DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

143rd Meeting of the
NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM

September 15, 2016 

The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened for its 143rd meeting at 10:24 a.m. on Thursday, September 15, 2016, at NIAAA headquarters in Rockville, Maryland. The Council met in closed session at 9:00 a.m. to review grant applications; the review session recessed at 10:02 a.m. 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.

 Council Members Present:

Carmen E. Albizu-Garcia, M.D.

Carol A. Casey, M.D.

Carlo C. DiClemente, Ph.D.

Tom Donaldson

James H. Eberwine, Ph.D.

Joseph Thomas Flies-Away, J.D.

Tatiana M. Foroud, Ph.D.

Paul J. Gruenewald, Ph.D.

Joe L. Martinez, Ph.D.

Sarah N. Mattson Weller, Ph.D.

Patricia E. Molina, Ph.D.

Adolf Pfefferbaum, M.D.

Arun J. Sanyal, M.D.

Rajita Sinha, Ph.D.

Frank A. Sloan, Ph.D.

Constance M. Weisner, D.R.P.H. (on phone)

Karen Drexler, M.D., ex-officio

NIAAA Director and Chair: George F. Koob, Ph.D.

Acting NIAAA Deputy Director: Patricia Powell, Ph.D.

Executive Secretary: Abraham P. Bautista, Ph.D.

Senior Staff: Vicki Buckley, M.B.A.; Vivian Faden, Ph.D.; Ralph Hingson, Sc.D., M.P.H.; Robert Huebner, Ph.D.; M. Katherine Jung, Ph.D; Raye Litten, Ph.D.; Antonio Noronha, Ph.D.

Other Attendees at the Open Session:

Approximately 45 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 10:24 a.m. on Thursday, September 15, 2016. Council members and senior NIAAA staff introduced themselves. Dr. Koob thanked the retiring members of Council—Carol Casey, Ph.D.; Joseph Flies-Away, J.D.; Paul Gruenewald, Ph.D; Patricia Molina, Ph.D., M.D.; Robert Messing, M.D.; and Sarah Mattson Weller, Ph.D.—for their service.

 

Director’s Report

Dr. Koob highlighted key recent NIAAA activities, referring to the written Director’s Report which was distributed to Council members.

Budget: The National Institutes of Health (NIH)’s budget for FY 2016 is $32.3 billion. NIAAA’s budget of $467.4 million is a 4.9 percent over FY 2015. The overall NIH budget includes increases for the BRAIN Initiative, Alzheimer’s disease research, antibiotic resistance research, and the Institutional Development Award program, as well as support for the Precision Medicine Initiative and the Gabriella Miller Kids First Pediatric Research program. The President’s FY 2017 budget request for NIH is $33.136 billion, a 3.65 percent increase; the NIAAA request is flat at this point. The appropriation bill is before Congress, but is unlikely to pass before the November election, so that a continuing resolution is expected. NIAAA anticipates that its budget will remain at its current level.  

• NIAAA Strategic Plan: NIAAA staff submitted the draft Strategic Plan to Council and other experts during the summer for comments, and revisions are nearly complete. Feedback will be solicited from the public through a Request for Information (RFI) in September. The goal is to finalize it by the end of the year. Dr. Koob thanked Council members for their comments. 


• Surgeon General’s Report: This report, in which NIAAA and the National Institute on Drug Abuse (NIDA) played a major role, is expected to have a significant public health impact. It will present the state-of-the-science on alcohol and other substance misuse and substance use disorders (SUD) with a focus on neurobiology, prevention, treatment, recovery, and delivery of care. Dr. Koob and NIDA Director Dr. Nora Volkow co-authored the chapter on neurobiology.  The report will be released in November 2016. 


• ABCD Study: The Adolescent Brain Cognitive Development (ABCD) study began recruitment on September 13, 2016 at 19 sites across the country, with a goal of enrolling 12,500 9- to 10-year-olds over the coming year. The U.S. Centers for Disease Prevention and Control (CDC) and the Department of Justice are interested in supporting both the core and ancillary studies. There will be a Congressional briefing entitled “Brain Development and Our Kids’ Future – the Adolescent Brain Cognitive Development (ABCD) Study” on September 19, 2016, sponsored by Friends of NIAAA, Friends of NIDA, and the Congressional Addiction, Treatment, and Recovery Caucus.


• Staff Transitions: New staff at NIAAA include Anna Ghambaryan, M.D., Ph.D. as a Scientific Review Officer; Yvonne Horneffer, M.S.N., C.R.N.P., Clinical Nurse Practitioner; Timothy Karacki, Financial Analyst; Jennifer Leese, Office of Research Management; Donna Stringfield, Extramural Support Assistant; and Tonette Vinson, C.R.N.P., O.C.N., as Adult Nurse Practitioner. Congratulations were extended to Vicky Buckley, appointed Associate Director for Administration (Executive Officer), and to M. Katherine Jung, Ph.D., appointed Director of the Division of Metabolism and Health Effects.


• New Notice of Funding Opportunities (NOFOs): NIAAA has released Notice of Funding Opportunities (NOFOs) for a U.S.-Russia Bilateral Collaborative Research Partnership on the Prevention and Treatment of HIV/AIDS and HIV-Associated Comorbidities (R01); a Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) Consortium (U01/U24/UH2); Wearable Alcohol Biosensors (R34/R44) (Small Business Innovation Research); and Secondary Analyses of Alcohol and Chronic Disease (R01/R03).


• NIAAA Media Engagement: On a Satellite Media Tour, Dr. Koob participated in 28 separate interviews in 4 hours targeting parents with information about the risks of alcohol at college, timed as students were leaving for campus. The interviews included television stations in 12 cities in 9 states and statewide in North Carolina, as well as radio feeds to over 170 stations. The total audience reached was 8,305,040 people. Deidra Roach, M.D., of NIAAA’s Division of Treatment and Recovery Research, was featured in a story about correspondent Elizabeth Vargas’ struggle with alcohol in an episode of 20/20 on ABC that aired on September 9, 2016. The interview included shots of NIAAA publications, and the program’s website included links to NIAAA resources. Drs. Kob and Roach will also be featured in an upcoming HBO documentary.

