DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
145th Meeting of the
NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
May 2, 2017
Carmen E. Albizu-Garcia, M.D.
Louis E. Baxter, Sr., M.D
Daniel J. Calac, M.D.
Carlo C. DiClemente, Ph.D.
Tom B. Donaldson
Alex M. Dopico, M.D., Ph.D.
James. H. Eberwine, Ph.D.
Tatiana M. Foroud, Ph.D.
Robert J. Hitzemann, Ph.D. (by telephone)
Paul J. Kenny, Ph.D.
Joe L. Martinez, Ph.D.
Adolf Pfefferbaum, M.D.
Arun J. Sanyal, M.D.
Vijay H. Shah, M.D.
Rajita Sinha, Ph.D.
Frank A. Sloan, Ph.D.
Susan M. Smith, Ph.D.
Constance M. Weisner, D.R.P.H.
Approximately 55 observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.
NIAAA Director George Koob, Ph.D., called the open session of the Council meeting to order at 10:17 a.m. on Tuesday, May 2, 2017. Council members and senior NIAAA staff introduced themselves. Dr. Koob introduced new Council members: Louis Baxter, M.D.; Daniel Calac, M.D.; Alex Dopico, M.D., Ph.D.; Robert Hitzemann, Ph.D.; Vijay Shah, M.D.; and Susan Smith, Ph.D.
- New NIAAA Staff and Transitions: Li Lin, Ph.D., joined the Division of Metabolism and Health Effects in January 2017 as a Program Officer. Mohammed Akbar, Ph.D., joined the Division of Neuroscience and Behavior as a Program Officer in February 2017 from the Division of Metabolism and Health Effects. Bridget Grant, Ph.D., retired from her position as Chief, Laboratory of Epidemiology and Biometry, after more than 29 years of federal service, and has returned to NIAAA as a contractor.
- Budget: NIAAA is operating under a continuing resolution (CR) that extends FY 2016 funding levels until May 5, 2017. A bill to fund the Government through the remainder of FY 2017 has been proposed; Congress is expected to vote on it this week. Following NIH policy under the CR, all grants will be funded at 90 percent. President Donald Trump released a preliminary FY 2018 budget blueprint in March that included $25.9 billion for NIH, a $5.8 billion decrease from the FY 2017 CR level. A more detailed FY 2018 budget request is expected this month.
- Collaborative Research on Addiction at NIH (CRAN): The main effort under CRAN is the Adolescent Brain Cognitive Development (ABCD) study. Over two thousand (2,152) participants have completed fMRI and neuropsychological baseline measures as of April 20, 2017. New sites at the University of Wisconsin-Milwaukee and the Medical University of South Carolina are now enrolling participants. The University of Hawaii site has relocated to the University of Maryland-Baltimore and is expected to begin enrolling subjects soon.
- New Funding Opportunity Announcements (FOAs): New NIAAA FOAs include Alcohol-PTSD Comorbidity: Preclinical Studies of Models and Mechanisms (R01); Mechanisms of Alcohol-Associated Cancers (R01); Nutrition and Alcohol-Related Health Outcomes (R01, R03, R21); and Alcohol Research Resource Awards (R24). New NIH-wide FOAs with NIAAA participation include Intensive Longitudinal Analysis of Health Behaviors: Leveraging New Technologies to Understand Health Behaviors; Blueprint Neurotherapeutics Network (BPN): Small Molecule Drug Discovery and Development for Disorders of the Nervous System; and National Cooperative Drug/Device Discovery/Development Groups (NCDDG) for the Treatment of Mental or Substance Use Disorders or Alcohol Addiction.
- NIAAA Policy for Submission of Applications Containing Genome-Wide Association Studies: The policy, available at https://grants.nih.gov/grants/guide/notice-files/NOT-AA-17-002.html, includes the following provisions: NIAAA will only support collection of human samples containing many severely affected subjects; each application is required to develop/use a core set of questions or available assessment instruments that are compatible across all studies for the evaluation of alcohol use disorder (AUD) and co-occurring disorders; applicants are expected to collect and make available high-quality DNA samples for genotyping; broad sharing of genome-wide association study (GWAS) datasets and key phenotypic data is expected; collaborative efforts for sharing/harmonizing genotype and phenotype datasets for large-scale meta-analyses are encouraged; and innovative research by individual groups that are complementary to large-scale gene discovery efforts is encouraged and supported.
- NIAAA Strategic Plan: The document is now available at https://www.niaaa.nih.gov/about-niaaa/our-work/strategic-plan.
“Alcohol Abuse and Cardiac Disease” was published in the Journal of the American College of Cardiology (2017 Jan 3) 69, 13-24. doi: 10.1016/j.jacc.2016.10.048 by IR Whitman, V Agarwal, G Nah, JW Dukes, E Vittinghoff, TA Dewland, and GM Marcus. They showed that in a retrospective longitudinal analysis of over 14 million California residents, a diagnosis of alcohol abuse increased the relative risk of atrial fibrillation, myocardial infarction, and congestive heart failure more prominently in individuals without traditional cardiovascular risk factors.
“Alcohol Consumption, Left Atrial Diameter, and Atrial Fibrillation” was published in the Journal of the American Heart Association (September 2016) 5, e004060. doi: 10.1161/JAHA.116.004060 [published online 2016 Sep 14] by DD McManus, X Yin, R Gladstone, E Vittinghoff, RS Vasan, MG Larson, EJ Benjamin, and GM Marcus. They examined the correlation between atrial fibrillation (AF) and alcohol consumption, finding that for every 10 g increase (just under 1 drink) in daily alcohol consumption, risk of AF increases 5 percent. This increase is associated with enlargement of the left atrium, a possible contributor to the development of AF.
