DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
144th Meeting of the
NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
February 9, 2017
The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened for its 144th meeting at 9:00 a.m. on Thursday, February 9, 2017, at NIAAA headquarters in Rockville, Maryland. The Council met in closed session at 9:00 a.m. to review the evaluation of the NIAAA intramural program, closing at 9:20 a.m., and at 9:45 a.m. to review grant applications; the review session recessed at 10:40 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.
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.
Tatiana M. Foroud, Ph.D.
Robert J. Hitzemann, Ph.D
Paul J. Kenny, Ph.D.
Joe L. Martinez, Ph.D.
Adolf Pfefferbaum, 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.
Karen G. Drexler, M.D., ex-officio
Col. Charles S. Milliken, 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: Ralph Hingson, Sc.D., M.P.H.; Robert Huebner, Ph.D.; M. Katherine Jung, Ph.D; Raye Litten, Ph.D.; Erin Manor; Antonio Noronha, Ph.D.; Kenneth Warren, Ph.D.; Bridget Williams-Simmons. Ph.D.
Other Attendees at the Open Session:
Sixty two (62) 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 11:06 a.m. on Thursday, February 9, 2017. 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. Council members and senior NIAAA staff introduced themselves.
Dr. Koob highlighted key recent NIAAA activities, referring to the written Director’s Report, which was distributed to Council members.
- Budget: NIH received $32.3 billion in FY 2016; NIAAA received $467.7 million, a 4.9 percent increase over FY 2015. The new overall NIH budget includes Increases for the BRAIN Initiative, Alzheimer’s disease research, antibiotic resistance research and an Institutional Development Award program, as well as support for the Precision Medicine Initiative and the Gabriella Miller Kids First Pediatric Research program. It covers 634 NIAAA Research Project Grants, 170 NIAAA competing awards, 146 other research grants, 20 research centers, and 289 training positions. This is a significant increase in the number of training positions. Currently, NIAAA is operating under a continuing resolution (CR) that extends FY 2016 funding level until April 28, 2017. It provides NIH with $872 million to support the 21st Century Cures Act research initiatives in FY 2017. Following NIH policy under the CR, NIAAA is funding all grants at the 90 percent level, with the expectation that the remaining monies will be refunded to investigators when the CR is over. Preliminary work on the FY 2018 budget has begun; the President’s budget request is forthcoming.
- 21st Century Cures Act: Signed into law in December, the 21st Century Cures Act authorized $4.9 billion to NIH over 10 years for the Precision Medicine, BRAIN, and Cancer Moonshot Initiatives, as well as for regenerative medicine. NIAAA expects to play a role in the three Initiatives. It also reauthorized the Sober Truth on Preventing Underage Drinking Act (STOP) Act through 2022; STOP established the Interagency Coordinating Committee on the Prevention of Underage Drinking (ICCPUD), of which NIAAA is a member. The 21st Century Cures Act also designates the NIAAA Director and the National Institute on Drug Abuse (NIDA) Director as ex-officio members of the National Advisory Council to the Substance Abuse and Mental Health Services Administration (SAMHSA).\
- Collaborative Research on Addiction at NIH (CRAN): The main effort under CRAN is the Adolescent Brain Cognitive Development (ABCD) study. ABCD research sites have recruited 998 participants since October 2016 who completed fMRI and neuropsychological baseline measures as of December 2016. The annual ABCD meeting was held in November 2016. Another CRAN initiative was the establishment of a single, recurring Institutional Training Grant (T32/T35) special review panel by NIAAA and NIDA. The Panel, jointly managed by NIAAA and NIDA, will meet annually to review T32/T35 applications. Investigators are not discouraged from submitting CRAN-research related grant applications, but no additional special monies are being set aside. NIAAA will also be instructing review panels not to discriminate against applications in which two drugs are being studied.
- Congressional Meet & Greet: On January 25, 2017, the Friends of NIAAA hosted a very successful Meet-and-Greet to provide Members of Congress an opportunity to learn more about NIAAA. Dr. Koob presented an overview of the Institute's research priorities and key accomplishments, and met personally with Congressional staff.
- Staff Transitions: New staff at NIAAA include Tara Blackwood, Program Analyst in the Division of Treatment and Recovery Research; Jacquai Kane, Staff Assistant, in the Office of the Director; Elizabeth Powell, Ph.D., Program Director, and Kamilah Scott, Program Specialist, in the Division of Neuroscience and Behavior. Congratulations were extended to Bonnie Ellis, new Chief of the Administrative Services Branch; Jennifer Hobin, Ph.D., Acting Science Policy Branch Chief; Erin Manor, Deputy Executive Officer; and Bridget Williams-Simmons, Ph.D., who replaces Vivian Faden, Ph.D., now retired, as Acting Director of the Office of Science Policy and Communications.
- New Funding Opportunity Announcements (FOAs): New FOAs include Public Policy Effects on Alcohol-, Marijuana-, and Other Substance-Related Behaviors and Outcomes (R21); Increasing the Use of Medications for the Treatment of Alcohol Use Disorders (R01); and Leveraging Electronic Health Records for Alcohol Services Research (R21/R33). NIAAA is also participating in the following NIH-wide FOAs: BRAIN Initiative; Big Data to Knowledge; Implementation of Substance Use Prevention and Treatment Services; Sexual and Gender Minority Populations; Workforce Diversity; Informationist Services in NIH-funded Research Projects; Health Disparities; Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Brain Development Mediating Substance Use and Dependence; HIV-1 infection of the Central Nervous System; and Health of Women of Underrepresented, Understudied and Underreported Populations.
- Surgeon General’s Report on Alcohol, Drugs and Health: Facing Addiction in America, released in November 2016, is the first Surgeon General’s Report on alcohol and drug misuse and substance use disorders. With substantial input from NIAAA and NIDA, the Report presents the state of the science, with a focus on neurobiology; prevention; treatment; recovery; and delivery of care. It outlines future directions and includes action recommendations.