 

NIAAA Research Highlights: Dr. Koob presented highlights of NIAAA-funded studies, both extramural and intramural. The theme is translational research, with a focus on the work of Council members and NIAAA intramural researchers. 

S Jabbar, LG Chastain, O Gangisetty, MA Cabrera, K Sochacki and DK Sarkar reported that maternal alcohol consumption three weeks prior to conception was associated with increased stress hormone response to an immune challenge and changes in expression and female offspring during adulthood (“Preconception Alcohol Increases Offspring Vulnerability to Stress” In Neuropsychopharmacology  (2016) 41, 2782–2793 )

“A Decision Tree to Identify Children Affected by Prenatal Alcohol Exposure” published in the Journal of Pediatrics (2016) 177:121-127, by council member Dr. Sarah Mattson and co-authors, P Goh, LR Doyle, E. Riley, PA May, ER Sowell and JR Wozniak, provided pediatricians with a tool to distinguish children and adolescents affected by prenatal alcohol exposure from non-exposed children, including those with other behavioral conditions.

 A study conducted by Dr George Kunos and his group (R Cinar, MR Iyer, Z Liu, Z Cao, A Rosenberg, JS Liow, RG Lorenz, P Pacher and RB Innis) from the NIAAA’s Division of Intramural Clinical and Biological Research, “Hybrid Inhibitor of Peripheral CB1R and Inducible Nitric Oxide Synthase Mitigates Liver Fibrosis” published in JCI Insight (2016;1(11):e87336) revealed that dual-target peripheral cannabinoid receptor 1 (CB1R)/inducible nitric oxide synthase (iNOS) antagonist (MRI-1867) slowed liver fibrosis progression and attenuated established fibrosis in mouse models. NIAAA is currently working on patents and licensing of this compound with pharmaceutical companies.

Another NIAAA study by CW Kahler, T Liu, PA Cioe, V Bryan, MM Pinkston, EM Kojic, N Onen, JV Baker, J Hammer, JT Brooks and P Patel, entitled “Direct and Indirect Effects of Heavy Alcohol Use on Clinical Outcomes in a Longitudinal Study of HIV Patients on ART” in AIDS and Behavior (2016: doi:10.1007/s10461-016-1474-y ) found that alcohol use leads to physiological injury and increased mortality risk at lower levels in people living with HIV (PLWH), and increased heavy drinking frequency deleteriously affects HIV viral load, CD4+ T-cell counts, and estimated liver fibrosis in PLWH on antiretroviral therapy (ART). Some of these effects are mediated by alcohol’s effect on ART adherence.

“Alcoholism and Sexual Dimorphism in the Middle Longitudinal Fascicle: A Pilot Study,” published by J Seitz1, KS Sawyer, G Papadimitriou, M Oscar-Berman, I Ng, A Kubicki, P Mouradian, SM Ruiz,  M Kubicki, GJ Harris, and N Makris in Brain Imaging and Behavior (DOI 10.1007/s11682-016-9579-5) addressed the role of the middle longitudinal fascicle (MdLF), a white matter fiber tract thought to play a role in language and attention. It found that abstinent men with alcohol use disorder (AUD) and a history of chronic alcohol misuse had greater structural deficits in MdLF compared to women. These deficits were associated with impairments in verbal IQ and fluency in men but not in women.

Council member Dr. Rajita Sinha and co-authors CM Lacadie, RT Constable and D Seo published an article entitled “Dynamic Neural Activity during Stress Signals Resilient Coping” in the Proceedings of the National Academy of Sciences (2016 )113 (31) 8837-8842, describing that acute, functional neuroplasticity occurs in distinct brain networks underlying critical components of the stress response during sustained stress. Individual differences in neural signals during stress are predictive of coping ratings and coping behaviors, including alcohol consumption.

Council member Dr. Adolf Pfefferbaum, and co-authors AP Le Berre, EM Muller-Oehning, D Kwon, MR Seventi and EV Sullivan reported in an article on “Differential Compromise of Prospective and Retrospective Memory Monitoring and Their Dissociable Structural Brain Correlates” (Cortex (2016 81:192-202) that judgment of prospective (future) recognition performance was impaired in alcohol-dependent participants compared to controls; judgment of retrospective (past) memory performance was not impaired in either group. Overestimation of future memory performance by individuals with AUD suggests an unawareness of their memory deficits that may contribute to AUD maintenance.

In an article entitled “Episodic Future Thinking: Expansion of the Temporal Window in Individuals with Alcohol Dependence” (Alcoholism: Clinical and Experimental Research (2016) 40:1558-1566), SE Sinder, SM LaConte and WK Bickel found that individuals with alcohol dependence used training in episodic future thinking (EFT) to imagine positive future events for each of 5 time points and to generate a cue to remind them of each event. These cues were then presented during a delay discounting task to measure preference for immediate and delayed rewards. EFT increased the temporal window for selecting rewards such that future rewards became more valued.

A study entitled “An Exploratory Evaluation of Take Control: A Novel Computer-Delivered Behavioral Platform for Placebo-Controlled Pharmacotherapy Trials for AUD” published by EG Devine, M Ryan D Falk, J Fertig and RZ Litten in Contemporary Clinical Trials (2016) 50:178-185 compared Take Control, a computer-delivered behavioral platform derived from NIAAA’s Rethinking Drinking, with therapist-delivered behavioral platforms (TDP), Medical Management and Brief Behavioral Adherence Enhancement Treatment, on measures of retention, medication adherence, and placebo response. It found that the Take Control group had a medication adherence rate that was statistically greater than the TDP group.

Another NIAAA-funded study by SP Lane, D Stenley and KJ Sher, “Meta-Analysis of DSM Alcohol Use Disorder Criteria Severities: Structural Consistency is Only Skin Deep” published in Psychological Medicine (2016) 46:1769-1784, found considerable disagreement on the AUD criterion severity in the Diagnostic and Statistical Manual of Mental Disorders (DSM) across assessment instruments, protocols, and alcohol research studies, suggesting challenges to generalizability of results across population groups, thus highlighting the need for improved standardization of diagnostic measures to better inform validity of AUD diagnostic assessment. 

