advent of 5G technology, citing the example of Singapore. Dr. Horgan noted that health care in the United States provides high quality care for some populations but has not yet successfully addressed health disparities.
Council broke for lunch at 12:34 p.m. and reconvened at 1:20 p.m. for the afternoon session.
Consideration of Council September 12, 2019 Minutes/Future Meeting Dates
Council members voted unanimously to approve the minutes of the NIAAA Advisory Council meeting held on September 12, 2019.
Dr. Bautista announced upcoming meeting dates for 2020-2024. In 2020, the Council will meet on May 12, and September 10; the CRAN Council will meet in 2020 on May 13. In 2021, the Council will meet on February 4, May 11, and September 9; the CRAN Council will meet on May 12, 2021. In 2022, Council will meet on February 10, May 10 and September 8; the CRAN meeting will be on May 11. In 2023, Council will meet on February 9, May 9, and September 7; the CRAN Council will meet on May 10. In 2024, Council will meet on February 8, May 14, and September 12; the CRAN Council meeting will meet on May 15.
Council of Councils Report
Dr. Koob introduced former Advisory Council member Paul Kenny, Ph.D., Icahn School of Medicine, who reported on the Council of Councils (CoC). Composed of 27 members selected from NIH Institutes and Centers (IC) Advisory Councils, the CoC is supported by the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI). It reports to NIH Director Francis Collins, M.D., Ph.D. on matters related to the policies and activities of DPCPSI.
Directors’ Update: Dr. Collins’ report to the CoC included an update on the Helping End Addiction Long-term (HEAL) initiative to address the opioid epidemic. NIH spent $930 million on HEAL in FY2019 on 26 research projects across 12 ICs and over 40 FOAs. The CoC was asked to advise DPCPSI on the HEAL focus: unmanaged pain as a major issue and how treatments can be improved for substance misuse and addiction. In response, it is looking at preclinical research in pain management and the expansion of therapeutic options. The two main initiatives it considered were the identification of biomarkers or predictive capability if an individual experiencing acute pain will transition into chronic pain and the SPARC program which seeks to better understand how the brain and body interact, i.e., to map how the brain communicates with peripheral sites involving pain. Since new tools are emerging, this is a good time to study this phenomenon.
The Director’s update also addressed artificial intelligence (AI) in biomedicine, which is an important tool in analyzing Big Data. A Working Group was established to address how to handle Big Data sets. It issued initial recommendations in a June 2019 report, calling for more AI-ready data, more multi-lingual researchers with experience in both biomedicine and computer science, and the identification of important areas where AI may be applied.
Genome editing for disease intervention was another topic in the Director’s update. Currently, there is an international moratorium on clinical application of germline editing that NIH supports, as its consequences are not well understood.
Sexual and Gender Minority Research Working Group—a Report to Council of Councils: The Sexual and Gender Minority (SGM) Research Working Group of the Council was convened on September 5, 2018 to review progress to date on the SGM NIH Research Strategic Plan. In its interim report, the Working Group made the following recommendations in regard to Goal 4 (evaluate progress on advancing SGM research) of the Strategic Plan: 1) Explore the most effective ways to collect and report on the SGM status of participants in clinical research funded by NIH; 2) Provide a more exhaustive portfolio analysis, including by SGM population, of NIH-funded SGM research and identify comparison groups for the purpose of conducting analyses; and 3) Include in the next NIH SGM Research Strategic Plan goals related to operational activities, as well as scientific opportunities within the field.
Investigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE): Dr. Kenny highlighted a video clip of Mr. Frank Stephens’ testimony to the House Appropriations Committee on October 25, 2017 in which he said that Down Syndrome is looked upon incorrectly as a handicap. Individuals with Down Syndrome were not included in clinical trials at that time, so little is known about their health disparities. It is known that they are more vulnerable to some diseases, e.g., Alzheimer’s Disease and leukemia, but are protected from many cancers and heart disease/heart attacks. Initiated in FY 2018, INCLUDE is a trans-NIH initiative to study trisomy 21 to yield scientific discovery regarding the health and neurodevelopment of those with Down Syndrome and those at risk for co-occurring conditions such as Alzheimer’s. INCLUDE’s research plan has three components to address quality-of-life issues for those with Down Syndrome and their families: 1) Targeted high-risk, high-reward basic science studies on chromosome 21; 2) Building of a large cohort of individuals with Down Syndrome for comprehensive analysis and biomarker evaluation; and 3) Inclusion of individuals with Down Syndrome in existing and future clinical trials.