- HBO Documentary on Risky Drinking: Produced in conjunction with and featuring NIAAA experts, this documentary premiered on the HBO network on December 19, 2016. The film presents intimate stories of four people whose drinking dramatically affected their relationships. Its goal is to provoke conversation about how to identify risky drinking and to suggest alternatives to a one-size-fits-all treatment approach. NIAAA is showing the film at the Research Society on Alcoholism (RSA) annual meeting in June and at the American Psychiatric Association meeting in May.
- NIAAA Media Engagement: Dr. Koob recently participated in 22 live and recorded interviews in a 5-hour satellite media tour. Following the tour, the Rethinking Drinking website experienced a 28 percent increase in visitor traffic.
- NIAAA Strategic Plan: The document will appear online and in print in March 2017.
NIAAA Research Highlights: Dr. Koob presented highlights of NIAAA-funded studies, both extramural and intramural, focusing on biomarkers for alcohol use disorder (AUD) and other factors (e.g., behavioral, psychological) that predict AUD:
“Aging Aggravates Alcohol Liver Injury and Fibrosis in Mice by Downregulating Sirtuin 1 Expression” was published in the Journal of Hepatology (2016 Nov 18) pii: S0168-8278(16)30651-1. doi: 10.1016/j.jhep.2016.11.004 [Epub ahead of print] by T Ramirez, YM Li, S Yin, MJ Xu, D Feng, Z Zhou, M Zang, P Mukhopadhyay, ZV Varga, P Pacher, B Gao, and H Wang. They reported that Sirtuin 1 (SIRT 1), a key metabolic sensor, was markedly downregulated in the livers from aged mice, and such downregulation contributed to the increased susceptibility of aged mice to alcoholic liver injury. Activation of SIRT1 may be a novel therapeutic strategy for the treatment of alcoholic liver disease.
“Extracellular Vesicles Released by Hepatocytes from Gastric Infusion Model of Alcoholic Liver Disease Contain a Microrna Barcode That Can be Detected in Blood” was published in Hepatology (2017) 65, 475-490 by A Eguchi, RG Lazaro, J Wang, J Kim, D Povero, B Willliams, SB Ho, P Stärkel, B Schnabl, L Ohno-Machado, H Tsukamoto, and AE Feldstein. The authors demonstrated that there is increased production and release of extracellular vesicles (EVs), predominantly by hepatocytes, in mouse models of experimental alcoholic steatohepatitis (ASH). These EVs contain a miRNA signature detectable in blood that can be used as a “barcode” to identify ASH. These findings point to EVs as potential novel biomarkers and therapeutic targets for ASH.
“Orphan GPR110 (ADGRF1) Targeted by N-Docosahexanoylethanolamine in Development of Neurons and Cognitive Function” was published in Nature Communications (2016) 19:13123, by JW Lee, BX Huang, H Kwon, MA Rashid, G Kharebava, A Desai, S Patnaik, J Marugan, and HY Kim. Here, the authors identified the orphan receptor GPR110 as the receptor for synaptamide, an endogenous DHA metabolite that promotes neuronal development, and demonstrated that GPR110 mediates the development of neurons and cognitive function in mice. The results suggest that GPR110 may be a novel target for neurodevelopmental control.
“The Use of Cardiac Orienting Responses (COR) as an Early and Scalable Biomarker of Alcohol-Related Neurodevelopmental Impairment” was published in Alcoholism: Clinical and Experimental Research ( 2017), 41, 128-138 by DA Mesa, JA Kable, CD Coles, KL Jones, L Yevtushok, Y Kulikovsky, W Wertelecki, TP Coleman, and CD Chambers. , The study, which was part of NIAAA’s Collaborative Initiative on Fetal Alcohol Syndrome Disorders (CIFASD), found that a COR-based assessment during infancy (at six months) may serve as an early screening tool for identification of aspects of the neurobehavioral profile of fetal alcohol spectrum disorders that historically have been unobtainable until later in childhood.
“Impairments in Component Processes of Executive Function and Episodic Memory in Alcoholism, HIV Infection, and HIV Infection with Alcoholism Comorbidity” was published in Alcoholism: Clinical and Experimental Research (2016), 40, 2656-2666 by R Fama, EV Sullivan, SA Sassoon, A Pfefferbaum and NM Zahr. This paper shows that patients with HIV infection (HIV), chronic alcoholism (ALC,) or HIV + ALC that found both disease specific and disease overlapping deficits in executive function and episodic memory. The findings suggest that cognitive deficits may be exacerbated by aging in people with HIV + ALC.
“Ethanol-Sensitive Pacemaker Neurons in the Mouse External Globus Pallidus,” was published in Neuropsychopharmacology (2016 Dec 14), doi: 10.1038/npp.2016.251. [Epub ahead of print] by KP Abrahao, JH Chancey, CS Chan, and DM Lovinger. This paper shows that low dose ethanol inhibited both in brain slices and in vivo of the activity of a specific subset of neurons in a brain region involved in action and habit control, namely the Globus Pallidus external segment. The affected neurons project to an addiction-related brain region known as the striatum; this inhibition likely contributes to acute intoxication and striatal inhibition that can foster habitual ethanol seeking.
“Kv7 Channels in the Nucleus Accumbens are Altered by Chronic Drinking and are Targets for Reducing Alcohol Consumption” was published in Addiction Biology (2016) 21, 1097-1112 by NS McGuier, WC Griffin 3rd, JT Gass, AE Padula, EJ Chesler, and PJ Mulholland. This paper shows that administration of the Food & Drug Administration (FDA)-approved anticonvulsant retigabine, a Kv7 channel opener, reduces voluntary ethanol consumption in rats. Genes that encode Kv7 channels are implicated in the regulation of ethanol drinking, and chronic alcohol consumption produces neuroadaptations in Kv7 channels. This study suggests that retigabine may be repurposed as a treatment for alcohol use disorder (AUD) and identifies Kv7 channels as a novel therapeutic target for AUD.
“Neural Predictors of Initiating Alcohol Use During Adolescence” was published in the American Journal of Psychiatry (2017) 174, 172-185 by LM Squeglia, TM Ball, J Jacobus, T Brumback, BS McKenna, TT Nguyen-Louie, SF Sorg, MP Paulus, and SF Tapert. This paper shows that a machine learning technique called the random forest model (with a combination of demographic, neurocognitive, and brain imaging data) was significantly more predictive of which individuals at age 18 would initiate alcohol use based on data obtained when they were 12-14 years old, than the standard demographic model.
