164th Meeting of the NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM

DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH

NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM

September 7, 2023

NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM164th Meeting of the

The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened its 164^th meeting at 11:23 a.m. on Thursday, September 7, 2023, in hybrid format, i.e., both in-person and via Zoom videoconference. The Council met in closed session from 10:40 a.m. to 11:05 a.m. to review grant applications and cooperative agreements. Dr. Philippe Marmillot, Acting Director of the Office of Extramural Activities, presided over the Council’s review session which, in accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C., and 10(d) of Public Law 92-463, excluded the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds. The closed session recessed at 11:05 a.m.

Council Members Present:

Nancy Barnett, Ph.D.
Christopher S. Carpenter, Ph.D.
Christina Chambers, Ph.D.
Nancy Gonzales, Ph.D.
Rhonda J. Jones-Webb, Dr.P.H.
Beth Kane-Davidson, LCADC, LCPC
David Kareken, Ph.D.
Charles H. Lang, Ph.D.
Mary E. Larimer, Ph.D.
Michael J. Lewis, Ph.D.
Laura E. Nagy, Ph.D.
Laura O’Dell, Ph.D.
Katie Witkiewitz, Ph.D.

Ex-Officio Members

Col. Charles S. Milliken, M.D.

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

NIAAA Deputy Director: Patricia Powell, Ph.D.

Acting Executive Secretary: Ranga V. Srinivas, Ph.D.

Senior Staff: Vicki Buckley, M.B.A.; David Goldman, M.D.; Ralph Hingson, Sc.D.; M. Katherine Jung, Ph.D.; Raye Litten, Ph.D.; David Lovinger, Ph.D.; Phillippe Marmillot, Ph.D.; Antonio Noronha, Ph.D.; and Bridget Williams-Simmons, Ph.D.

Other Attendees at the Open Session

Approximately 275 people observed the meeting in person or online, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.

Call to Order

NIAAA Director Dr. George F. Koob called the open session of the Council meeting to order at 11:23 a.m. on Thursday, September 7, 2023. Council members and NIAAA senior staff introduced themselves.

Director’s Report

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

In Memoriam: Dr. Ann Stresissguth. Dr. Koob announced the passing of Ann Stresissguth, Ph.D., Professor in the Department of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine. Dr. Streissguth was renowned as an expert on fetal alcohol spectrum disorders (FASD) and co-published the first study identifying “fetal alcohol syndrome” in the U.S. and its link to maternal alcohol consumption during pregnancy. For 30 years, she led the NIAAA-funded longitudinal study "Alcohol Intake during Pregnancy: Offspring Development" that followed study participants from childhood into adulthood to better understand the long-term neurodevelopmental consequences of FASD.

New Scientific Director: Dr. David Lovinger. Dr. David Lovinger is NIAAA's new Scientific Director for the Division of Intramural Clinical and Biological Research. He was previously NIAAA’s Acting Scientific Director. In addition to his new role, Dr. Lovinger will continue to direct the Laboratory for Integrative Neuroscience.

New Scientific Diversity Officer: Ms. Dawn Wayman. Ms. Dawn Wayman is NIAAA's new Scientific Diversity Officer, helping to catalyze and coordinate NIAAA-specific goals and resolve critical issues that will enhance the diversity and equity of research programs. Ms. Wayman was previously the branch director for Strategic Diversity and Inclusion in NIH's Office of Equity, Diversity, and Inclusion.

NIAAA Budget. In FY 2023, NIAAA received a total of $596.6 million, including a $1.3 million AIDS transfer. The budget for FY 2024 has not been finalized. It is currently anticipated that FY 2024 will be fiscally constrained. NIAAA’s priorities continue to includebe support for Early-Stage Investigators and At-Risk Investigators.

NIAAA Funding Opportunities. Dr. Koob announced the following new Funding Opportunity Announcements (FOAs) from NIAAA:

• Alcohol Research Center Program: The overall purpose of the Alcohol Research Centers is to provide leadership in conducting and fostering interdisciplinary, collaborative research on topics relevant to the NIAAA mission. Letters of Intent are due October 15^th. A Plan for Enhancing Diverse Perspectives (PEDP) will be required. Two types of Centers will be supported:
  • Specialized Alcohol Research Centers (P50, RFA-AA-23-001)
  • Comprehensive Alcohol Research Centers (P60, RFA-AA-23-002): These Centers must include a dissemination core to initiate and expand community education related to the activities of the Center.
• Alcohol Treatment and Recovery Research (R01, PAR-23-250 and R34, PAR-23-249): To support a broad range of topics, including medications development, precision medicine, behavioral therapies, mechanisms of behavioral change, recovery, and innovative methods and technologies.
• Alcohol Health Services Research (R01, PAR-23-251 and R34, PAR-23-252): To support research on closing the treatment gap for individuals with AUD, including increasing access and making treatment more appealing, and reducing health disparities.
• Alcohol and Other Substance Use Research Education Programs for Health Professionals (R25, PAR-23-240): To support projects designed to engage health care professionals in education and research on AUD and other substance use disorders.
• HIV Prevention and Alcohol (R01, PAS-23-173 and R34, PAS-23-172): Solicits applications to expand the HIV/AIDS prevention toolkit among alcohol-impacted populations and associated behavioral and biological risks for HIV.