Stimulating Peripheral Activity to Relieve Conditions (SPARC): The SPARC program, a trans-NIH initiative supported by the Common Fund, seeks to accelerate development of therapeutic devices that modulate electrical activity in nerves to improve organ function. SPARC is generating maps and tools to identify and influence therapeutic targets that exist within the neural circuitry of a wide range of organs and tissues. This therapeutic strategy, also known as “bioelectronic medicine,” could offer new treatment options for diverse diseases and conditions such as hypertension, heart failure, gastrointestinal disorders, type II diabetes, inflammatory disorders, and more. It includes five interdependent initiatives: SPARC1 is constructing anatomical and functional datasets from organ-specific neural circuitry. SPARC2 is creating new tools and technologies to enable precise manipulation and measurement of nerve-organ interactions and their associated functions. SPARC3 is establishing effective research partnerships with clinicians, basic scientists, engineers, and private industry to pursue data-intensive, mechanistic clinical studies. SPARC4 is producing a suite of publicly available resources that allow data to be shared, cited, remixed, visualized, and computed. SPARC5 is generating anatomical and functional datasets from neural circuitry mediating visceral pain. This effort is associated with the HEAL initiative to speed scientific solutions to the national opioid public health crisis. Dr. Kenny shared some examples of projects funded under SPARC5 that address anatomical and functional mapping of pain-related visceral organ neural circuitry.
National Primate Research Centers: There is a consortium of National Primate Research Centers that provide primates for research across all ICS, and a concept clearance to continue funding them. Dr. Collins announced last year that NIH is no longer using chimpanzees in research but is housing approximately 250 NIH-owned or supported chimpanzees at the Alamogordo Primate Facility. They will be transferred to a chimpanzee haven; many of these animals are geriatric and can’t be moved easily. The CoC has established a Working Group to develop recommendations to facilitate this process.
Discussion: Dr. Koob commented that the NIH Blueprint for Neuroscience Research has a not-yet-released interoception program that is similar to SPARC; and addresses central nervous system control over the periphery. As a result, SPARC is “sparking” other interactive programs. He also noted that NIAAA has a strong interest in primate research, e.g., germline editing of marmosets, and has been invited to participate in the CoC Working Group; he suggested that he, Dr. Kenny, and Associate Director Patricia Powell, Ph.D., have a conversation in regard to NIAAA’s interests in the CoC. Dr. Smith commented that she was thrilled with the Down Syndrome initiative. In regard to the AI initiative, she asked if there was discussion about the crucial issue of reproducibility problems in the data sets. Dr. Kenny confirmed that discussion of this issue in the CoC has been extensive, with a goal of identifying best practices.
Hyperkatifeia Portfolio Analysis
Dr. Koob introduced Jenica Patterson, Ph.D., Division of Neuroscience and Behavior, and Rachel Anderson, Ph.D., Office of Science Policy and Communications, to demonstrate how NIAAA can use portfolio analysis, a systematic look at currently funded research projects, to identify trends and gaps in research as well as to identify and quantify outputs of funded projects. Portfolio analysis is supported by tools developed by NIH’s Office of Portfolio Analysis (OPA).
Dr. Patterson and Anderson specifically focused on hyperkatifeia for their portfolio analysis. Dr. Anderson explained that hyperkatifeia refers to an exacerbated negative emotional state during alcohol and drug withdrawal (Shurman, Koob, Gutstein, Pain Medicine, 2010). It is characterized by emotional distress and emotional pain during abstinence. Individuals in this state are vulnerable to relapse as they may return to alcohol drinking to alleviate negative affective symptoms. Understanding the neurobiological and behavioral processes that mediate hyperkatifeia can inform development of effective strategies for intervention.