“Addictions Neuroclinical Assessment: A Neuroscience-Based Framework for Addictive Disorders” in Biological Psychiatry (2016) 80:179-189 by NIAAA researchers, LE Iwako, R Momenan, RZ Litten, G Koob and D. Goldman,  lays the conceptual foundation for assessments of AUD and other addictive disorders using the Research Domain Criteria (RDoC) approach that engages a biological framework based on genetics, neuroscience, and behavioral science to provide a better understanding of the complexities of psychiatric disorders, and thereby to better target prevention and treatment to the individual.

Discussion: Joseph Flies-Away, J.D. inquired if the findings from the delay discounting study took cultural concordance into account, i.e., if one cultural group doesn’t think as much as others about the future, how could discounting be explained in that group? Dr. Koob responded that different socio-economic groups may have different baselines for optimism, but that individuals with AUD within each group would likely show a deficit compared to his or her peers within the group. He acknowledged the importance of this concern and stated that the field will need to do more work in this domain and the cultural aspects of it.

 

NIH Training and Early Stage Investigator Programs: Updates from the Division of Biomedical Research Workforce

Dr. Koob introduced Kay Lund, Ph.D., Director of the NIH Division of Biomedical Research Workforce Programs. The Division is tasked with developing, maintaining, enhancing, and assessing NIH policies and programs that support innovative research training, career development, and diversity of the biomedical research workforce. Dr. Lund reported on current activities of the Division, including the following:

K99-R00 Program: The K99-R00 initiative is a new training program established in 2006 in response to the Bridges to Independence report. It consists of a two-year mentored phase (K99), followed by a three-year independent phase (R00), with the goal of promoting earlier transition to faculty positions and lowering the average age of new investigators (42 in 2006). Key findings of an outcomes study of K99-R00 applicants between 2007-2015 found that they averaged age 34 at the time of application; there were fewer women (40 percent applicants and awardees); 86-95 percent transition from a K99 to an R00; fewer women than men move to another institution; and there were many fewer M.D.s and M.D./Ph.D.’s than Ph.D.’s. The success rate of applicants is around 22 percent with just over 200 awards made annually. The first cohort from 2007 has had remarkable success (almost 80 percent) in obtaining R01 and New Innovator (DP2) grants or other Research Project Grants (RPG); 2008-2010 cohorts were also successful in obtaining further grant funding. The median age among these individuals for obtaining an R01 or DP2 grant was 39; most were Ph.D.’s. The age of successful M.D. grant applicants remains over 40.

IRACDA Program: The Institutional Research and Academic Career Development Awards (IRADCA) program is a K12 grant for early stage postdoctoral students in the first or second year after they receive their Ph.D. degrees, run through the National Institute for General Medical Sciences (NIGMS). Initiated in 1999 with two institutions, it now numbers 21 and boasts 450 alumni. The program promotes consortia between research-intensive institutions (RII) and partner institutions that serve students from groups underrepresented in the biomedical and behavioral research enterprise of the nation, providing support for a traditional mentored postdoctoral research experience at the RII combined with mentored teaching assignments at the partner institution. There is a high expectation that participants will achieve a faculty position at the end of their training; an outcome study among IRADCA alumni between 1999 and 2014 found that over 70 percent were successful in doing so. Further, a higher proportion of these alumni were teaching at institutions serving underrepresented groups than were an F32 comparison cohort. IRADCA alumni were also found to be more diverse and more likely to be drawn from underrepresented groups, so this program represents a novel approach to enhancing the diversity of the biomedical workforce.

Other Post-Doctoral Training Issues: A trans-NIH National Research Service Award (NRSA)/F32 evaluation is currently nearing completion; initial findings indicate enhanced retention and success in obtaining RPGs among awardees. Dr. Lund led a working group on post-doctoral benefits that considered issues such as the discrepancy between NRSA training-related expenses/institutional allowance and the benefits for RPG-supported postdocs. The working group recommended increased benefits and a separate category of subsistence allowance to cover benefits and these recommendations have been presented to the Director of the Office of Extramural Research (OER). These recommendations will be further discussed.  

A recent Department of Labor (DOL) rule such that salaried professionals earning less than $47,476 are eligible for paid overtime has raised a dialogue about how post-doc training fits into a 40-hour work week.  NIH Director Francis S. Collins, M.D., Ph.D., has indicated support for increased pay for postdoctoral researchers. NIH issued a Guide notice indicating projected increases in NRSA stipends for FY 2017 to levels above the new threshold (subject to FY 2017 appropriations). Many institutions plan to raise pay for RPG-supported postdocs, but there are some concerns this will lead to reductions in the number of postdocs.

Diversity: Enhancing the diversity of the biomedical research workforce is a major goal.  A new website providing information and resources regarding NIH programs which provide support to enhance diversity has been under development within DBRW and with both NIH and Institute/Center(IC)-specific information and will be launched soon.  A Request for Information (RFI) on increasing diversity of the physician scientist workforce, was issues and responses provide insight into needed programs and resources.  Dr. Lund is a member of an NIH working group on Women in Biomedical Careers led by the Office of Research on Women’s Health. The group focuses on re-entry and retention programs supported by NIH, and considers new programs like Doris Duke Helping Hands for those with work-life balance issues.

Physician-Scientist Workforce: A workshop was convened in February 2016 to develop new approaches to enhancing the physician-scientist workforce, which is not increasing in size despite an increased need. Participants included physician-scientists; leaders at academic health centers; early stage investigators; representatives of professional societies and licensing boards; and NIH staff from the Office of Director and multiple ICs. Three major issues emerged: The need for more support for research during residency; partnerships for faculty career development; and a greater number of research on-ramps to facilitate entry into research activity. Specific recommendations included research in residency programs tailored to specialty; input from accreditation boards; new pilots to support research in residency and transition to fellowships; retention and diversification of faculty through mentoring networks; engagement of professional societies in co-training /faculty development; broadening metrics of success beyond being Principal Investigator; and optimizing administrative supplements to research grats (e.g., diversity, on-ramps for residents/M.D.’s).