“Multi-Level Prevention Trial of Alcohol Use Among American Indian and White High School Students in the Cherokee Nation” was published in the American Journal of Public Health, (2017) 107, 453-459by KA Komro, MD Livingston, AC Wagenaar, TK Kominsky, DW Pettigrew, BA Garrett, and The Cherokee Nation Prevention Trial Team. It documents the effectiveness of utilizing novel citizen-driven, community-based environmental strategies to reduce youth access to alcohol, and school-based, universal screening and brief intervention to reduce overall alcohol use, heavy episodic drinking, and associated consequences among American Indian youth, thus reducing health disparities.
“Comparison of 12-Step Groups to Mutual Help Alternatives for AUD in a Large, National Study: Differences in Membership Characteristics and Group Participation, Cohesion, and Satisfaction” was published in Substance Abuse Treatment (2017), 73, 16-26, by SE Zemore, LA Kaskutas, A Mericle, and JJ Hemberg. This publication describes 12-step alternatives (including LifeRing, Women for Sobriety, and SMART Recovery) high levels of participation, satisfaction, and group cohesion among members of these alternative mutual help groups.
“Is Alcoholics Anonymous Religious, Spiritual, Neither? Findings from 25 Years of Behavior Change Research” was published in Addiction (2016 Oct 8). doi: 10.1111/add.13590. [Epub ahead of print]) by JF Kelly. This publication summarized the latest scientific research conducted on AA and its mechanisms of behavior change, finding that AA confers benefits through multiple mechanisms simultaneously, but in particular by facilitating adaptive social network changes and boosting social abstinence self-efficacy and negative affect abstinence self-efficacy.
“A Phase 2, Double-Blind, Placebo-Controlled Randomized Trial Assessing the Efficacy of ABT-436, a Novel V1b Receptor Antagonist, for Alcohol Dependence,“ was published in the journal Neuropsychpharmacology (2016 Oct 19). doi: 10.1038/npp.2016.214. [Epub ahead of print]) by ML Ryan, DE Falk, JB Fertig, B Rendenbach-Mueller, DA Katz, KA Tracy, EC Strain, KE Dunn, K Kampman, E Mahoney, DA Ciraulo, L Sickles-Colaneri, N Ait-Daoud, BA Johnson, J Ransom, and C Scott, GF Koob and RZ Litten. This publication shows that a novel compound, ABT-436, significantly reduced the frequency of drinking, as well the number of cigarettes smoked by alcohol dependent smokers. In a subgroup analysis, patients with relatively higher baseline levels of stress responded better to ABT-436 than to a placebo in reducing the frequency and amount of drinking.
Discussion: Carlo DiClemente, Ph.D., stated that there is a need to make a distinction between the mutual support programs of AA versus AA as a treatment program, which has been incorporated in the Hazelden Betty Ford Foundation Addiction Treatment Center. Louis Baxter, Sr., M.D. stated that his research suggests that patient support doesn’t have to be AA or a 12-step program, but should include a group that offers support and overcomes shame. Dr. Koob responded that both comments raise important issues and that NIAAA’s strategic plan will be emphasizing recovery. He suggested that both Dr. DiClemente and Dr. Baxter, as well as Keith Humphreys, Ph.D., Stanford University, who has studied AA and other 12-step groups, be invited to make presentations to Council on this topic. He said he would like to foster cross-talk between the clinical and basic science fields, e.g., by screening Risky Drinking at RSA. Constance Weisner, Dr.P.H., interjected that 90 percent of people with an alcohol problem are not full-blown alcoholics. Researchers should become aware of medications and treatments for them, in addition to prevention and early intervention. Dr. Koob said she would also be asked to give a presentation, noting that this is an area where individual differences are important in terms of type of care. Paul Kenny, Ph.D., mentioned Bin Gao, Ph.D., at NIAAA as the driving force in the development of animal model of alcohol feeding (the NIAAA model). Dr. Baxter cited the value of the criteria from the American Society of Addiction Medicine (ASAM) for determining level of care needed. Susan Smith, Ph.D., asked if there were plans to make Risky Drinking more widely available to the public. Fred Donodeo, NIAAA, explained that HBO wants to make the documentary available through its online platforms first, but plans to make it available in the future as a DVD with a modest cost. Dr. Koob reported that HBO has asked NIAAA to suggest venues for additional screenings and praised the network’s commitment to accuracy throughout the production of the film.
Council Concept Clearance: Alcohol PTSD Comorbidity Concept Clearance
Dr. Koob introduced Dr. Lindsey Grandison, from NIAAA’s Division of Neuroscience and Behavior, and is leading the work in the Institute to develop initiatives in the area of stress and post-traumatic stress disorder (PTSD). Dr. Grandison explained the nature of the comorbid condition in which post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) co-occur. PTSD is the fourth most common psychiatric disorder; it can last a lifetime and poses a substantial mental health burden. AUDs occur in 30 percent of PTSD subjects and can occur at a much higher rate in specific populations of PTSD patients. Investigation of the comorbid PTSD-AUD condition will provide insight into the link by which PTSD increases the risk for alcohol dependence as well as identify the neurobiological processes common to both PTSD and alcohol use disorders. Development and validation of animal models of PTSD-AUD comorbidity may lead to interventions to prevent the progression from PTSD to comorbid PTSD-AUD and to effective treatments for this refractory condition. Symptom severity is greater with comorbidity and treatment is more difficult. Previously, providers tried to treat the AUD first, but treating them together would be more efficient. Potential areas of investigation include: 1) Assessment of compulsive-like alcohol consumption in a well characterized animal model of PTSD. Such a model would provide a basis for examining the mechanisms for the transition to compulsive-like alcohol consumption in animals with no compulsive-like responding for alcohol prior to development of PTSD, see 6 below. 2) Characterization of the impact of an adverse, early life experience on development in adulthood of PTSD-AUD comorbidity in response to a trauma. 3) Determination of the effect of alcohol exposure on the development of PTSD. For alcohol exposure prior to PTSD, moderate drinking (BAL <80 mg percent), binge (BAL >80 mg percent) and alcohol dependent or compulsive-like levels of consumption may be considered. 4) Assessment of the effect of sex on development of PTSD/AUD comorbidity and if observed, an attempt to identify the impact of gonadal hormones from chromosomal sex composition. 5) Characterization of the role of neuroimmune activation in PTSD/AUD comorbidity. 6) Identification of the neurobiological processes, neurobiological targets for potential treatment, and/or the biomarkers that will predict transition of PTSD to comorbid PTSD-alcohol misuse. Investigation is not limited to these topics. All relevant proposals will be considered.