A full list of FOAs and Notices of Special Interest (NOSIs) may be found in the NIAAA Director’s Report.

NIAAA Alcohol Pharmacotherapy Evaluation Program: Request for Letters of Interest (NOT-AA-23-016): To help advance medications development for alcohol use disorder (AUD), NIAAA supports the Alcohol Pharmacotherapy Evaluation Program, an integrated program consisting of the NIAAA Clinical Investigations Group, a Human Laboratory Program, and a new Alcohol Interaction Program. The Alcohol Pharmacotherapy Evaluation Program is seeking letters of interest for promising medications for AUD ─ both novel compounds and repurposed medications ─ to evaluate their safety and efficacy in Phase 1 and 2 clinical trials. Clinical trials will be supported by an NIAAA contract and conducted by the Alcohol Pharmacotherapy Evaluation Program. Letters are due September 15^th.

Advancing Diversity, Equity, Inclusion, and Accessibility (DEIA): NIAAA is participating in several funding opportunities to enhance the diversity of the research workforce across the career spectrum:

• ADVANCE Predoctoral T32 Training Program to Promote Diversity in Health Disparities Research, Preventive Interventions, and Methodology (RFA-OD-23-018)
• BRAIN Initiative Advanced Postdoctoral Career Transition Award to Promote Diversity (K99/R00) (RFA-MH-23-331, RFA-MH-23-330)
• NIH Neuroscience Development for Advancing the Careers of a Diverse Research Workforce (R25) (PAR-23-178)
• Research Supplements to Promote Diversity in Health-Related Research (PA-23-189)

 More information on these opportunities may be found in the Director’s report.

Examples of Recent NIAAA-sponsored Scientific Meetings. 1) The Interagency Work Group on Drinking and Drug Use in Women and Girls, led by NIAAA, hosted “Achieving Equity in Women’s Addiction Prevention and Treatment: Accent on Promising Programs” on June 16. The webinar highlighted the Imani Breakthrough Program which develops culturally relevant, faith-based recovery interventions for Black and Latino communities. 2) NIAAA and the National Cancer Institute (NCI) co-hosted the webinar “Policy Approaches to Alcohol and Cancer Prevention: Resources, Results, and Gaps” on July 18 which highlighted NIAAA's Alcohol Policy Information System. 3) NIAAA and the National Institute on Aging (NIA) held the workshop “Role of Alcohol Misuse in the Onset and Progression of Alzheimer’s Disease and Its Related Dementias” on July 26-27. The workshop featured preclinical and clinical research on how chronic heavy alcohol exposure may intersect with pathways of developing and exacerbating Alzheimer’s and related dementias.

What’s Ahead? The National Institute on Drug Abuse (NIDA) and NIAAA will convene the virtual 2023 NIDA-NIAAA Mini-Convention on Frontiers in Addiction Research on November 7-8. Scientific sessions include 1) Alcohol and Substance Use Disorders and the Glymphatic System; 2) Glial Cells and Neuroimmune Mechanisms in Substance Use Disorders; and 3) Using Neuroscience to Inform Prevention Interventions for Substance Use.

Research Highlights. Dr. Koob presented highlights of alcohol-related human research studies that reflect the breadth of NIAAA-supported research:

“Initiation of and Escalation to High-Intensity Drinking in Young Adults” was published in JAMA Pediatrics (2023 Mar 1;177(3):286-293. PMID: 36716022) by ME Patrick, RJ Evans-Polce, BJ Arterberry, and Y Terry-McElrath. High-intensity drinking (HID), defined as consuming 10 or more drinks in a row, is a particularly concerning pattern of drinking behavior. This study used a sample of 451 young adults who reported past 30–day drinking while in 12th grade and initiated HID by age 20. Initiating HID by grade 11 (vs later) was associated with higher average weekly alcohol consumption, HID frequency, and an Alcohol Use Disorders Identification Test (AUDIT) score at age 20 years.