New Tools & Resources: The Division of Biomedical Research Workforce Programs launched an NIH research training website (https://researchtraining.nih.gov), organized by career stage, in 2015.  A new Biomedical Research Workforce Dashboard, which includes NIH and Association of American Medical Colleges (AAMC) data is under development with an anticipated public launch in late 2016/2017.

Other Issues: Concerned about the morale of biomedical research trainees and early stage investigators, Dr. Lund seeks to address questions such as these: How can pre- and post-doctoral training be better aligned with needed and essential jobs/career paths, e.g., integration with business, policy, communication? Can more be done to promote earlier independence, for all scientists including physician scientists? What are the characteristics of effective mentors/mentoring at different stages of career development and can we collect better data? In talking with early career investigators, she emphasizes the positive outcomes of a biomedical research career, such as exciting new scientific discoveries, flexible and rewarding career paths, pride in the accomplishment of mentees, etc.

Discussion: Carmen Albizu-Garcia, M.D. asked how many biomedical researchers applied to the NIH Loan Repayment Program (LRP) and their subsequent success compared to other professionals. Dr. Lund responded that the Division of Loan Repayment (DLR) is completing an evaluation of the LRP to obtain that information. There are plans for an American Association for the Advancement of Science (AAAS) Fellow who recently joined her Division, to join a study evaluating the K awards and LRP awards in terms of retention and success. James Eberwine, Ph.D., reflecting on the number of women who stay at their home institution, inquired if people, who stay at their home institution, with a K award received a reduced package from institutions. Dr. Lund said she thinks that having an award enhances the package, but that this is an issue that requires further investigation. Dr. Eberwine posed a second question: What is NIH’s position on unionization of postdocs? Dr. Lund responded that this issue is not within NIH’s purview. Dr. Mattson Weller asked if researchers who stay at home institutions have better success rates. Dr. Lund responded that her Division doesn’t know yet but will definitely will be looking at that in its analyses. Regarding the K99 program, Carlo DiClemente, Ph.D. inquired if there was a difference in tenure decisions between those in academic vs. those in medical settings, since universities are balancing research with teaching. Dr. Lund replied that people seeking tenure need to document their informal teaching and their mentoring activities, particularly the outcomes of their mentees.  Dr. DiClemente asked if NIH had considered the fact that people sometimes seek to work for clinical programs because their institutions are unable to support them unless they’re successful in obtaining grant support. Dr. Lund noted that it is important to consider broader metrics of success for physician-scientists than serving as a PI including a different context, such as, significant contributions to research as a co-investigator. Dr. Lund responded affirmatively to Dr. Koob’s inquiry whether the data on the Dashboard can be broken out by the IC.  Dr. Pfefferbaum noted that Dr. Lund’s presentation was university-centric, but that much research is also done at non-profit research institutions. Dr. Lund responded that the presentation was intended to be relevant to all institutions. Dr. Pfefferbaum stated that a faculty position is an irrelevant issue at a non-profit organization, where different criteria apply. Dr. Lund stated that IRADCA is focused on faculty positions at institutions engaged in teaching, but obtaining a position at a non-profit is a success.

 

BRAIN Initiative Research

Dr. Koob introduced Dr. Eberwine who serves as the NIAAA representative to the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative. Dr. Eberwine reported on the Initiative’s Mid-Council Working Group Meeting, which was held on August 2, 2016. Dr. Eberwine stated that the Mid-Council Working Group (MCWG) includes representatives from ten ICs, as well as some at-large members. The Initiative is now three years into its 10-year program. The first five years were set aside to develop new methodologies; the second five years will see their implementation. There have been two to three NOFOs released each year thus far, and over 130 articles have been published from BRAIN-funded programs. Joshua A. Gordon, M.D., Ph.D., the new NIMH Director, joined NIH in September and will be assuming co-leadership of the MCWG. NIH is actively recruiting for new scientific staff to join the Initiative, including a new BRAIN Director and BRAIN Program Directors/Analysts who will divide their time between the Initiative and BRAIN-related activities at their respective ICs.

FY 2014 and 2015 BRAIN awards included 3 for Short Courses; 10 for Cell-­‐Type Classification; 25 for Novel Tools – Cells and Circuits; 14 for Next Generation Human Imaging; 3 for Next Generation Human Invasive Devices (2 Requests for Applications [RFAs]); 53 for Large-­‐scale Recording & Modulation (5 RFAs); and 17 for Integrating Approaches to Understand Circuit Function. The FY 2016 budget was $150 million. The President’s FY 2017 budget request for the Initiative is around $195 million. The Working Group’s recommendation is to increase this amount to $400 million per year in FY 2018 and to a stable $500 million by 2021, resulting in a $4.5 billion investment by FY 2025.  The largest single category of funding is set aside for human imaging/modulation studies, which are very expensive to conduct.

A Joint Meeting between NIH and the U.S. Department of Energy (DOE) was held on October 16, 2015 to explore DOE joining the Initiative.

A Mammalian Brain Cell Diversity and Census Meeting was held September 7-8 to initiate and promote discussions among international groups in identifying, classifying, and phenotyping cell types in the mammalian brain and to discuss the potential to coordinate the production of broad reference cell catalogs for the mammalian brain.

BRAIN Neuroethics Workgroup: The BRAIN Initiative research poses major ethical issues. A consultative ethics group co-­chaired by Christine Grady, R.N., Ph.D., Chief of the Department of Bioethics at the National Institutes of Health Clinical Center, and Hank Greely, Director of the Stanford University Program in Neuroscience and Society, has been established to work with BRAIN leadership and BRAIN investigators. The Workgroup held its first meeting on February 9, 2016, with BRAIN Principal Investigators conducting invasive human studies. A second meeting was held on August 3, 2015. The Workgroup is considering workshops on privacy and ethics of research with invasive neurotechnologies.

An RFI for Guidance for Opportunities in Neuroethics closed July 29.

Upcoming Events and Opportunities: There will be a satellite meeting entitled “BRAIN Initiative TAD Talks: Technology Accelerating Discovery” as a pre-session at the 2016 meeting of the Society for Neuroscience in November that will feature short talks about what the Initiative has developed.  The 3^rd Annual Brain Investigators meeting will be held December 12-14, 2016, with sessions open to those without BRAIN grants. Over 1000 people are expected to attend, double the number that attended the 2015 meeting. There will also be additional RFAs released soon.