“Inflammation is Independent of Steatosis in a Murine Model of Steatohepatitis” was published in Hepatology (2017 Feb 21). doi: 10.1002/hep.29129 PMID: 28220523 [Epub ahead of print] by W Wang, MJ Xu, Y Cai, Z Zhou, H Cao, P Mukhopadhyay, P Pacher, S Zheng, FJ Gonzalez, and B Gao. They found that the role of peroxisome proliferator-activated receptor-gamma (PPARγ) in the development of liver diseases is paradoxical insofar as PPARγ signaling promotes fatty liver, but also down-regulates liver inflammation. In a clinically relevant mouse steatohepatitis model of 3-month high-fat diet (HFD) feeding plus a binge of ethanol (HFD-plus-binge ethanol), hepatocyte-specific Pparg gene disruption reduced liver steatosis, but increased hepatic neutrophil infiltration after HFD-plus-binge ethanol. Thus, blocking PPARγ as a treatment for alcohol-related liver diseases may result in unintended liver injury that ultimately leads to pathological consequences.
“PARP Inhibition Protects Against Alcoholic and Non-Alcoholic Steatohepatitis” was published in the Journal of Hepatology (2017 March) 66, 598-600, by P Mukhopadhyay, B Horváth, M Rajesh, ZV Varga, K Gariani, D Ryu, Z Cao, E Holovac, O Park, Z Zhou, MJ Xu, W Wang, G Godlewski, J Paloczi, BT Nemeth, Y Persidsky, L Liaudet, G Haskó, P Bai, AH Boulares, J Auwerx, B Gao, and P Pacher. They reported that Poly(ADP-ribose) polymerases (PARP) are overactivated in livers of individuals with alcoholic liver disease. PARP inhibitors, including FDA-approved targeted therapy for cancers olaparib (Lynparza), attenuate high fat or alcohol-induced liver injury, abnormal metabolic alterations, fat accumulation, inflammation, and fibrosis. These data suggest that PARP inhibition is a promising therapeutic strategy for treating alcoholic and non-alcoholic liver disease, and hepatic fibrosis.
“In Vivo Imaging of Translocator Protein, a Marker of Activated Microglia, in Alcohol Dependence” was published in Molecular Psychiatry (2017 Feb 28). doi: 10.1038/mp.2017.10 [Epub ahead of print] by AT Hillmer, CM Sandeigo, J Hannestad, GA Angarita, A Kumar, EM McGovern, Y Huaung, KC O’Connor, RE Carson, SS O’Malley, and KP Cosgrove. They measured microglia activation in the brain of alcohol-dependent individuals via positron emission tomography. There were significantly lower levels of activated microglia and a lower peripheral immune response in alcohol-dependent individuals compared to healthy controls, suggesting that the neuroimmune system may be a potential target for medications development.
“Oxytocin Reduces Ethanol Self-Administration in Mice” was published in Alcoholism: Clinical and Experimental Research, (2017 May), 41, 955-964, by CE King, WC Griffin, LN Luderman, MM Kates, JF McGinty, and HC Becker. They investigated the effects of systemic administration of oxytocin on alcohol self-administration in a binge-like drinking model, a 2-bottle choice paradigm, and using operant conditioning procedures. Oxytocin selectively decreased alcohol consumption in these models at doses that did not affect sucrose consumption under similar testing conditions, supporting the therapeutic potential of oxytocin as a treatment for AUD.
“Oxytocin by Intranasal and Intravenous Routes Reaches the Cerebrospinal Fluid in Rhesus Macaques: Determination Using a Novel Oxytocin Assay” was published in Molecular Psychiatry (2017 March 14). doi:10.1038/mp.2017.28 [Epub ahead of print] by MR Lee, KB Scheidweiler, SS Diao, F Akhlagh, A Cummins, MA Huestis, L Leggio, and BB Averbeck. They developed a sensitive and specific quantitative mass spectrometry assay that distinguishes between administered labeled (d5-deuterated) and endogenous (d0) oxytocin (OT) in cerebrospinal fluid (CSF) and plasma. They demonstrated CSF penetrance of d5, exogenous OT delivered by intranasal and intravenous administration, suggesting that exogenous OT crosses the blood-brain barrier.
“Prefrontal Cortex KCA2 Channels Regulate MGLU5-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior” was published in the Journal of Neuroscience, (2017 March 20), pii: 2873-16. doi: 10.1523/JNERUOSCI.2873-16.2017 [Epub ahead of print] by R Cannady, JT McGonigal, RJ Newsom, JJ Woodward, PJ Mulholland, and JT Gass. They showed that inhibition of KCa2+ channels in the infralimbic prefrontal cortex by the allosteric SK inhibitor apamin facilitates extinction of alcohol seeking-behavior. These data suggest that KCa2+ may be a novel therapeutic target for relapse prevention.
“Trajectories of Substance Use Frequency Among Adolescents Seen in Primary Care: Implications for Screening” was published in the Journal of Pediatrics (2017 February 10), pii: S0022-3476 (17) 30143-9. doi: 10.1016/j.jpeds.2017.01.033 [Epub ahead of print] by SE Hadland, SH Copelas, and SK Harris. They reported that adolescents whose substance use increases between annual primary care visits are more likely to have substance-using peers and siblings than those who abstain. This finding supports the recommendation in NIAAA’s youth alcohol screening guide that practitioners ask youth about peer substance use as an indicator of substance use risk. Understanding adolescents’ typical use trajectories may also help physicians decide whether to schedule follow-up visits.