Rajita Sinha, Ph.D. asked why NIAAA was limiting it to animal studies. Dr. Grandison stated that the Institute wanted to start with animal models to gain insight. Investigations may be expanded to clinical ones in the future. Dr. Koob interjected that the National Institute of Mental Health (NIMH) does not currently have activity in the animal model area, so NIAAA decided that it could address this gap. Dr. Grandison noted the new Cohen Veterans Foundation issued funding opportunity announcement (FOA) RFA PTSD 0002
entitled Translational Preclinical Animal Model Systems of Post-Traumatic Stress Disorder.
In addition, NIAAA is collaborating with the Department of Defense (DoD), which has a consortium looking at PTSD and substance use disorders (SUD); DoD has an FOA for developing new treatments for PTSD. Thus, NIAAA is trying to coordinate efforts and resources on the alcohol PTSD interaction across funding agencies. Dr. Koob stated that NIAAA is also interested in conducting a joint workshop with NIMH about the clinical treatment of PTSD and AUD, but is waiting for the new NIMH Director to settle in. Dr. Sinha emphasized that human studies are being completed on PTSD but not on comorbidity. Understanding how alcohol use is affecting PTSD is more difficult to disentangle in animal models. Therefore, she encourages animal to human translation. Dr. Grandison responded that NIAAA would welcome any proposals that come in. Dr. DiClemente noted the qualitative differences between exposures to different types of violence, and suggested that a variety of models will be needed. Dr. Grandison agreed, observing the goal is not to identify a single model but to describe the impact of alcohol use. Dr. Koob also agreed that multiple models will be needed. He noted that he and Dr. Litten had attended a meeting at Fort Detrick on the topic of PTSD and traumatic brain injury (TBI), which are also comorbid. This is another area to be examined.
Consideration of Minutes of the September 2016 Council Meeting and Future Meeting Dates
Council members unanimously approved the minutes of the NIAAA Advisory Council meeting held September 15, 2016.
In 2017, the NIAAA Council will meet 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 12:40 p.m. and reconvened at 1:33 p.m. for the afternoon session. At that time, Dr. Koob introduced ex-officio member Charles S. Milliken, M.D., who joined the meeting.
Council Member Presentation: Neuroimaging in Alcoholism: Human-Animal Translation
Dr. Koob introduced Council Member Dr. Adolf Pfefferbaum, SRI International, to report on his group’s brain imaging studies in alcoholism. Dr. Pfefferbaum’s presentation focused on structural imaging, including macrostructure, microstructure, and recovery in humans, as well as parallel animal studies and ongoing collaborative human studies.
Macrostructure: Clinical MRI scans show the macrostructure of the brain. There are a variety of radiological signatures of alcohol subsyndromes visible on such images, such as Wernicke’s Encephalopathy. If untreated, it can lead to Korsakoff's Syndrome (KS) which is characterized by mammillary nuclei atrophy, and results in profound neurocognitive sequelae, especially dense amnesia. Dr. Pfefferbaum’s colleague, Edith Sullivan, Ph.D., has led collaborative studies at Stanford and SRI to compare the brain structures of uncomplicated alcoholics and those with KS using an age-regression model, required since the brain changes dramatically over a lifetime. The scans in these studies reveal a graded deficit from the healthy condition to uncomplicated alcoholism to Korsakoff’s in several areas, including the mammillary bodies, the thalamus, and the cerebellum, both the vermis and the pons. One of the questions Dr. Pfefferbaum’s group is exploring is whether this is caused by a thiamine deficiency.
Microstructure: To study microstructure and structural connectivity, Dr. Pfefferbaum and his colleagues used diffusion tensor imaging (DTI). DTI provides an index of the microstructural fiber integrity of white matter and its primary constituents, axons and myelin, on a voxel-to-voxel basis. The two principal metrics of DTI are diffusivity and fractional anisotropy (FA), a measure of the linear organization of white matter fiber tracts. The assumption is that low FA and high diffusivity in white matter typically indicate pathology. Comparing brain images of both non-alcoholic and alcoholic men and women, deficits in FA have been observed in white matter regions that did not exhibit macrostructural volume deficits.
With fiber tracking, researchers can assess the microstructural integrity of the major fiber systems of the brain: the commissures—used for interhemispheric communication, association fibers important for intrahemispheric communication, and projection fibers that enable communication between the brain stem and cortex. Using quantitative fiber tracking to examine other white matter fiber bundles, Dr. Pfefferbaum and his colleagues found a pattern of disruption in alcoholics where frontal and superior fibers are especially vulnerable, leaving posterior and inferior fibers relatively preserved and perhaps avenues for escape of function.
Recovery: The dynamic course of alcoholism follows a variable course typically through periods of drinking and abstinence, with high rates of recidivism. Tracking the course requires naturalistic study in humans, with little control over critical variables or, alternatively, application of viable animal models to target specific aspects of the development, maintenance, and reversal of physiological dependence on alcohol. Such studies attempt to answer the question: Can the brain recover? Brain scans of alcoholics reveal that continued drinking can lead to continued insult; those who stop drinking may show some recovery.
Tract-based spatial statistics (TBSS) allows the researchers to survey the white matter microstructure of the entire brain simultaneously. It is used to pinpoint regions of the brain where alcoholics have low FA relative to controls. Affected regions were especially notable in the frontal and superior white matter. The researchers followed some of these individuals longitudinally. FA declines even in healthy individuals with aging; the trajectory for alcoholics is the same. However, comparing those who were heavy drinking relapsers with those who didn’t drink as much and those who were abstinent, the trajectory was much steeper for the heavy drinkers. Those who stop recover to almost normal, providing some evidence for recovery.