Changhai Cui, Ph.D., from the Division of Neuroscience and Behavior at NIAAA reported that alcohol researchers have submitted six applications in response to four different BRAIN Initiative RFAs in 2016.  Three of these applications were scored. One, from Paul Slesinger, Ph.D. at the Icahn School of Medicine at Mount Sinai, to adapt a cell-based approach to achieve real-time in vivo imaging of neuropeptides released in a defined brain area, was funded. The RFAs to which the researchers responded will be reissued and they will have an opportunity to revise their applications and resubmit them in 2017.

Discussion: Dr. Noronha added that NIAAA is supporting another researcher, Tom Kash, Ph.D., at the University of North Carolina. He’s working on the development of optogenetic models to differentiate and stimulate different cell types in the brain. Dr. Koob expressed his appreciation to Dr. Eberwine for representing NIAAA on the MCWG and noted the importance of full-time leadership for the Initiative, which has emerged as a major program.

 

Consideration of Minutes of the June 2016 Council Meeting and Future Meeting Dates

Council members unanimously approved the Council’s Standard Operating Procedures (SOP) (see Appendix A*) for the coming year, as well as the minutes of the NIAAA Advisory Council meeting held June 9, 2016.

In 2017, the NIAAA Council will meet on February 9, on May 2, and September 14. The Collaborative Research on Addiction at NIH (CRAN) Council meeting will take place on May 3, 2017. In 2018, the Council will meet on February 8, May 15, and September 13; the CRAN Council will meet on May 16, 2018.

Council broke for lunch at 12:11 p.m. and reconvened at 1:17 p.m. for the afternoon session.

 

Council Member Presentation: Alcohol Interaction with HIV; Translational Approach to Understanding Comorbidities

Dr. Koob introduced Council Member Patricia Molina, Ph.D., M.D. Dr. Molina is the Director of the Comprehensive Alcohol Research Center (CARC) at Louisiana State University (LSU). Her presentation about alcohol’s interaction with human immunodeficiency virus (HIV) centered on the following themes:  importance of a comprehensive alcohol research center in contributing new research; the value of such a research center as a training ground for new researchers; and the challenge of conducting translational research.

Researchers at the LSU Alcohol Research Center, first funded in 1993, initially used in vitro and rodent studies to examine the impact of alcohol on host defense from lung bacterial infections, and subsequently to HIV proteins. Subsequently, the scientific focus expanded to the effects of alcohol on HIV disease, leading to the development of a non-human primate model of chronic binge alcohol administration and simian immunodeficiency virus (SIV) infection in collaboration with the Tulane Primate Center. The initial outreach component was developed in collaboration with the College of Pharmacy at Xavier University, a historically Black University, and consisted of a community-based pharmacist-delivered HIV and alcohol use disorder prevention program. However, when New Orleans was hit by Hurricane Katrina in 2005 much of the infrastructure supporting this initiative was destroyed. Two years later, the outreach focus shifted to a prevention program focusing on HIV risk and protective behaviors among alcohol-using African American social networks in rural communities.  In 2014, the focus of outreach efforts returned to the high-risk underserved urban HIV primary care clinic population. In addition, a bidirectional translational approach added clinical studies to the center.  Today, the Center has five research components, two in female macaques and three in human subjects that will continue its emphasis on the impact of alcohol on the immune system, with a focus on aging and comorbid conditions ranging from cancer to metabolic syndrome and integrating an environmental and behavioral dimension that complements its studies by factoring in stressors that impact on patterns of alcohol consumption, medication adherence, and, consequently, disease progression.

A considerable amount of scientific progress has been achieved using the Center’s longitudinal integrated systems biology approach to examine how chronic binge alcohol (CBA) consumption affects disease progression, response to antiretroviral therapy (ART), and end organ pathophysiology in SIV-infected macaques. This model has provided a unique opportunity to conduct a comprehensive study of the biomedical consequences of chronic binge alcohol consumption on disease progression. The most salient finding from these studies is that CBA accelerates progression to end-stage disease, as reflected by the shorter mean time to death in alcohol vs. sucrose control SIV-infected animals not treated with ART. Two major domains have been identified as the main mechanisms underlying alcohol’s impact on disease progression: alterations in immunoregulation that Center researchers believe initiate with immune activation, altering mucosal immunity, driving viral replication; and increasing infectivity and the second; metabolic dysregulation, particularly at the level of skeletal muscle and adipose tissue.

As the Center moves to a bidirectional translational approach, it is in a unique situation to conduct clinical studies, as LSU Health Sciences Center’s HIV Outpatient Clinic provides care for approximately 50 percent of New Orleans Parish patients with HIV/AIDS (~7200). This population is predominantly African American, 35 percent female; and with a substantial fraction being above 50 years of age and with AUD present in over 30 percent of patients. These translational studies address several of the high priorities for NIH-funded research on HIV, but are particularly posed to address two urgent challenges facing the HIV/AIDS epidemic:  Aging and its associated increased risk for comorbidities with an emphasis on the understudied female HIV/AIDS population. Ongoing studies have completed baseline assessments in over 150 subjects. Approximately 15 percent of subjects have CD4 counts below 200 and a similar number have uncontrolled viral loads.

Collectively, studies from the Center have shown that alcohol increases lymphocyte turnover and decreases the total number of lymphocytes in the small intestine, while increasing the percent of gut and vaginal mucosal HIV target cells. The decrease in total lymphocyte numbers in the gut is accompanied by marked increases in both CD4+ and CD8+ T-cell proliferation, coupled with increased T-cell death, especially in the CD8+ T-cell population. These observations of T-cell loss and turnover have been mostly restricted to the intestine, where alcohol has been demonstrated to adversely affect mucosal barrier function.

Researchers at the Center believe that the increased infectivity may be explained by changes in mucosal microbiome and increased inflammatory cell infiltrates in the genital compartment. The absence of lactobacillus morphotypes in the vaginal flora is characteristic of bacterial vaginosis and increased vaginal pH, which impair genital innate defenses. Bacterial Vaginosis is associated with increased risk of sexually-transmitted diseases (STDs). Several studies have also shown an association between lack of lactobacillus and an increased risk of HIV infection, as well as higher levels of vaginal virus shedding.