Working with three years of data, the researchers began their analysis by identifying a list of potentially relevant projects from FY 2017-FY 2019 using iSearch, an OPA-developed tool. Next, they manually coded each project as to whether it addressed hyperkatifeia and then sorted those that did into categories. Finally, they conducted a descriptive analysis of categories and outputs. Next, limiting the search to R, P, U, K99 mechanisms only, the researchers searched for pairs of terms, i.e., withdrawal or abstinence or relapse AND dependence with the following terms: amotivation; anhedonia; anxiety; depression; dysphoria; irritability; negative affect; negative emotion; negative reinforcement; negative urgency; pain / hyperalgesia; stress response; suicide; unease; reward deficit; emotional regulation; and sleep disruption. Out of 198 projects, 73 addressed hyperkatifeia.
The researchers then conducted a backwards analysis to see which terms emerged most frequently using Visual Results, a clustering algorithm from OPA that uses words and phrases from the Title, Abstract, and Specific Aims of grants. It generated a figure that displayed the predominant concepts that emerged. Another tool, FoamTree, provides a tree map visualization of hierarchical clusters of category data sets.
In the categorization approach, the researchers manually categorized the 73 hyperkatifeia grants into underlying themes where the grants had some commonalities. For the preclinical studies, they identified 13 neurocircuitry grants; 17 neurotransmitter grants; five pharmaceutical/medicine development grants; two genetics grants; and five “other” grants. Human grants had similar categories except for the creation of a treatment/ non pharmaceutical category and omission of the neurotransmission category, i.e., three neurocircuitry grants; 17 pharmacology grants; eight treatment/non-pharmaceutical grants; one genetics grant; and four “other” grants.
The analysis revealed the most commonly-studied brain regions and targets among the 73 human and animal grants. Among brain regions, the amygdala and its subregions, as well as prefrontal cortex (PFC) and the bed nucleus of the stria terminalis (BNST) were most common; for circuits related to these brain regions, the common ones studied were the PFC to amygdala and Insula to amygdala circuits. Commonly studied targets (including ligands and receptors) were norepinephrine (NE) and corticotropin-releasing factor (CRF). The analysis also identified a subset of projects studying co-occurring disorders including post-traumatic stress disorder (PTSD) and depression. Ten of the 73 grants were conducting imaging analysis.
Next, the researchers analyzed the grants in terms of cost and activity code for animal and human grants within their respective categories, learning that NIAAA spent a total of $29.5 million for animal studies on hyperkatifeia (investing mostly in neurocircuitry and neurotransmission) and $34.5 million for human studies (investing mostly in pharmacology/medication development), for a total investment of $64 million. Examining the funding pattern over all three years, some trends began to appear, including an increase in funding over the years for neurotransmission studies and a decrease in funding for studies on neurocircuitry in humans.
Finally, the researchers wanted to take a deeper dive into the grant outputs including any publications, patents, clinical trials or approved drugs, using OPA-developed tools to collect this type of data. Many of the grants included in the analysis had funding predating the present analysis’ timeframe. Therefore, the researchers analyzed data that includes all years that those grants were actively funded up to 2019. This may add some bias to the analysis.
Over 2,500 publications were produced between 1984-2020 for the 73 grants. Further, the analysis showed an exponential increase in the number of publication per year over that time period. Animal studies generated 1673 publications; the majority were in the neurocircuitry and neurotransmission grant categories. Among human studies, 865 articles were published.
Other outputs of this research investment that the analysis identified include 30 clinical trials and four patents (but no approved drugs to date).
In conclusion, portfolio analysis provided an insightful view of the NIAAA hyperkatifeia funding landscape; the analysis should be expanded to include grants prior to FY17 to allow for trend analysis and a deep dive on publication outputs is needed. The researchers found that hyperkatifeia is an emerging theme in alcohol research; that hyperkatifeia translational research will provide information in human nosology (measurement and diagnosis), genetics, imaging, and prevention; and that new technology, new behavior models, and analysis tools will provide a better perspective of the hyperkatifeia state. Finally, other research domains may benefit from a conceptual portfolio analysis.
Discussion: Dr. Calac commented that he didn’t see many of the microbiology grants that were funded between 1980 to present included in this analysis. Dr. Patterson explained that was because the majority of grants included in the analysis had some type of behavioral outcome, so only human or animals studies were included. Dr. Baxter inquired about why withdrawal was used as a search term, rather than detoxification. Dr. Anderson responded that the researchers conceived of detoxification as one possible step in the withdrawal process. Dr. Koob suggested adding detoxification to the analysis to determine if its use resulted in different findings. NIAAA staff member Pamela Wernett, Ph.D., asked if NIAAA could use portfolio analysis in the NIH Research, Condition, and Disease Categorization (RCDC) System and become a tool readily used by the Institute. Dr. Patterson responded affirmatively.