“Trends in Alcohol Consumption Among Older Americans: National Health Interview Surveys, 1997-2014” was published in Alcoholism: Clinical and Experimental Research, (2017 March 24 April). doi: 10.1111/acer.13365 [Epub ahead of print] by RA Breslow, I-JP Castle, CM Chen, and BI Graubard. They reported an upward trend in the prevalence of drinking among adults 60+ years of age, particularly women, between 1997–2014. These findings indicate a need for alcohol-related public-health education, screening, and treatment for the growing older population.
Discussion: Louis Baxter, M.D. emphasized the increased prevalence of binge drinking among older adults, and stressed the need for the field to do more to educate primary care physicians. Dr. Koob concurred. NIAAA and NIDA are working together to explore how to expand education for primary care physicians, possibly using the new Surgeon General’s report as a framework for course development. Constance Weisner, D.R.P.H. encouraged training physicians on how to integrate advice about alcohol into clinical communication with patients by emphasizing the improvement of health outcomes. Arun Sanyal, M.D. recommended including such information into the medical school curriculum, where it is notably absent, and most likely to have an impact on clinical practice. Dr. Koob responded that NIAAA has participated in two meetings thus far with medical education associations on this topic; many medical schools have yet to appreciate the importance of including the impact of alcohol in their curricula. Carlo DiClemente, Ph.D., recommended multiple avenues for physician training. He indicated there is money available to states to implement Screening, Brief Intervention, and Referral to Treatment (SBIRT) training. He noted that residency training provides another opportunity to intervene, as well as emergency room practices. Dr. Koob stated that Acting Deputy Director Patricia Powell, Ph.D., will incorporate these recommendations into NIAAA’s discussions with relevant organizations. Rajita Sinha, Ph.D., suggested putting alcohol screening into the electric health record, which would force physicians to assess alcohol use. Frank Sloan, Ph.D., stated that it’s unrealistic to expect physicians to do too much in the short time they have with patients, many of whom have complex conditions; physicians complain the electronic health record is already too complicated. He noted that the serious challenge is reimbursement for such screening. Dr. Weisner replied that her research has indicated that even brief advice is helpful and can be tied into an issue the patient is interested in. Susan Smith, Ph.D., agreed and encouraged such advice to be included in pediatrician wellness visits, as well.
Dynamic Neuroimmune Interactions in the Transition from Brain Function to Dysfunction
Dr. Koob introduced a new FY 2018 initiative of the NIH Blueprint for Neuroscience Research, for which NIAAA has initiated and will lead the effort to implement this initiative. The NIH Blueprint is a collaborative framework that includes the NIH Office of the Director and 14 NIH Institutes and Centers (ICs) that support research on the nervous system. Blueprint science projects aim to catalyze research with the potential to transform basic understanding of the brain and approaches to treating brain disorders. He invited Changhai Cui, Ph.D., who is the lead of the initiative, to present the concept of the RFA for the council clearance.
Dr. Cui explained that the goal of the initiative is to understand the dynamic interactions of multiple neuroimmune components in the transition from brain function to dysfunction at the molecular, cellular, and circuitry level. Currently, scientists know that: 1) multiple central nervous system (CNS)-cell types, such as neurons, microglia, astrocytes, play a role in neuroimmune interaction and neuroinflammation; Altered neuroimmune signaling in these cell types or neuroinflammation are associated with a variety of CNS disorders. 2) Both microglia and astrocytes are also involved in normal brain function, including neural development, adult neurogenesis, and synaptic interaction. Thus, these cell types may contribute to CNS disorders through the disruption of their roles in normal brain functions as well as through the neuroinflammatory process; 3) Inflammation may regulate neurocircuit function, e.g., it decreases the activity of neurocircuit related to reward and motivation, but also activates the stress and anxiety circuits. Taken together, these advances have established that central immune signaling is an important component for both normal brain function and disease conditions.
The challenge, however, is to understand how the dynamic changes of multiple neuroimmune components mediate the transition from normal brain function to disease conditions at the molecular, cellular, and circuitry levels. Through this initiative, NIH blueprint seeks to achieve: Concurrent measurements of dynamic molecular and cellular activity changes in multiple neuroimmune components, such as microglia, astrocytes and neurons, to define the role of each cell type in the transition from normal brain function to disease onset and progression; an understanding of how inflammatory signals, either within the CNS or the peripheral systems, alter the cross-talk among neuroimmune components, and what their roles are in the dysregulation of specific neuronal or synaptic activity; a determination of how the function of specific types of neurons or synapses are impacted by changes of neuroimmune signals or genetic alterations of neuroimmune components; an understanding of how alterations of neuronal activity disrupt the homeostatic interactions of multiple neuroimmune components; an understanding of how cell-type specific interference impacts the interaction of neuroimmune components and regulates transition to pathophysiological conditions of CNS diseases; and identification of molecular signature of the critical time points at which alterations in neuroimmune interactions may promote or suppress disease onset or progression.
To achieve these goals, this RFA will encourage an integrative approach that may combine neuroscience, neuroimmunology, novel techniques and methods, or recent technological advances (e.g., those supported by the BRAIN Initiative, NIH Common Fund Programs) to track multi-component interactions. With a budget of $4.3 million from the NIH blueprint in FY 2018, 7-9 R01s may be funded.
Discussion: James Eberwine, Ph.D., inquired if specific diseases would be emphasized. Dr. Cui responded that this initiative does not emphasize specific diseases; investigators can choose to focus on specific diseases or animal models. Dr. Koob stated he intends to publicize this research opportunity widely and encouraged Council members to share the opportunity with their colleagues.