Animal Studies: In vivo imaging of animals is useful in expanding understanding because 1) MRI measures are the same in humans and animals; 2) Researchers can control the environment, age at exposure, amount, rate and duration of alcohol exposure, and nutrition; and 3) Researchers can examine brain images before, during, and after treatment in the same animal, thus increasing statistical power.
Natalie Zahr, Ph.D., at SRI conducted a labor-intensive experiment to demonstrate what would happen to the structural brain image result if she sent rats on a bender, i.e., she administered 12 grams of ethanol per kilogram per days for four days, resulting in blood alcohol levels above 250. She scanned them prior and immediately afterwards, and then gave them time to recover. The results showed an expansion of the cerebrospinal fluid (CSF) spaces immediately following exposure to alcohol, and then a return to the pretreatment condition after a week of recovery. That led researchers to the question: If acute recovery occurs after a binge, could the researchers cause cumulative damage in the rats, thus replicating the human condition? Dr. Zahr undertook an experiment in which she conducted six cycles of gavage and recovery on a group of animals, followed by another five cycles in another group of animals. Blood alcohol levels increased to 300 milligrams. During the experiment, the animals adapted quickly to the alcohol. The pattern of expansion and contraction in their CSF spaces paralleled that of the single 4-day binge experiment, but there were diminishing returns. There was no evidence of cumulative damage in this model, but instead neuroadaptation to the alcohol in rats. A different pattern is seen when there is a dietary insult. When animals are made thiamine-deficient, they exhibit hyperintense signals indicating enema in the thalamus, mammillary nuclei and inferior colliculi. But unlike with the pure alcohol treatment, there is incomplete recovery.
Using an invasive animal model, Dr. Zahr examined effects on the dopamine system. The researchers infected transgenic CRE recombinase rats with a virus that contained a channel rhodopsin in the ventral tegmental area (VTA) in order to trigger dopamine neurons before implanting an optical fiber for transmitting blue laser stimulation. Behaviorally, the rats behaved as expected. Their responses to a visual stimulus and to an optogenetic stimulus were then compared, with an expectation that there would be an enhanced fMRI signal in the superior colliculi and an effect in the dorsal striatum. The results showed a very strong signal in the superior colliculus and nothing in the dorsal striatum with the visual stimulation, and a strong signal in the dorsal striatum with a lesser one in the superior colliculus with the optogenetic stimulation. The superior colliculus respnse occurred because the stray light from the optogenetic fiber was enough to stimulate the rat’s visual system in a dark environment.
Collaborative Human Studies: Studying alcoholism in humans ideally requires longitudinal studies and is best done collaboratively to accrue larger samples than can be recruited by a single laboratory. Currently, SRI is engaged in two collaborative endeavors, one on HIV infection with alcohol comorbidity with the University of Florida, and the other as part of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study. In the first one, SRI examined the total cortical gray matter volume of those with HIV infection and those with both HIV and AUD. Volume for everyone declines with age, but it declined more rapidly in those with HIV, and even faster for those who were comorbid. Ventricles, in contrast, expanded with age to make up for loss of tissue. Among the HIV-infected, the ventricles expanded faster than for others and, again, the ventricles of the comorbid expanded even faster. NCANDA enrolled more than 800 adolescents at five sites across the country in a cohort sequential design; most of those youth have had their brains scanned at baseline and at annual laboratory visits thereafter. A preliminary analysis of unpublished data suggested accelerated decline in the normal trajectory of frontal lobe volume development in heavy-drinking youth relative to youth who remained in the no-to-low drinking category.
Discussion: Dr. Koob inquired about what the mammillary nuclei do during alcohol impairment. Dr. Pfefferbaum responded that scientists previously thought it prevented dense anterograde amnesia, but that’s an incomplete explanation because the hippocampus is also affected. Dr. Kenney said it is part of the feedback loop into the hippocampus to sustain theta rhythm, which would most likely lead to spatial learning deficits and possibly anxiety effects. Dr. Smith asked about the current thinking on the role of thiamine. Dr. Pfefferbaum responded that a history of trace thiamine deficiency (e.g., from missed meals, ataxia) predicts how great the behavioral deficits are in chronic alcoholics. Dr. Smith noted that people lose many micronutrients due to poor eating behaviors so the field may be missing part of the bigger picture by focusing only on thiamine. Dr. Shah interjected that the liver is not a major target of thiamine deficiency. Dr. Kenney asked if there was any evidence of inflammation and calcification. Dr. Pfefferbaum responded that a CT scan reveals calcification better than an MRI. He noted, however, than the manganese blush on certain brain images goes away if liver failure is resolved. Dr. Kenney stated that it would be worth investigating whether this brain immune inflammation plays a key role in driving behavior, thus providing evidence for calcification. Dr. Pfefferbaum concurred. Dr. Sinha inquired, in regard to the NCANDA findings, if there were other factors, such as trauma exposure, that contribute to the transition from lighter to heavier drinking. Dr. Pfefferbaum said that the data collection for that study just closed, so findings are not yet available. Dr. Koob noted that he would be invited back to speak when the analysis was complete.
Council Member Presentation: Alcohol and Stress Mechanisms: From Risk to Relapse and Recovery
Dr. Koob introduced Council member Dr. Rajita Sinha, Yale University School of Medicine. She reviewed the increasing incidence of trauma; over 55 percent of respondents in an annual survey by the American Psychological Association (APA) reported experiencing adverse events that were traumatic. She then presented evidence about the impact of stress on alcohol use, and on relapse/recovery.
Alcohol and Stress/Trauma: Trauma and stress are positively associated with alcohol use and binge drinking. High stress and trauma in children and adults increases risk of AUDs. Sources of stress include adverse life events; child/adult life trauma; and chronic stressors. Animal studies have revealed that high cumulative stress reduces brain tissue in the prefrontal neurons/regions of the brain that regulate stress. In a study of 100 healthy community-based adults, Dr. Sinha and her colleagues found a similar pattern: The gray matter in the prefrontal cortex, i.e., the striatum and the insula, decreased in volume as a function of cumulative stress.