Dr. Wernett also asked if the researchers had plans to look at publications to determine if they still fit the designated word classifications and determine how many of the grants were producing hyperkatifeia research. Dr. Patterson responded positively, but noted that this analysis will take time as there are 2,500 publications to consider. Dr. Koob stated that portfolio analysis is a tool to help NIAAA staff think outside the box.
FASD Concept Clearance
Kathy Jung, Ph.D., Director of the Division of Metabolism and Health Effects, presented a concept clearance for a Request for Applications (RFA) for developmental projects for the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD). Fetal Alcohol Syndrome Disorders (FASD) is a spectrum of lifelong health conditions affecting individuals with prenatal alcohol exposure, including facial anomalies, growth retardation, neurological abnormalities, and cognitive deficits. The estimated prevalence is 1 to 5 percent among 1st graders in four US communities (May PA et al., 2018. JAMA).
The CIFASD consortium was established to meet major challenges to FASD research: the need for multi-disciplinary/translational approaches as well as the need for a large number of study subjects to control for confounding variables. The current consortium (CIFASD4), operating from 2017 to 2022, includes nine U01 projects and two UH2 developmental projects that utilize 3D imaging, neuroimaging, neurobehavior, biomarkers, and telemedicine to address diagnosis/screening, interventions, and genetic/mechanism. It shares cohorts from the United States, Canada, England, and Ukraine.
Past CIFASD developmental grants have been successful. For example, five of the seven projects in CIFASD3 successfully competed for U01, R01, and R21 grants. New research directions were also established, e.g., maternal miRNA predictors of child outcomes and maternal cytokine biomarkers of exposure and effect. In CIFASD4, two UH2 developmental grants funded from 2017-2019 addressing “biomarker for intellectual disability in children prenatally exposed to alcohol” and “prenatal alcohol effects on the gut microbiome contributing to failure to thrive and altered immune function” were completed. Currently, analysis of their findings is ongoing and several manuscripts are in preparation.
A new RFA is needed to fund additional developmental projects to be completed during the final two years of CIFASD4. The goals of the new RFA are to solicit exploratory projects in novel and underexplored areas of FASD research. Awardees are encouraged to establish collaborative relationships with the CIFASD consortium to leverage resources and maximize the impact. Proposed as a UH2 grant for two years with open competition, proposed research topics include diagnosis and screening, etiology and mechanism, prevention approaches, and interventions.
Discussion: Dr. Smith expressed her full support for the concept, noting the progress that previous developmental projects have made and the new external review process that allows new voices to be heard. Laura E. Nagy, Ph.D., also voiced her support and inquired if collaboration with CIFASD would be a required element in proposals. Dr. Bautista responded that NIAAA would consider that idea in the development of the RFA, e.g., making it a scorable criterion. Dr. Calac inquired about the inclusion in CIFASD of a cohort of aborigines in Australia where the alcohol issues are different than in the United States. Dr. Jung referred the question to Bill Dunty, Ph.D., FASD coordinator in her Division. Dr. Dunty noted that CIFASD has not established a formal relationship with Australia; there are several researchers there actively addressing the issues that Dr. Calac raised. Dr. Koob noted that NIAAA funds foreign investigators in situations with unique circumstances, e.g. a significant concentration of cases.
Secondary Analysis DEPR/DNB Concept Clearance
Dr. Koob introduced Wenxing Zha, Ph.D., Division of Epidemiology and Prevention Research (DEPR), and Abbas Parsian, Ph.D., Division of Neuroscience and Behavior (DNB), who presented a concept clearance for the reissuance of a current Program Announcement (PA) with R01 and R03 mechanisms that expires in December. Dr. Zha explained that the purpose of this future solicitation in the form of a Notice of Special Interests (NOSI) is to encourage the submission of applications on secondary data analyses to enhance understanding of the patterns and trajectories of alcohol consumption, as well as the epidemiology and etiology, including genetics, of alcohol-related problems and disorders. It will support grant applications that propose innovative analyses of existing alcohol research data; answer novel research hypotheses and questions, and/or develop and test advanced analytical methodologies.