Brain Initiative Update
As NIAAA’s representative to the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative’s Multi-Council Working Group (MCWG), Dr. Eberwine provided an update about the Initiative’s recent activities. He reported that $1.5 billion will be invested over 10 years with the long-term goal of making circuit abnormalities the basis of diagnostics, and normalization of circuit function the target of intervention. The first five years of the initiative emphasize technology development, followed by five years of discovery-driven science.
There are seven high priority research areas: Identifying/providing experimental access to the different brain cell types to determine roles in health/disease; generating circuit diagrams that vary in resolution from synapses to the whole brain; producing a dynamic picture of the functioning brain with new methods for large-scale monitoring of neural activity; linking brain activity to behavior with precise interventional tools that change neural circuit dynamics; understanding the biological basis of mental processes with new theoretical/data analysis tools; developing innovative technologies to understand the human brain and treat its disorders; creating human brain research networks; and integrating new technological and conceptual approaches produced in goals #1-6 to discover how dynamic patterns of neural activity are transformed into cognition, emotion, perception, and action in health and disease.
The BRAIN MCWG assessed progress in February 2017, recognizing investments towards 65 of 74 short-term goals. In 2014, the Initiative made 58 awards totaling $46 million. In 2015, 67 awards for $38 million were made and 130+ investigators from the United States and 8 other countries participated. In 2016, there were 100+ awards, representing an investment of $150+ million. One hundred and seventy investigators in the United States and eight other countries participated. Since FY 2014, 13 countries in total have been involved in U.S. BRAIN projects.
Dr. Eberwine invited Dr. Cui to report on NIAAA’s participation in the program. Seven researchers have submitted applications for FY 2017; six are still pending review. These new NIAAA BRAIN applications focus on the application of novel technologies to understand neurocircuits and behavior. One of the seven is a Small Business Innovation Research (SBIR)/Small Business Technology Transfer (STTR) grant to develop and validate a unified system for wireless optogenetic and brain dialysis for small molecules, which has the potential to be funded. The BRAIN Initiative is also open to the intramural community. In FY 2016, only two intramural groups from NIH applied; one was from NIAAA under the leadership of David Lovinger, Ph.D. A few alcohol researchers will serve on the review panel for the BRAIN Initiative applications.
Dr. Eberwine reported that there will be 30 funding opportunities under the Initiative in FY 2017. Four FOAs will build on cell phenotyping efforts, including classifying human and non-human brain cells, building a mouse brain atlas, and establishing associated data centers. Two FOAs will focus on post-doctoral training and career enhancement. Three will build informatics infrastructure for the Initiative. Two FOAs will support small businesses via the BRAIN awards for the SBIR/STTR programs. One FOA will address ethical issues in human brain research and advances in neurotechnology. Four FOAs will create a new BRAIN Circuits Program, supporting integrated, interdisciplinary research on circuit function. Multiple opportunities (12) have been re-issued from FY 2016 supporting imaging and non-invasive neuro-modulation in humans, as well as tool and technology development across scales. There are also opportunities to capitalize on the BRAIN Public-Private Partnership Program, which seeks to facilitate partnerships between clinical investigators and manufacturers of latest-generation neural stimulation and/or recording devices. Some of these have already been issued, and some will be issued soon. There is currently a firm commitment of $160 million toward the total $195 million intended for FY 2017.
In December 2016, the 21st Century Cures Act was passed by Congress. It includes funds for BRAIN research, among other areas.
There is a consultative ethics group, co-chaired by Christine Grady, Ph.D., and Hank Greely, to work with BRAIN leadership and BRAIN investigators that meets three times per year. Dr. Eberwine is a member of this working group. It has completed one neuroethical consult with a study and developed a one-page information sheet about what neuroethics is and how to think about it. A Request for Information (RFI): Guidance for Opportunities in Neuroethics closed July 29. There is a new Funding Opportunity, informed by the RFI: BRAIN Initiative: Research on the Ethical Implications of Advancements in Neurotechnology and Brain Science (R01); applications are due January 30.
The BRAIN Initiative Alliance coordinates and facilitates communications from its members related to the BRAIN Initiative. Its most prominent activity is the BRAIN Initiative website (www.brainintitative.org) which went online seven months ago.
BRAIN 2025, the 2014 blueprint for the BRAIN Initiative, called for NIH to establish appropriate data repositories and other informatics infrastructure for data related to the BRAIN Initiative. An upcoming focus of the BRAIN Initiative is supporting the creation and management of large datasets (e.g., imaging) to facilitate data sharing and foster collaborations across each type of data. Three specific Requests for Applications (RFAs) have been issued: Standards to Define Experiments Related to the BRAIN Initiative (R24); Data Archives for the BRAIN Initiative (R24); and Integration and Analysis of BRAIN Initiative DATA (R24).