In another multi-factors experiment involving physiologic, neuroendocrine, and brain imaging assessments, Dr. Sinha and her colleagues exposed individuals in the treatment condition to terrifying pictures while those in the control condition saw neutral pictures. During the experiment, the researchers provoked a sustained acute stress response for a few minutes in which subjects experienced heightened arousal, heart rate, and cortisol response, as well as activation in the brain’s specific stress circuitry, the amygdala, the hippocampus, the ventral striatum and dorsal striatum, the insula, and a number of other regions. The critical finding from the study is that a resilient coping signal is seen with dynamic activation in the prefrontal cortex after initial blunted prefrontal cortex response. The greater the dynamic return in prefrontal activation, the more the active coping ability reported by participants. If the prefrontal cortex comes back with online during stress, the individual is likely to regulate emotions better and also not engage in binge drinking. If the individual is not an active coper, she or he may drink more heavily and have difficulty handling negative emotions.
In a cross-sectional community study of 847 people, the researchers compared the number of drinks consumed by individuals among those with little/no trauma, past trauma and recent trauma. They discovered that the number of drinks consumed increased the most among those with recent trauma. Those with recent trauma prior to the past 12 months consumed more than those with no trauma, and more than those with past trauma. Examining association maps of the brain, it is evident that the higher the level of recent trauma, the more hyperactivity occurs in the prefrontal cortex, ventromedial prefrontal cortex, and in the ventral striatum under relaxed conditions, but there is a blunted response in the stress condition.
These studies highlight the prefrontal cortex being a hotspot in regulating emotions, attention, cognition and behavior.
Relapse/Recovery: Much of Dr. Sinha’s work has focused on trying to understand relapse, and whether it is possible to get people to remain abstinent, particularly in the context of high levels of stress and trauma which are related to craving. Alcoholism is a chronic, relapsing illness. Despite effective FDA approved treatments, more than half of individuals relapse within weeks to months of initiating treatment. In particular, no effective treatments exist that target stress and trauma related-relapse factors and related high craving that increase relapse risk.
Dr. Sinha and her colleagues have focused on identifying predictors of relapse in terms of brain mechanisms with the hope that treatments can then be tailored to address those biomarkers or predictors of relapse. Currently, there is no biological measure of relapse. Predictors may include structural brain changes; altered negative emotion and anxiety and drug craving; altered hypothalamic–pituitary–adrenal (HPA) axis, autonomic and other biochemical function; and altered response in brain emotional and motivational circuits. Sensitivity and specificity analyses of these predictors are higher than 80 percent. Thus, the researchers believe they are ready to begin validating these measures as predictors of relapse. For example: Examining brain scans of alcoholics vs. controls in a prospective longitudinal study, the volume of the medial frontal region of the brain can be seen as a predictive measure of relapse. Those with the lowest brain volume relapsed very quickly, within 40 days. Those who don’t lose frontal volume did not relapse. In addition, studies at multiple laboratories have shown that the craving response predicts future relapse very well.
Alcoholics often say that although they have the cognitive/behavioral skills that they need, they relapse when they are stressed. Dr. Sinha and her colleagues have studied this phenomenon in the laboratory, provoking study subjects with stress exposure, cue exposure, and then a controlled relaxing exposure. Both alcoholic and control subjects experience stress under the stress condition. But alcoholic subjects during the early four-week abstinence state do not experience a return autonomically; instead, they remain hyperactive physiologically in the autonomic system and show a blunted response to stress and cues. When shown neutral relaxed images or are imagining neutral relaxed states, they remain hyperactive in the ventral striatum and in the prefrontal region so that they are unable to mobilize a stress response in the frontal system. This pattern predicts relapse. The more blunted their response under stress conditions, they more quickly they relapse. The less blunted, the ability to mobilize the frontal system under stress helps and they are likely to sustain recovery.
Other physiological measures, including basal heart rate, cortisol response, adrenocorticotropic hormone (ACTH), and adrenal sensitivity also serve as predictors. A hyperactive cort/ACTH ratio predict relapse. Thus, there is an overall stress system dysregulation/disruption that is a function of high alcohol use that is presented in multi-method assessments. In analyzing these various elements, Dr. Sinha and her colleagues have determined that the brain response is the most sensitive predictor of relapse but the Cortisol and Cortisol/ACTH ratio are also very good predictors of relapse.
In summary, the psychobiological and neural response profile of relapse risk includes: Increased anxiety and provoked alcohol craving; high cortisol/ACTH ratio and blunted cortisol responses as well as altered stress endocrine responses (NPY, BDNF and anandamide); a hyperresponsive brain during neutral relaxed state associated with greater anxiety and alcohol craving and blunted prefrontal cortex (PFC) response with stress; and smaller gray matter volume in medial frontal and posterior regions.
With NIAAA funding, Dr. Sinha and her colleagues are working on replicating these data and validating the predictors as biomarkers for relapse susceptibility, using the multi-factor methodology discussed above for resilient coping in which there are alcohol cues, stress cues, and neutral cues, and concurrent measures of cortisol, ACTH, and other neurocranial and physiological measures.
Early analyses of their ongoing studies show that alcoholics just entering treatment have higher cravings, including sustained stress-induced craving, than the control drinkers, as well as higher levels of stress. They also demonstrate a blunted cue relative to neutral responding in the ventromedial pre-frontal cortex under both stress condition and cue condition, in contrast to the healthy controls, as well as hippocampal and amygdalar activation. With NIAAA funding, Dr. Sinha and her colleagues are looking at whether these changes can be reversed with pharmacological strategies. In particular, they are looking at prazosin, an old hypertensive drug that has been shown to rescue repeated stress related impairment in the prefrontal cortex; decrease post-traumatic stress disorder (PTSD) clinical symptoms; and decrease stress-induced craving and drinking in alcohol dependent individuals. At Yale, they are in the last year of a clinical trial in which they are replicating these findings in a laboratory subcomponent but also testing them with heavier alcoholics. Their findings show that those in the placebo group demonstrated very suppressed cortisol response in both the stress and cue conditions, while those in the prazosin condition experienced normalization of the cortisol stress response.