NIAAA has issued this announcement since 2001, in response to the increasing cost of data collection on human subjects; the rich existing data resources yet to be fully utilized; and the fact that secondary data analysis is a cost-efficient way to conduct research. Linkages and/or combination of data sets increases statistical power, as well as expanding the scope and impact of research. For the current funding cycle from 2017, NIAAA has received more than 30 applications to this PA.
The proposed scope of the research includes developing, improving and validating effective measurement of underage drinking, high- intensity binge drinking, drinking during pregnancy, adult alcohol misuse and alcohol use disorders (AUD); applying “Big Data” approaches to 1) integrating and harmonizing qualitative and quantitative measurements from various study designs and sources, and 2)
developing comprehensive analytical methods for the study of alcohol misuse and progression to alcohol use disorder; developing effective data analytical approaches for real-time assessment of alcohol consumption and related behaviors; developing machine learning and other artificial intelligence algorithms to study drinking patterns, identify and predict risky drinking behaviors, and enable timely targeted preventive interventions; developing a common metric of alcohol-related phenotypic and environmental measures across study designs; developing and engaging new genetic analysis methods such as pathway, network and multi-omics analyses; using new and novel Genetic/Genomics analytical tools to relate AUD Genome-Wide Association Study (GWAS) data with brain expression data to establish their relationships; and using novel bioinformatic tools to perform cross species genomics or comparative genomics to detect new Expression Quantitative Trait Loci (eQTL) related to AUD.
Data sources suitable for this PA include public domains, NIH-funded research studies, and others, such as health records. A list of available data sources includes the Alcohol Epidemiologic Data Directory;
Alcohol Policy Information System; NIAAA Data Archive; National Institute on Drug Abuse (NIDA) Data Share for clinical trials; NIH Data Repositories; and Data Base of Genotypes and Phenotypes at the National Center for Biotechnology Information (NCBI).
Discussion: Dr. Koob noted that data from the Adolescent Brain and Cognitive Development (ABCD) study are available in the National Institute of Mental Health (NIMH) Data Archive for use in secondary analyses. He expressed his enthusiasm for such studies because they often reveal hidden gems. He asked Council members to encourage researchers in their institutions to use secondary analysis as a way to generate hypotheses for further testing, noting such studies represent the perfect use of an R21 award. Dr. Horgan shared her own enthusiasm for the concept, noting that secondary analysis is also relevant in health services research. She asked if any consideration had been given to topics beyond epidemiology. Both Dr. Zha and Dr. Koob responded that the focus is broad and health services research would be suitable for this announcement. Dr. Nagy commented that there are many new publicly-available data sources beyond those listed by the presenters; Dr. Koob asked her and others to send an email to Dr. Bautista with suggestions for other data sets so that they can be added to the list. Scott Russo, Ph.D., asked for clarification regarding sources, e.g., would individual hospital databases be eligible? Dr. Koob responded affirmatively. Dr. Parsian commented that there are some restrictions on gaining access to different databases; he encouraged prospective applicants to contact NIAAA staff in advance of the application so that they can help the researcher gain access.
Integrative Neuroscience Initiative on Alcoholism (INIA)
Dr. Koob introduced Mark Egli, Ph.D., Deputy Director of the Division of Neuroscience and Behavior, to present a concept clearance on the Integrative Neuroscience Initiative on Alcoholism (INIA). Launched in 2001, INIA’s primary goal is to identify brain adaptations that result in excessive alcohol consumption at multiple levels of analysis. INIA supports translational, multidisciplinary, collaborative research efforts by two interactive consortia studying brain mechanisms of excessive alcohol consumption associated with AUD and the relationship between excessive alcohol use, stress, and anxiety.
INIA pioneered the use of the NIH cooperative agreement “U” mechanism to support multidisciplinary basic research. INIA also recognized that understanding AUD required knowledge of actions and interactions at multiple biological levels. Further, INIA proactively addressed broader research issues that subsequently emerged as priority NIH concerns: reproducibility (it developed standard alcohol drinking and neuroimaging paradigms now widely used in multiple labs); translation and backtranslation (including cross-species analysis ([from drosophila, to rodents, to non-human primates, to humans]), preclinical validation of systems pharmacology approaches for AUD medication target discovery, and nomination of repurposed medications for human lab AUD studies; and Sex as a Biological Variable (SABV). INIA was also successful in recruiting non-alcohol researchers into the alcohol field because of the collaborative nature of the consortia located at multiple institutions.