Discussion: Adolf Pfefferbaum, M.D. asked about the primary ethical issues that have come up in the ethics working group. Dr. Eberwine responded that issues included standard ones, such as informed consent and data security, but also unique issues, e.g., does human tissue retain aspects of the individuals “human-ness” when it is being cultured for a study? Dr. Pfefferbaum noted that an issue that has come up in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) and the Adolescent Brain and Cognitive Development (ABCD) studies is how to handle information sharing when anomalies and/or pathologies are encountered during clinical readings. A satisfactory answer has not yet been determined, and he encouraged Dr. Eberwine to add this issue to the working group’s concerns. Dr. Koob inquired about the number of serious anomalies that showed up in NCANDA. Dr. Pfefferbaum responded that anomalies were noted in about 12 percent of clinical readings; most were benign. Only three needed potential intervention. One occurred not at baseline but at follow-up; thus, the issue is not a one-time event, but is ongoing. None received an intervention. Opinion is divided about when researchers should inform subjects of anomalies. Dr. Eberwine noted that the neuroethics working groups is trying to develop suggested guidelines that Institutional Review Boards (IRBs) can consider. David Goldman, M.D., NIAAA, suggested consulting with the NIH Clinical Center about its guidelines on this issue; NIH policy requires anyone getting a research MRI needs a clinical MRI scan first. Tatiana Foroud, Ph.D. suggested extending the discussion to genetics, where conscious revisiting of data as scientific understanding changes is the norm; researchers may need to consider additional disclosures throughout the study. Dr. Pfefferbaum stated that the NIH Clinical Center policy would be impractical for large studies of normal subjects. In NCANDA and ABCD, all scans are read by a neuroradiologist and there is a neuroradiological report. Dr. Koob urged Council members to encourage others at their institutions to visit the BRAIN Initiative website and to consider responding to the Initiative’s funding opportunities.
NIAAA Alcohol Treatment Navigator
Dr. Koob described NIAAA’s challenges to assist those looking for treatment options for AUD since reliable information about evidence-based treatment can be difficult to find. He invited Robert Huebner, Ph.D., to introduce the NIAAA Alcohol Treatment Navigator. The Navigator is an online resource to help family members and friends of those with AUD to find the best treatment in their communities. This is often a stressful and very difficult process; many programs that pop up during an Internet search are neither evidence-based nor accredited, but have simply paid the search engine to advertise their services.
Dr. Huebner invited Lori Ducharme, Ph.D. to provide a “sneak preview” of the new tool, which is not yet publicly available. She explained that the primary audience for the Navigator is those searching for treatment for self or family member/friend. Dr. Ducharme reviewed the factors that prompted development of the Navigator: High quality treatment is hard to find; existing online resources are limited; the public is unfamiliar with quality indicators; there is no “consumer report” for addiction treatment; aggressive search engine optimization and advertising can lead consumers to poor quality programs; there are common stereotypes about treatment, such as AA or long-term treatment as the only options; and, finally, NIAAA can’t endorse specific providers.
The Navigator provides a 4-step strategy to search for evidence-based treatment: 1) Learn the basics (what AUD is, how is it treated, five signs of high quality care); 2) Know where to search (reliable sources for finding licensed therapists, accredited programs, and board-certified physicians); 3) Know what questions to ask (“10 Questions to ask a Therapist/Program” – and answers to listen for); and 4) Compare and choose.
The process for building the Navigator included the following steps: Search and review of all existing resources; identification of areas where NIAAA could add value; decisions about what not to take on (e.g., treatment services for adolescents); early focus group with Al-Anon members; definition of territory and message; review of health services research findings; focus groups with target audience; meetings with stakeholders (e.g., American Society of Addiction Medicine [ASAM], Substance Abuse and Mental Health Services Administration [SAMHSA]); and expert outside reviewers.
Dr. Ducharme showed a sample page from the Navigator website, noting how the search strategy steps appear as the top navigation menu. Users can search via three specific provider directories to find Master’s-level licensed therapists, accredited treatment programs, or physicians who are Board-certified in addiction medicine. There is also a custom widget for searching the SAMHSA treatment program locator that accesses SAMSHA’s database directly. The site has a downloadable toolkit that helps users organize their notes, provides a script for interviewing treatment providers (and answers to listen for), and includes a Treatment Options Chart to help people visually compare their options and highlight indicators of quality. There is also an infographic emphasizing that people can take different paths through treatment in order to explain levels of care and problem severity through an engaging set of vignettes.
User feedback in focus groups has been very positive. After further testing and development, the Navigator is expected to launch in September 2017.
Discussion: Dr. Koob shared his excitement about the potential of the new tool and encouraged Council members to share it with others. Joe Martinez, Jr., Ph.D. asked why NIAAA focused on master’s level counselors when Ph.D.-level therapists are available. Dr. Ducharme responded that she meant master’s level or greater. Dr. Baxter commented that the Navigator is exactly what the field needs. Carmen Albizu-Garcia, M.D., inquired if cultural competence was among the 10 questions included. Dr. Ducharme noted that NIAAA sought to limit the search strategy to only 10 questions, with instructions to users to identify what is important to them. An audience member asked if the Navigator will be housed on the NIH website or can one find it via a Google search. Dr. Ducharme answered that the Navigator is a sub-domain of the NIAAA website; however, the development team is highly versed in search engine optimization so NIAAA is confident it can be found in a browser search. Dr. DiClemente asked how the program accounts for the fact that alcohol may not be a single factor issue. Dr. Ducharme noted that one of the signs of high quality treatment is a comprehensive assessment that addresses multiple domains. Vijay Shah, M.D. commented that people need to search for help within their health insurance networks. Dr. Ducharme explained that the Navigator instructs users in how to conduct a step-by-step search; one step is to call their health insurer and find out what is covered. Dr. Sloan inquired about how network providers were addressed. Dr. Ducharme said that the tool introduces the concept of in-network providers and suggests calling those providers, asking 10 questions, and reviewing the five signs of quality care. Daniel Calac, M.D. asked if the tool covered adults only or also children. Dr. Ducharme responded that it only addresses adults. Dr. Eberwine commented that this looks like a helpful tool, and asked if it included a link to clinical trials. Dr. Ducharme replied that this would be a good idea and an easy addition to the tool. Dr. Koob observed that the Navigator could possibly be a game-changer for NIAAA as an Institute if people begin to use it. The field worries about provider education, but consumers may start demanding information from their doctors based on this tool.