In another study funded by NIDA of those with both cocaine and alcohol addiction and led by Verica Milivojevic, 400 milligrams/day of progesterone was administered for seven days with the goal of increasing neural steroids. Animal data indicated that progesterone naturally increases allopregnanolone, a neural steroid, which goes back into the brain and increases GABA levels. In the present study, they measured Allo levels, comparing high vs. low levels. The findings indicate that cortisol baseline came down which was positive because there was initially high basal cortisol followed by improvement in reactivity with cortisol in the high Allo group, as well as an improvement in reduction in craving scores and improvement in a Stroop task (a prefrontal-based marker for executive function). They have begun using a different agent to increase Allo levels, and would like to extend this experiment to alcoholics.
Dr. Sinha concluded her presentation by summarizing the main points. Chronic stress and alcohol abuse each result in peripheral and neural adaptations associated with maladaptive coping such as increases in alcohol craving, compulsive alcohol motivation and return to alcohol intake and relapse. Specific blood and brain biomarkers of alcohol relapse have been identified and they are now working to validate these biomarkers. This work addresses Personalized Medicine Goal 1: Identify those are most vulnerable at treatment entry or during early recovery; and Goal 2: Develop specific treatments to reverse chronic alcohol brain effects to help those most susceptible to high alcohol relapse risk and to treatment and recovery failure.
Discussion: Dr. Koob asked if Dr. Sinha’s team has looked at the frontal cortex’s role in delayed discounting. Dr. Sinha responded that her group has published data from a large sample of social drinkers and alcoholics looking at behavioral impulsivity tasks, as well as self-reported impulsivity; the latter is a stronger predictor of how much alcohol people are consuming. She asserted that the ventromedial PFC is very important in discounting functions in studies with monkeys. Yale has laboratory data involving the Stroop task, which is a variation on impulse control, as well as cognitive control pre- and post-stress. Both alcoholic and drug users show greater impairment post-stress. Dr. Sloan inquired about the external validity of the stress measures Dr. Sinha had shown, and also if the relationships on the biomarkers plot represented a causal relationship or an association. Dr. Sinha responded that the plot represented a proportional hazards regression model and thus showed an association, not a causal relationship. Dr. Sloan asked if the Y-axis in the plot was a marker for AUD; Dr. Sinha explained that it represented the relapse function. Dr. Sloan asked if the predictive measure, cortisol, is a marker for alcohol use or if it has an independent effect. Dr. Sinha responded that their findings indicate alcoholics experiencing greater cortisol disruption than healthy subjects do. Within the alcoholic subjects, the greater the disruption, the worse the outcome. Her group is working on further validation of the cortisol and frontal brain disruption to support biomarker development. The important thing to take away from Yale’s stress manipulation studies is that one can start to see, under basal state, where the brain remains disrupted at different points in the alcohol cycle. That matters for relapse. In regard to the validity of the stress measures, Dr. Sinha and her colleagues have found that the same brain circuitry is observed independent of whether the stimulus is terrifying pictures or having people imagine their worst recent stressful event. Dr. Kenny inquired if the altered cortisol levels reported in Dr. Sinha’s studies might reflect something deeper about complete autonomic dysregulation that might be considered in the context of alcohol-related disorders, such as cardiovascular disease or diabetes risk. Dr. Sinha responded that this is true. The peripheral cortisol is likely a marker of how the glucocorticoid function may be disrupted in the alcoholic brain.
Ex-officio Members’ Reports
Dr. Karen Drexler, ex-officio member from the Veterans Administration (VA) where she is National Mental Health Program Director for Addictive Disorders, gave a report about opportunities for research collaboration with the Veterans Health Administration (VA). The agency’s scientific capabilities are extensive, with over 3,500 researchers working on over 2,500 research projects at over 100 VA Medical Centers. Partnering, however, is critical to achieve the VA’s goal to advance care. The VA partners with numerous federal agencies, academic institutions, foundations and nonprofits, as well as with industry.
Priority research needs at the VA are for military service-related conditions, including PTSD and mental health, TBI, SUDs (cannabis, stimulants), and non-opioid pain management. For FY 2016 mental health and TBI research priorities, research on addictive disorders is the fourth level of funded projects. At approximately 20 percent of the total research budget, mental health research remains one of the VA’s highest priorities, focused on scientifically based treatment advances.
Precision Medicine is changing how the VA treats patients. Current Precision Medicine initiatives include Clinical Precision Medicine in Mental Health (PRIME Care); Precision Oncology Program (RePOP); and the Million Veteran Program (MVP), which is the largest genomic cohort of its kind in the world with a database of health, lifestyle, military exposure and genetic data. There are eight scientific projects using MVP data underway within a secure, central computing infrastructure within the VA (called GENISIS). These include PTSD, schizophrenia & bipolar disorder, Gulf War Illness, chronic kidney disease, cardiovascular and metabolic diseases, and age-related macular degeneration (eye disease). Dr. Drexler noted that AUD is missing from this list of topics and emphasized that MVP is an area where the VA would welcome more collaboration. She noted that the VA has heard from other organizations that it can be daunting to partner with the VA. For example, the VA has separate Institutional Review Boards (IRBs) at each branch; the agency is currently trying to move to a single VA-wide IRB.
Discussion: Dr. Koob asked Dr. Drexler to send him a list of points of contact at the VA that he could disseminate to Council members who might be interested in partnering with the VA. Tatiana Foroud, Ph.D., said that she and her colleagues have been trying to pursue a collaboration with the VA for a year, specifically trying to find a point of contact for cirrhosis-related studies for the Million Veterans Program. Dr. Drexler promised to send Dr. Koob a list of VA contacts.
Dr. Milliken reported that one of the exciting things happening at DoD is that the Secretary of the Army has directed that Army Level 1 outpatient treatment of addictions, previously under the Installation Management Command, be integrated with Army behavioral health within the Army medical system. Providers will be located in embedded behavioral health clinics within military units so that soldiers can walk to care, i.e., this will be a population community-based model with much better integration of care.