Additionally, higher numbers of white blood cells (WBC) were observed in the genital fluids of most CBA animals even before SIV infection, and this has been associated with increased risk of HIV acquisition. The WBC represent both neutrophils and lymphocytes; they could be inducing damage to the epithelial barrier as well as providing target cells for the virus.

Despite higher viral load at set-point, Center researchers have shown that CBA did not prevent the ART-mediated suppression of plasma viral load. However, they recognize that this response was seen under controlled conditions in which the animals were young, exposed to behavioral enrichment, not stressed, and fed a nutritionally complete diet. In addition, the administration of ART was continuous. The higher viral loads in the CBA animals were not associated with greater numbers of infected cells in reservoirs, but were associated with higher replication in viral reservoirs.

The question was whether AUD in the Center’s clinical sample would also be associated with increased viral loads and viral replication. Analysis of initial subjects from the clinical studies show that persons living with HIV/AIDS (PLWHA) with higher Alcohol Use Disorders Identification Test (AUDIT) scores have higher viral loads similar to those observed in the macaque model. In addition, individuals with alcohol use disorders show greater seropositivity for Kaposi’s sarcoma herpes virus (KSHV), which is the virus that causes Kaposi’s sarcoma, a common HIV-associated tumor. Among the factors leading to increased KSHV are increased inflammatory cytokines and reactive oxygen species (ROS) production, both associated with alcohol use disorders. AUDIT scores correlate with KSHV serotiters (latency-associated nuclear antigen [LANA]) for PLWHA. The researchers predict that together, the increased viral replication, lymphocyte turnover, changes in the microbiome and gut barrier leaks with the resulting translocation of toxins and bacterial products, promote immune activation, leading to an underlying state of chronic inflammation, which results in immune senescence and dysfunction. Overall, alcohol use disorders in the HIV-infected host not only perturbs tissue and organ homeostasis, but also promotes accelerated aging. In bidirectional translational studies, Center researchers did, in fact, show that AUD increases the percentage of CD8+ immunosenescent lymphocytes in PLWHA and that CBA resulted in a similar change at 12-14 months after SIV inoculation in rhesus macaques that was normalized with ART. Furthermore, the increase in immunosenescence appears to positively correlate with AUDIT scores. Moreover, when they analyzed those immune activated senescent cells they found that these cells have shorter telomere length, a well-accepted marker of cell senescence. This has led the researchers to propose inflamm-aging as a mechanism of alcohol-mediated comorbidities in HIV/AIDS.

The other major domain that Center researchers have identified to underlie alcohol’s impact on disease progression is metabolic dysregulation particularly at the level of skeletal muscle and adipose tissue. The Center’s studies have shown that the shorter time to death in the CBA animals not treated with ART is associated with a decrease in weight gain and body mass index and accentuated skeletal muscle wasting. Multiple mechanisms have been shown to be responsible for this enhanced wasting including increased skeletal muscle inflammation, oxidative stress, and enhanced proteasome activity. Because of the Center’s ability to perform molecular, cellular, tissue, and whole body studies it has shown that these changes in skeletal muscle mass and function have a systemic impact, seen as a marked decrease in disposition index reflecting insulin resistance and a decrease in skeletal muscle total oxidative capacity strongly suggesting mitochondrial dysfunction. Alcohol inhibits myogenic gene expression and muscle regenerative capacity through a number of mechanisms studied by the researchers. Microarray analysis has confirmed the role of metabolic processes and inflammation to end-stage muscle wasting in CBA/SIV animals but has also uncovered an additional mechanism, increased fibrosis, which the researchers believe can contribute to impaired regenerative potential in muscle. The Center’s data have also provided evidence for the relevance of alcohol-mediated epigenetic alterations as a mechanism contributing to metabolic dysregulation. And one muscle specific miRNA in particular, miR-206, shown to be decreased by SIV and alcohol, is currently the focus of a KO1 project led by Liz Simon, Ph.D. Center researchers have shown decreased anabolic and regenerative capacity in a milieu of enhanced inflammation, oxidative stress, and catabolism. They predict that in the clinical population these will translate into decreased skeletal muscle strength, lipodystrophy, and insulin resistance. Indeed, initial analysis shows that lean body mass and body mass index, two parameters shown to be markedly decreased in alcohol-treated SIV-infected macaques, are negatively correlated with AUDIT scores, further strengthening the value of the bidirectional translational approach being used by the Center’s studies.

The Center is well positioned to examine the impact of neighborhoods and environmental stress on biological correlates of stress and their modulation by alcohol. Katherine Theall, Ph.D., has taken an early look at where subjects come from. Tracking by neighborhood, she has seen significant clustering of biological stress markers and alcohol use disorders. In contrast to the controlled conditions under which Center researchers have studied the impact of alcohol on SIV disease progression, her initial analysis using linear regression curve fit shows strong association between urban life stressors and telomere length (TL).

Currently two translational pilot projects focus on expanding on the dimension of brain pathology and behavioral consequences of alcohol and HIV. Among the challenges the Center has encountered in its translational studies is how to communicate across different disciplines.