Consideration of Minutes of the February 2017 Council Meeting and Future Meeting Dates
Council members unanimously approved the minutes of the NIAAA Advisory Council meeting held February 9, 2017.
In 2017, the NIAAA Council will meet on 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 meetings in 2019 will be held on February 7, May 14, and September 12; the CRAN Council will meet in 2019 on May 15.
Council broke for lunch at 12:30 p.m. and reconvened at 1:33 p.m. for the afternoon session.
Council Member Presentation: Training Research Scientists: Fostering Independence
Dr. Koob invited Dr. Martinez to address the recruitment of underrepresented minorities (URMS) into the research scientist workforce. Dr. Martinez stated that the primary focus of his presentation was the period in an individual’s career between getting a doctorate and getting the first R01; many researchers are lost during that transition. According to the National Science Foundation, Native Americans earned 0.25 percent, African Americans 5.06 percent, Hispanic Americans 6.22 percent, and Asian Americans 25.20 percent of doctorates awarded in 2015. Most demographic groups had a NIH RO1 success rate of 25.4-29.3 percent. African Americans, however, had only a 16.1 percent success rate over that same timeframe.
Mentoring programs are designed to increase URM success. An intensive mentoring program is the Summer Program in Neuroscience, Excellence and Success (SPINES). Dr. Martinez presented data about SPINES drawn from internal evaluations collected by the American Psychological Association and the Marine Biological Laboratory. SPINES includes seminars by leading scholars on contemporary neuroscience and research, and addresses topics such as neuroscience laboratory techniques, ethical issues for scientists, scientist survival skills (e.g., how to interview, how to publish), insights into a career in neuroscience, and professional/personal concerns. Participants generally rated all of these elements highly. Outcome data examining the classes of 1988-2004 indicate that SPINES students published in higher impact journals than non-SPINES student did (p<.05). Over 90 percent of students remained in contact with SPINES faculty and former students, allowing continued mentoring. Such frequent contact is the cement that holds mentoring relationships together.
Dr. Martinez also presented data from internal reports about NIAAA training of URMs. These data indicate that NIAAA URM representation in T training programs varied between 9.1 and 20.1 percent. NIAAA pre- and postdoctoral funding for URMs varied between 9.0 and 12.1 percent. Total K awards for URMs varied between 6.1 and 10.1 percent.
Dr. Martinez recommended that NIAAA establish a two-year mentoring program for URMs by creating a residential 3-4 week transitional mentoring program at one or more Alcohol Centers to which all NIAAA Fellows or young assistant professors could apply, regardless of ethnicity or race. This would allow mentors and mentees to establish a lifelong bond. The most important skill to teach during the program would be grant writing, with the goal of submitting an NIH grant application. Designing the training as a two-year program would permit time to allow evaluation of Integrated Review Group (IRG) critiques and possibly a resubmission. The second year could also focus on journal writing, including a submission to a scientific peer-reviewed journal. The program could incorporate science lecture classes and learning techniques related to alcohol research, and should also include informal social/science time with the mentor faculty to foster a mentor-mentee connection.
Possible mechanisms to support a transitional mentoring program include supplementing existing Alcohol Centers, which would allow a transitional mentoring program to be rapidly created; supplementing Centers following a competition; creating an R25 for an open competition; and creating a Special Emphasis Panel for review if there is an open R25 competition.
Discussion: Dr. Koob asked Dr. Martinez to outline what takes place in residence for four weeks. Dr. Martinez described evaluated activities, such as bringing in neuroscientists to speak about the frontiers of science, teaching highly-specialized lab techniques, as well as practical survival skills. He suggested that the program could rotate among different institutions so that students had the opportunity to meet a wide array of people. Dr. Foroud inquired if NIAAA prioritized URMs to be Center for Scientific Review (CSR) early stage reviewers so that they could learn what happens during a grant review. Dr. Bautista explained that the early stage reviewer program is a CSR activity, not an NIAAA one. However, when NIAAA looks for reviewers, it actively searches within scientifically and medically underserved communities for reviewers to represent these groups. He noted that the early stage reviewer program offers a great process for helping people. Judith Arroyo, Ph.D., interjected that NIAAA has conducted mock review panels and that the CSR panel is very over-subscribed. Although there are ways to advocate for URMs to participate, mentoring efforts are more important.. Dr. Martinez noted that Richard Nakamura, Ph.D., CSR Director, is looking for the names of people to serve on review panels. Dr. Koob asked if anyone had participated in the Cold Spring Harbor program. Dr. Eberwine responded that there are different types of programs at Cold Spring Harbor. Workshops run from four days to a week, but do not include any experimental research. Experimental courses last two to three weeks, and include hands-on laboratory work. He observed that the mentoring done there has served the community well, and emphasized the importance of writing skills for scientists, recommending that NIAAA consider requiring a course in scientific writing in its training programs. Dr. Shah congratulated Dr. Martinez and noted that T32 training program requirements prescribe certain levels of URM participation; supplemental slots are also available. In other programs, URM representation is encouraged but there are no requirements. Dr. Martinez noted that his recommendation is a “value add” to the T32 programs. He agreed with Dr. Eberwine that writing skills are a key part of success for scientists. Dr. Koob observed that URMs often fail to resubmit when they get a good score that’s not quite fundable. He wondered if this was a writing issue or a mentoring issue. He also noted that NIAAA has had success getting URMs into T32 programs, but does not follow them over time to track what they’ve accomplished. Paul Kenny, Ph.D. asked Dr. Martinez if he had looked earlier in the pipeline, e.g., at high schools. Dr. Martinez responded that was a university priority. He noted that a proportion of SPINES are admitted after they are accepted into a graduate program and these students have not had any graduate experience. Nevertheless, they emerge motivated and wanting to start their doctoral education. Some say they wanted to quit before they went to SPINES. Dr. Calac described a successful small workshop in which students submitted proposals that were reviewed over the course of an hour. He asked where the field is looking for students so it can identify those who are interested in going into research, noting sources such as extramural programs. Dr. Albizu-Garcia observed that the Health Resources and Services Administration (HRSA) has Spanish Centers of Excellence, and programs for Historically Black Colleges and Universities (HBCUs) and Native American Centers of Excellence within medical school settings; students have to conduct a research project. They provide a pipeline of minority candidates. Dr. Koob stated he was appointing Dr. Arroyo to convene a group of four to six volunteers within or outside Council to work with Dr. Martinez to develop a SPINES/Cold Spring Harbor-like course with an emphasis on writing that could be inserted into all NIAAA T32 training programs.