INIA remains relevant today because peripheral and central stress and neuroimmune pathways remain active neuroscience research topics; there is expanding appreciation of the AUD phenotype beyond excessive drinking to include negative affect, cognitive control disfunction, sleep dysregulation, and pain; and the opportunity now exists to take advantage of new tools developed in the BRAIN Initiative, as well as artificial intelligence (AI) tools and technologies and modeling approaches.
Thus, NIAAA is proposing continuing INIA. In its future iteration, INIA will consist of two research consortia each centered around a common theme and lead by Consortium Coordinator; a cluster of Cooperative Agreement projects (U01); and research resources (U24s) as needed. Each project will contribute data and analyses to other consortium components and address hypotheses which integrate different levels of analysis or mechanistically related manifestations of AUD, requiring between-consortium cooperation. Engagement of early-stage investigators and relevant experts outside the alcohol field will also be encouraged.
Discussion: Dr. Koob supported Dr. Egli’s key points, noting that the engagement of non-alcohol researchers is a strong part of INIA’s strategic approach.
Col. Charles Milliken, M.D., reported that the healthcare services of all Department of Defense (DoD) service branches will be merged as of the week following the present meeting. Speaking about the Army, which he currently represents, Col. Milliken noted that additional funding was appropriated for its healthcare system in 2008, which allowed the Army to triple its addiction assets.
It’s important for the military healthcare service to look at the whole person, rather than adopting a simplistic approach to addiction. The Army healthcare service was previously a heavily siloed system with paper charts; it was equivalent in nature to court-ordered care (i.e., care ordered by one’s commander). Following a cluster of suicides at Fort Bragg in 2002, the system added mental health questions to its existing post-deployment screening. Following research published in the New England Journal of Medicine that indicated increases in depression and anxiety, as well as excessive alcohol intake, among service members returning in the first wave from the war in Iraq compared to pre-deployment cohorts, the Army added alcohol-related questions to the screening in 2005. In a subsequent study published in the Journal of the American Medical Association (JAMA), researchers reported that soldiers were unwilling to go to a mental health clinic because they were worried about their military careers, i.e., only 2 percent of the 12 percent of soldiers identified with an alcohol problem based on screening three-to-six months post-deployment were referred for treatment because most persuaded their primary care physician to not refer them in order to protect their careers.
Funding increased again in 2007-2008; each service received $3 million to add additional resources. In 2016, Army researchers published a report in the Harvard Business Review describing how improved business practices were implemented to create an excellent mental health system, although alcohol services remained located elsewhere in the system. In 2012, Congress asked the Institute of Medicine (IOM) to examine substance abuse services in the military. Despite the IOM’s strong recommendations, it was not until 2015 when internal documents were leaked to the media that the Secretary of the Army put together a panel to consider current practices in light of the IOM recommendations. Among these were the recommendation that the military create a voluntary care path where service members could get treatment if their substance use was not so profound that it would cause problems. A pilot test of this approach was conducted in 2015 to show this was a feasible strategy and the voluntary path was accepted.
Since 2016, the Army’s behavioral health providers have been housed in the Army’s primary care clinics with approximately one provider for 1400 soldiers. All substance use providers are credentialed treat alcohol and other substances, as well as issues such as depression and PTSD. At the Army’s 12 largest installations, there are partial hospital programs and there are four residential treatment facilities with 60 beds. Today, there are 6,000 soldiers enrolled in the voluntary care track, and treatment has been vastly improved.
Discussion: Dr. Koob commented that he always feels hopeful after hearing about treatment services in the military and the Veterans Administration healthcare system. He offered assistance with the identification of evidence-based practices.
There were no public comments.
Dr. Koob adjourned the meeting at 3:20 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
George F. Koob, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
National Advisory Council on Alcohol Abuse and Alcoholism
Abraham P. Bautista, Ph.D.
Office of Extramural Activities
National Advisory Council on Alcohol Abuse and Alcoholism