Discussion: Dr. Koob thanked Dr. Molina for an excellent presentation. Dr. Eberwine inquired if the Center’s researchers had examined the role of mitochondria, in light of their findings about decreased regeneration in myoblast. Dr. Molina responded that Center researchers have begun looking at the genes involved in mitochondrial homeostasis and have observed significant dysregulation. Frank Sloan, Ph.D., asked about the human living in the community, noting that the challenge is establishing causation between higher AUDIT scores and behavior. He noted that the Center’s sample sizes are still too small to account for this. Dr. Molina concurred, stating that one of their studies will be looking at a number of issues such as sexual choices and early life adversity, but that a much larger study is not currently feasible. The objective now is to parse out those influences that are worth pursuing with a larger cohort. Dr. Kenny wondered if mir-206 was the micro-RNA that the Center planned to focus its studies on, since recent work suggests it might play a regulatory role in the brains of mice who drink alcohol.  Dr. Molina replied that Center researchers currently only look at it in the context of skeletal muscle, given research constraints. Arun Sanyal, M.D., asked about cell turnover in muscle tissue, specifically how important myogenesis is compared to myoaptosis in the pathophysiology of sarcopenia. Dr. Molina responded that approximately two percent of skeletal muscle mass is turned over each day and approximately two percent of muscle cells are myoblasts. Thus, it is minor; there are multiple factors contributing to a decrease in muscle mass. Dr. Koob asked if there was any evidence that alcohol contributes to an increased viral reservoir in the brain. Dr. Molina replied that they’ve seen no significant difference in viral load between animals treated with alcohol and those not treated; what they have seen, however, are significant differences in the brain-derived neurotrophic factor (BDNF) pathways. Dr. Kenny noted that mir-206 is one of the major micro-RNA regulators of BDNF.

Council Member Presentation: Context and Place: Modeling Social Mechanisms of Alcohol Problems

Dr, Koob introduced Council member Paul Gruenewald, Ph.D., Scientific Director of the Prevention Research Center (PRC) at the Pacific Institute for Research and Evaluation (PIRE).  Dr. Gruenewald’s presentation focused on individual drinking agents and environmental opportunities for drinking that affect drinking behaviors and related problems.  He reported on three global factors that have structurally specific effects on alcohol use: the price of alcohol; the minimum drinking age; and the ecology of heavy drinking and dependence.

Beverage Prices and Alcohol Use: Alcohol is a “complex” good, made up of three types of beverages (wine, beer, spirits) with a wide range of quality and price. If prices go up, then consumers can reduce use or switch to a beverage of lower quality or price. What happens if you increase all prices at one time? Everyone shifts down in quality. But at the low end, people who can’t afford the price increase stop drinking. Thus, a 10 percent price increase leads to a 1.69 percent decrease in alcohol use. However, if only the price of low quality alcohol beverages increases, there is a greater impact. The 10 percent price increase leads to 4.15 decrease in consumption. In contrast, if prices increase only on high quality alcohol, then a 10 percent price increase leads to a 2.83 percent increase in alcohol use as people switch to lower-cost beverages but drink more. The moral of the story is that producers and distributors can choose to pass on taxes through prices in many ways. In the case of complex goods, they can do so in ways that defeat the public health intent of the tax. Examining other substances, it appears clear that tobacco is not a complex good. It is likely that marijuana will be as that market continues to diversify products over time.

Minimum Drinking Age: New Zealand lowered its minimum purchase age (MPA) for alcohol from 20 to 18 in the 1990s. One of the primary arguments driving the change was that the lowered MPA would provide young people opportunities to model safe drinking practices in commercial establishments. National alcohol surveys of adults and youth before and after the change in the law revealed that the impacts of the lowered MPA were generally as expected: Greater use by 18-19 year olds; more use by underage 16-17 year olds; and more problems, such as fights, hangovers, trouble at work/school, etc.  The moral of this story is that the lowered MPA led to more use and problems; drinking in pubs appeared safer because many more lighter drinkers began to drink in those places; but, nevertheless, greater risks arose among these drinkers because they were drinking more than they normally would and doing so in these high-risk environments.  Since contexts are so intimately entwined with risks for drinking problems, these findings lead to a critical question: How much of the risks that we attribute to alcohol use are due to where people drink rather than how much they drink?

Ecological Correlates of Dependence:  Heavier drinking is generally related to diagnoses of dependence.  But this relationship is not consistent and many moderate drinkers are diagnosed as dependent who report symptoms at lower drinking levels.  This may occur because our measures of dependence are error prone.  But it is also possible that some social ecological circumstances of drinking are related to symptom reports among moderate drinkers.  For example, drinking greater amounts over longer times will be facilitated if life activities are not in conflict with drinking and drinking is induced and maintained by peer influence.  Activities given up or reduced due to drinking will be determined, at least in part, by the extent to which activities can be integrated with alcohol use.  Drinking despite persistent physical or psychological problems will continue if persistent drinking is supported and maintained by peer influence and if problems can be accommodated by other means.  One signature feature of heavy drinking that supports this suggestion is that there are large shifts in use of drinking contexts over age- and heavy drinking-groups; relative to lighter drinkers, youthful heavy drinkers favor use at social gatherings and parties, older heavy drinkers favor use at commercial establishments like bars.  Divergences like this in the use of drinking contexts are indicative of social ecological forces that shape heavy drinking behaviors.