The Government Accounting Office has issued a report that directs DoD and the Coast Guard to screen for gambling addiction because of its association with suicidality. Currently, DoD screens for alcohol, depression, suicidal thoughts, financial problems, etc. using validated instruments as part of an annual assessment. There is a concern that adding a 12-item scale to the current assessment effort will have an undesirable impact on young soldiers’ willingness to participate conscientiously in these assessments.
Making Data from NIAAA Funded Grants Available to the Research Community
Dr. Koob invited Dan Falk, Ph.D., NIAAA to introduce Greg Farber, Ph.D., Director of the NIMH Data Archive (NDA). Dr. Falk explained that NIAAA is interested in beginning a new initiative to archive its NIAAA-funded human research data studies in NDA to maximize the Institute’s investment in research. If successful, researchers will be able to do secondary research, analyzing data across multiple data sets.
Dr. Farber reviewed the factors that led NIMH to make a significant investment in this research infrastructure. He noted that understanding the biological basis of human disease is a very hard problem, and progress is not happening quickly enough for two reasons: the underlying biology is complex, and individual variation is surprisingly large. Most of what medicine deals with today are complex diseases where the individual variation and the environment are important components. In these cases, researchers need to both understand the biology as well as have data from many individuals to understand individual variation and the number of “sub-groups” in a population.
Many components within NIH, including the All of Us Research Program (formerly Precision Medicine), NHLBI clinical trials, and NIDA-funded clinical trials, are trying to make data from human subjects available. The NIH Genomic Data Sharing policy expects NIH-funded investigators to submit data to an appropriate repository, while the new 21st Century Cures Act appears to give the NIH director the authority to require data sharing, although that is not yet a requirement.
NIMH has created a data infrastructure to hold data from experiments involving human subjects.
That infrastructure now holds data from nearly 600 NIH-funded awards as well as data supported by other funding agencies. Data types include: Clinical assessments; imaging and other “complex” data (eye tracking, EEG, PET, etc.); and genomics data in the area of autism. The NDA evolved from the National Database for Autism Research (NDAR), which was started in late 2006. NIMH recently decided to expand NDAR to include data from: Clinical Trials (NOT-MH-14-005); the Research Domain Criteria (RDoC) Initiative (NOT-MH-15-012); and the Adolescent Brain Cognitive Development Study. All of the data is part of a single database (NIMH Data Archive, NDA) with branded web locations (https://data-archive.nimh.nih.gov/
). The data infrastructure has matured to the point where it is now possible to expand to areas like substance use. The NDA has a large staff available to provide assistance to investigators.
The NDA is a federal data repository that only contains data from human subjects that is broadly consented for use by the research community. NIMH data are available to the research community through an application process that involves a data access committee; summary data are available to everyone with a browser. The data types include demographic data, clinical assessments, imaging, –omic data, and other complex data types (EEG…). The NDA currently shares data from nearly 130,000 subjects with the research community. There is nearly a petabyte of data, including ~800TB of imaging, –omic, and other complex experimental data, that is secured in the Amazon cloud. NDA also has deep federation with a number of data repositories, which allows NDA to query data in those repositories and to return data to the user from multiple repositories simultaneously. These repositories include the Autism Tissue Program; Autism Genetic Resource Exchange; Interactive Autism Network; Simons Foundation Autism Research Initiative; and the Ontario Brain Institute.
NDA has two key features to allow data standardization and aggregation: data dictionaries and the Global Unique Identifier (GUID). The NDA data dictionary provides a flexible and extensible framework for data definition by the research community. It includes 1500+ data collection instruments, freely available to anyone and 130,000+ unique data elements (“questions”). Data collection instruments are defined by the research community with assistance from NDA staff. The data dictionary accommodates any data type and data structure. The NDA GUID software allows any researcher to generate a unique identifier using some information from a birth certificate. If the same information is entered in different laboratories, the same GUID will be generated. This strategy allows NDA to aggregate data on the same subject collected in multiple laboratories without holding any of the personally identifiable information about that subject.
NIMH users deposit data in the NDA in the following way: At the start of the award, a data submission agreement is signed and the data archive creates data dictionaries that will be required for the user to submit data. Every 6 months, data are submitted to the data archive. Submitting data is separate from releasing data to the research community (i.e., sharing). Sharing happens once a paper is published or one year after the completion of the grant. NIMH has created a cost estimator and asks its awardees to request data sharing costs (about $10,000 per R01) when they submit applications.
Discussion: Dr. Koob asked about the time commitment required of an investigator to contribute data to the NDA. Mr. Farber replied that what really takes time is to define the data dictionary upfront. The amount of time to upload data every six months is only a couple of hours. Dr. Sinha noted that many clinical studies are using web-based data collection tools. She inquired if that process helps. She also noted that there is a drive to do assessments which leads to 130,000 variables, rather than use PROMIS tools. Mr. Farber responded that electronic data capture facilitates the process. He also encouraged investigators to use existing validated measures, rather than creating their own. Judith Arroyo, Office of the Director for Health Disparities, stated that she hopes the NDA will pay attention to changing population demographics so it can be a dataset for the ages. There is a need to expand definitions of minorities (e.g., not simply Hispanic, but also designating country or origin, and refinements within the LGBT definition) as the population changes. Mr. Farber responded that if there is data that reflect those definitions, it can be queried in whatever way would be appropriate. Dr. Grandison asked if the NDA has been expanded to other federal programs. Mr. Farber stated that NIMH tries to work with other data depositories, but some projects (e.g., STARS) within DoD or the VA don’t want to open their data up to others. But other NIH Institutes are interested. Dr. Koob asked Council members to email him if they had any objections to NIAAA’s participation in the NDA.
There were no public comments.
The meeting adjourned at 3:30 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
George F. Koob, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
National Advisory Council on Alcohol Abuse and Alcoholism
Abraham P. Bautista, Ph.D.
Office of Extramural Activities
National Advisory Council on Alcohol Abuse and Alcoholism