Council Member Presentation: Tailoring Interventions to Client Motivation and Mechanisms of Change
Dr. Koob introduced Dr. DiClemente noting the widespread application of his theoretical work in the field, e.g., in motivational interviewing. Dr. DiClemente’s work focuses on how people change using the Transtheoretical Model of Intentional Behavior Change (TTM). His current conceptual and research focus is on key mechanisms of change – understanding the engines that make behavior change happen in addictions and health behaviors. He defined some important distinctions related to the search for mechanisms of change, including: Mechanisms (elements that are primary causative factors); moderators (variables that facilitate or hinder the change taking place but are only secondarily causative); markers (indicators that various mechanisms or moderators are occurring); and mediation (statistical mediation to support interpretation of a mechanism). He also reviewed the areas where researchers have looked for mechanisms to understand recovery and change. These include: Intervention/treatment (therapy theory or strategies, alliance, dose, type); provider (therapist characteristics, alliance, skill, empathy); a new focus on interaction attribute x treatment interactions; environmental mechanisms; person characteristics (personality, demographics); and new foci on neuroscience and the personal change process.
People change voluntarily only when certain conditions are met: They become interested and concerned about the need for change. They become convinced the change is in their best interest or will benefit them more than cost them. They organize a plan of action that they are committed to implementing. They take the actions necessary to make the change and sustain the change, and finally it becomes habit.
The substance use field used to believe that people came to treatment motivated to change, but that proved not to be true. Research in tobacco helped lead to the development of the Transtheoretical Model, a heuristic model that describes how people go through a sequence of stages in changing their behavior: Precontemplation, contemplation, preparation, action, and maintenance. Experiential (e.g., consciousness raising) and behavioral (e.g., reinforcement) processes drive the overall process of change. Decisional balance and self-efficacy also play important roles in explaining how change occurs.
From a Stages of Change perspective on addiction and recovery, alcohol dependence is viewed as the maintenance stage of the process of initiation of addiction, as well as the precontemplation stage of recovery. The process of recovery occurs as individuals decide, commit, prepare and take the actions leading to abstinence. As an individual moves through the process, motivation (e.g., personal concerns and environmental pressures) is most prominent at the precontemplation and contemplation stages. Decision-making becomes more prominent in the later contemplation and preparation stages with decisional balance and cognitive experiential processes playing a dominant role. Self-efficacy, driven by behavioral processes, becomes more important during the action and maintenance stages. When relapse occurs, individuals recycle through the stages.
There is research evidence to support the fact that people undergo a personal process of change both during and outside of treatment for AUD. Support for this personal process comes from research on intention/motivation; natural, unaided or self-change; patient behavior during treatment; patient self-evaluation of strengths and vulnerability; the impact of brief interventions; developmental periods and events that trigger change; processes of change that promote behavior change; and patient success profiles. Clinical trials like Matching Alcoholism Treatments to Client Heterogeneity (Project MATCH), Combining Medications and Behavioral Interventions for Treatment of Alcoholism (COMBINE), and the United Kingdom Alcohol Treatment Trial (UKATT) all found evidence for a personal process of change in recovery. It’s clear that initial motivation is important and affects treatment; patient goals regarding abstinence and medication use predict outcomes, independent of treatment. There have also been studies of “spontaneous recovery” that show that those who recover unaided from alcoholism made personal changes and commitments in their lives. Tobacco cessation research has documented the importance of intention, e.g. setting a date to quit. All of this suggests that what the patient does during treatment is critical. It’s what they’re doing, more than what the treatment itself is doing, that makes a difference. There is also evidence that social influences play a role, e.g., brief interventions administered by a provider can lead to significant reductions in drinking, getting married to a heavy drinker may lead to more drinking.
Project MATCH was a large alcoholism treatment trial involving nine centers, over 20 sites and 75 therapists, with 952 outpatients and 774 aftercare patients. It tested three distinct alcohol treatments: Cognitive Behavioral Treatment, Twelve Step Facilitation, and Motivational Enhancement Therapy. Few long-term differences were found among these treatments. The study examined 21 hypothesized matching effects and over 30 baseline predictors of drinking, with only a couple of significant matches. Almost all the predictors of outcomes were personal process variables, such as motivation and self-efficacy.