Discussion: Judge Flies-Away asked if there were studies indicating that some people drink more because they like the taste of alcohol, as opposed to wanting to get inebriated.  Dr. Gruenewald responded that there are known differences in preference for quality of alcoholic beverages, influenced by income, but he was unaware of any evidence for a genetic taste preference. Dr. Koob asked if there is a sweet spot in raising taxes on alcohol. Would raising taxes on all alcohol have a monotonic effect of decreasing consumption? Dr. Gruenewald responded that there would be a pressure to monotonically reduce use and states might get more tax revenue from increased alcohol taxes; those benefits must be balanced against the social and health costs that result from people using cheaper forms of alcohol in high-risk environments and the fact that, since the demand for alcohol is inelastic, these taxes are regressive; low income consumers would have to pay a proportionally higher portion of their income for alcohol.  In California, tobacco taxes have been increased over the past decade because the political choice has been made that the additional costs placed on low income consumers are not as important as the health care benefits incurred by reduced tobacco use.  It appears unlikely that any state in the US will move in this direction with respect to alcohol.  Dr. Koob inquired if this policy has had a monotonic effect on tobacco consumption.  Dr. Gruenewald stated that it has, but there is a core population of smokers that continue to use tobacco products despite price increases.  Lower income users continue to pay a higher proportion of their incomes for tobacco and it is reasonable to expect that lower quality tobacco products would be introduced to address this need.  Dr. Koob asked how the elasticity of tobacco compares to alcohol.  Dr. Gruenewald replied that tobacco, alcohol, and marijuana are all inelastic in terms of demand.  Dr. DiClemente, noting that the current heroin epidemic is driven by the high cost of opioids, inquired if people who now drink alcohol would be likely to switch to marijuana if alcohol prices increased.  Dr. Gruenewald explained that alcohol and marijuana tend to be complementary with heavy drinkers already using marijuana rather than turning to it as a substitute.  Dr. Koob observed that when Colorado legalized marijuana, alcohol sales increased to the surprise of the beverage industry which had been predicting a decline.  Dr. Albizu-Garcia asked how does one factor in the effects of expanding treatment on reducing consumption among those who are heavy users of alcohol.  Dr. Gruenewald responded that treatment has not been factored in to these analyses, so he doesn’t know what effect expanded treatment would have.  Since only a small fraction of the population is in treatment at any time and relapse rates are high, treatment impacts might be quite small.  Dr. Kenny asked if the availability of pharmacological treatment would be likely to affect price elasticity and if price elasticity could be modified by interventions.  Dr. Gruenewald noted that there are many inter-related factors.  He cited the example of alcohol marketing in low-income neighborhoods, where single servings may sell for $1.50.  This would depend on the pharmacological treatment’s effects upon demand.  It would be great if some intervention would affect a person’s willingness to decrease use in the face of a price increase.  Vivian Faden, Ph.D., asked Dr. Gruenewald to comment on Stanford University’s new policy for what kind of alcohol containers students can have in dorms, i.e., smaller containers to reduce problems.  Dr. Koob added that Stanford banned hard liquor on campus; students can buy minis, but not full bottles.  Dr. Gruenewald stated this policy was likely to be completely ineffective.  Hard liquor is not the beverage of choice among young people and drinking in dorms or on-campus is the least problematic aspect of college drinking; most problems arise in association with Greek or other off-campus parties and related drinking events.  Anecdotally, to give a sense of scale with regard to the notion of how large a large party could be, in a response to problems associated with fraternity parties at the University of California, Berkeley, it was observed that restricting parties to less than 300 people could be effective. Thus, there are larger more substantive factors that should be addressed. Dr. Sinha asked if Dr. Gruenewald had examined the pre-and post-effects of policy changes affecting alcohol advertising. Dr. Gruenewald explained that ads drive desire to a particular goal, such as purchasing a cheap bottle of alcohol at a grocery store, but do not create the desire. There may be a small impact of advertising on alcohol consumption, but he views the evidence in this regard as quite unclear.

Ex-officio Members’ Reports

Dr. Karen Drexler, ex-officio member from the Veterans Administration (VA), gave a report about activities at the Veterans Health Administration (VA). VA is the largest healthcare system in the country. Dr. Drexler’s role in its policy branch is to review the research literature and consider creative ways to disseminate evidence-based best practices for veteran care. Highlights of recent developments include the 2015 VA-Department of Defense (DOD) Clinical Practice Guidelines for Management of Substance Use Disorders, which are available online. Alcohol-related recommendations in the Guidelines include annual screening in primary care and other settings for at-risk alcohol use, brief intervention, and referral to treatment, if indicated. Over 90 percent of veterans are screened annually using AUDIT-C and 75 percent have the appropriate follow-up. For treatment of AUD, acamprosate, disulfiram, naltrexone, and topiramate are recommended; gabapentin is also suggested, rather than recommended. There is also a menu of recommended psychosocial approaches, including couples therapy for SUD, cognitive behavioral therapy for SUD, community reinforcement approach, motivation enhancement therapy, and 12-step facilitation. As policy, the VA requires that every specialty SUD program have at least one half of a full-time equivalent prescriber so that every program has the capability of prescribing medication, and that every program have at least one full-time licensed independent mental health provider. The recommended medications have been placed on the National Formulary through the VA’s pharmacy benefits management program, so they are easily accessible. On the operations side, the VA has implemented best practices, such as its Psychotropic Drug Safety Initiative, and provided a menu of options for programs to select, along with coaching and follow-up. The VA has also started multi-disciplinary fellowships for SUD through its Office of Academic Affiliations, and would be interested in partnering with NIAAA to connect these fellows to Institute resources. Sadly, the VA’s center for implementation science related to SUD has been closed; this provides another potential area for the VA to partner with NIAAA.

Discussion: Dr. DiClemente asked if the VA offers intensive residential treatment for AUD. Dr. Drexler replied that there are about 132 residential treatment programs across country, each with a different emphasis, e.g., post-traumatic stress disorder (PTSD) and substance use disorder (SUD). The stay is short (4-6 weeks) for SUD but veterans can then move to another program. The VA has a National Center for PTSD that has implemented some innovative strategies, such as a consultation program that is available to providers both within and outside the VA system. Another innovation was to fund one specialist (SUD/PTSD specialist) for each VA facility with the responsibility to bridge the silos in treatment.  Dr. Koob asked how many women are seen in the VA system. Dr. Drexler responded that she wasn’t certain, but it was less than 10 percent. Dr. Koob inquired if the VA was following up with any of its treatment programs to determine if they help with cost, lower the incidence of other disorders. Dr. Drexler noted that some information is available through the system’s electronic health record database, so the potential is there to study treatment impacts. Dr. Koob instructed Dr. Huebner to talk to the VA about this, noting that NIAAA could put out an RFA for a secondary analysis of the electronic health record data. Dr. Huebner responded that he and Dr. Drexler had already begun that discussion.

Council Discussion

Dr. Molina asked Dr. Koob if he would take action to demonstrate NIAAA’s commitment and support for early career funding. Dr. Koob responded that NIAAA has already demonstrated such commitment, e.g., increasing the number of K awards this year. Further analysis of where NIAAA should invest its funding for early career investigators is ongoing; the Institute is also part of a trans-NIH discussion about how to get more funding to this group. Judge Flies-Away stated that it has been an honor and a privilege to learn about alcohol’s effect on the body and the liver. He shared a Native American story to underscore the importance of tying the science about alcohol to the human being.

Public Comments

Steve Schmidt of the National Alcohol Beverage Control Association, a group that represents alcohol regulators across the country, commended NIAAA for its critically important work in disseminating the science that guides the policies that the Association’s members have to implement.

Adjournment

The meeting adjourned at 3:02 p.m.

 

CERTIFICATION

I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.

 /s/