Another major NIAAA-funded trial, COMBINE, was a project that evaluated the use of two medications, acamprosate and naltrexone, coupled with a low intensity medication management intervention and/or a higher intensity behavioral intervention. Clients received treatment for 16 weeks, and then were followed until 68 weeks after baseline. The clients were divided into three groups based on their drinking behaviors since the prior assessment: Abstinent, lighter, and heavier drinking. The drinking levels were based on the median percent days abstinent for each time period. Follow up analyses found that the measures of confidence, temptation, experiential processes of change (POC), and behavioral POC were significantly different between the three groups. Post hoc tests found significant mean difference between the heavier drinking group and moderate drinking group (p=.004), and between the heavier drinking group and the abstinent group (p<.001) Treatment group was not significantly related to TTM profile scores.
Bandura’s concept of self-efficacy is an important predictor and mediator of drinking outcomes. Recent analyses of relapse after at least one week of abstinence at end of treatment (EOT) indicated that the gap between self-reported temptation minus self-efficacy predicted time to first drink and the number of drinks consumed on the first day.
Most studies of alcohol treatment have focused on characteristics of the treatment, such as the relationship between the client and therapist, elements of treatment that lead to better adherence, and the environment’s role in supporting recovery. Dr. DiClemente suggests that findings from major trials to date suggest a shift in research focus to what the client does (e.g., motivation, efficacy, self-regulation), viewing treatment as a mediator or moderator of client processes that lead to recovery.
In summary, Dr. DiClemente emphasized that motivation (variously defined) seems to be an important piece of the mechanisms of change puzzle. Motivation clearly acts as a predictor and often acts as a moderator and/or mediator of drinking outcomes. Such analyses require complex statistical models.
Client coping activities and self-evaluations clearly are important--and probably more important--than static characteristics and even treatment and therapist. Many of the mechanisms of change under investigation are related to changes in brain activation, so a connection with neuroscience is critical.
Discussion: Dr. Koob initiated the discussion by asking Dr. DiClemente if there are techniques available, such as motivational interviewing, that can help a client develop or find the motivation to change. Dr. DiClemente responded that there are some available treatments, including motivational interviewing and interventions teaching significant others how to talk more effectively with family members with alcohol problems; reference to them could be included in the Navigator in the future. Dr. Weisner noted that clients enrolled in most public and private programs are there not because they are seeking treatment, but because their participation has been mandated. She inquired if there is research that examines the role that people’s reason (e.g., legal, family) for entering treatment plays in predicting outcomes. Dr. DiClemente said there is substantial research on drug court referrals. He also has written materials teaching people the stages of change and providing suggestions for families about how to support the client at each stage. He asserted that treatment and support systems can help make mandated referrals be successful. Dr. Sinha asked two questions: 1) what is the status of validating process measures at the beginning of treatment? and 2) how close is the field to putting such process variables together into a screener to use at the beginning of treatment? Dr. DiClemente replied that various trials have often used different process measures so trying to combine them and validate specific measures is difficult. He also noted that these processes change over the course of treatment and have not been sufficiently assessed in the middle of treatment, with studies relying instead only on baseline and end-of-treatment measures. He agreed that it would be useful to have a battery of measures. Dr. Sinha responded that biomarkers that can be used clinically are needed. She wondered if process measures could be stand-ins for biological measures. Dr. DiClemente said process measures could be used if further research indicated that they reflect biological and neurological activities as your work on brain activation in relapse and my work on self efficacy seem to indicate. Dr. Sloan stated that drug courts screen clients when they make treatment referrals. Dr. DiClemente agreed that the court-mandated programs are voluntary and often only take motivated people and won’t allow those with poor prognoses to participate; however, he noted that such clients are primarily motivated primarily to avoid jail rather than to stop drinking. Dr. Albizu-Garcia inquired if the research presented examined the therapeutic alliance. Dr. DiClemente responded that researchers measured therapeutic alliance at the beginning, and found that it predicted outcomes as well at the second session, but that readiness moderated the alliance, i.e., it was more effective for those who were highly motivated. Dr. Koob said his take-home message is that neuropsychological test markers can link researchers to the mechanisms that are going to lead to behavioral change. He suggested to Dr. Huebner that NIAAA may want to consider an addendum to the Navigator tool reflecting the research that Dr. DiClemente presented.
Council Roundtable Discussion
Dr. Martinez stated that he was interested in Cold Spring Harbor approach, inquiring about its greatest benefit. Dr. Koob responded that it offers instructional (e.g., neuroscience lectures) and new skill development elements that would attract participants; it could be strengthened with additional writing and mentoring emphases similar to SPINES. Dr. Shah inquired about the status of an NIAAA study on the beneficial aspects of low levels of alcohol on cardiovascular risk. Dr. Koob asked Andras Orosz, Ph.D., the project officer of the U10 award, to provide an update. Dr. Orosz stated that a protocol had been written, and a critical review in preparation for submission to an Institutional Review Board (IRB) and patient recruitment has been scheduled. Deidra Roach, M.D., NIAAA, announced that NIAAA will sponsor a national conference on substance use among women and girls on September 23-24, 2017 in the Washington, DC area; the primary audience is health care providers. Dr. Huebner reported that NIAAA is sponsoring a research track at the upcoming American Psychiatric Association that will include seven or eight symposia, four or five workshops, and a couple of forums. Drs. Koob and Sinha are featured speakers. Dr. Smith said she attended the Gordon Conference on End Organ Diseases, as well as the one on neuroscience. She noted little overlap in attendance between the two and encouraged NIAAA to think simultaneously about the effects of alcohol both above and below the neck. Dr. Koob acknowledged the need to address both, citing Dr. Cui’s remarks earlier about the neuroimmune blueprint initiative. Dr. Koob urged Council members to share their ideas with him and/or the division directors.
There were no public comments.
The meeting adjourned at 3: 07 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.