“A Web-based Sexual Violence, Alcohol Misuse, and Bystander Intervention Program for College Women (RealConsent): Randomized Controlled Trial” was published in the Journal of Medical Internet Research (2023 Jun 21; 25:e43740) by LF Salazar, AM Schipani-McLaughlin, Y Sebeh, Z Nizam, and M Hayat. Sexual violence toward college women is a major public health concern, and alcohol is a key contributor to sexual violence. This study aimed to determine the efficacy of an internet-based prevention intervention, called RealConsent, delivered to first-year college women and designed to reduce risk for exposure to sexual violence. Participants in the RealConsent group experienced less exposure to sexual violence, engaged in more alcohol protective behaviors, were less likely to binge drink, and were more likely to engage in bystander behavior than the placebo group.

“Association of an Alcohol Abstinence Program with Mortality in Individuals Arrested for Driving While Alcohol Impaired” was published in JAMA Psychiatry (2023; 80(5):520-522) by N Nicosia, B Kilmer, G. Midgette, and M Suttorp Booth. Alcohol-impaired driving fatalities are increasing. To help address this problem, the South Dakota 24/7 sobriety program orders driving under the influence (DUI) offenders to abstain from alcohol and provides frequent monitoring with swift, certain, and moderate penalties for violations. The current study examined time-to-mortality outcomes of ~12,000  24/7program participants and ~49,000 non-participants up to 5 years following arrest. The researchers found significant reductions in the risk of mortality among 24/7program participants relative to non-participants, demonstrating that 24/7 sobriety programs may improve health outcomes in addition to improving public safety.

“Frontal tDCS reduces alcohol relapse rates by increasing connections from left dorsolateral prefrontal cortex to addiction networks” was published in Brain Stimulation (2023 June 20; 16(4): 1032-1040) by J Camchong, D. Roediger, M. Flecas; CS Gilmore, M Kushner, E. Kummerfeld, BA Mueller, and KO Lim. Variations in functional connectivity between certain brain networks has been associated with risk of relapse to alcohol misuse. This study investigated the effects of transcranial direct current stimulation (tDCS), a brain-based non-invasive treatment, on relapse rates in individuals with AUD during early abstinence. Treatment for five days, compared to the sham condition, strengthened the connectivity from the lateral dorsal prefrontal cortex (LDLPRC) to the addiction networks supporting incentive salience (IS) and negative emotionality (NE). An increase in lateral dorsal prefrontal cortex incentive salience connectivity increased the odds of remaining abstinent at four months. These results support the potential utility of harnessing the brain’s functional connectivity to support behavior change.

“The Beneficial Effects of Lactobacillus GG Therapy on Liver and Drinking Assessments in Patients with Moderate Alcohol-associated Hepatitis” was published in the American Journal of Gastroenterology (2023 August 1; 118(8); 1457-1460) by V. Vatsalya, W Feng, M Kong, H Hu, G Szabo, A McCullough, S Dasarathy, LE Nagy, S Radaeva, B Barton, M Mitchell, and CJ McClain. Alcohol consumption leads to changes in the gut microbiota’s composition and growth, a phenomenon known as dysbiosis. In a pilot study, the probiotic Lactobacillus rhamnosus GG (LGG, 10⁹ CFU), administered daily for 6 months in patients with heavy drinking and moderate alcohol-associated hepatitis, reduced liver injury at one month and significantly reduced heavy drinking levels at six months. This study is ongoing and continues to recruit patients.

“Overall and Telehealth Addiction Treatment Utilization by Age, Race, Ethnicity, and Socioeconomic Status in California after COVID-19 Policy Changes” was published in JAMA Health Forum (2023 May 5; 4(5): e231018) by VA Palzes, FW Chi, VE Metz, S Sterling, A Asyyed, KK Ridout, and CI Campbell. This study investigated the impact of COVID-19 telehealth policy changes on addiction treatment utilization and potential disparities in utilization. Investigators analyzed electronic health records and claims data from adults with substance misuse in the Kaiser Permanente Northern California healthcare system. The researchers showed that telehealth addiction treatment utilization increased during the early phase of the pandemic for all subgroups without variation by race, ethnicity, or socioeconomic status. Younger adults in particular may have benefited most from the transition to telehealth.

Resources for the Pubic and HealthCare Professionals: Dr. Koob concluded his report by emphasizing that NIAAA is committed to disseminating accurate information about alcohol use and misuse. Key resources developed by NIAAA include:

• Rethinking Drinking: A website and print publication for a general audience to help individuals assess their drinking habits and find ways to make a change.
• CollegeAIM: Comprehensive information on prevention approaches found to be effective in college environments.
• Alcohol Treatment Navigator: Helps individuals understand treatment options and search for nearby treatment, including telehealth services. It also includes a portal to assist health care providers in making referrals for their patients.

Healthcare Professional’s Core Resource (HPCR)-- What Every Healthcare Professional Should Know about Alcohol: Designed to help address common barriers to optimum alcohol-related healthcare by providing core knowledge about alcohol and its effects on health Key elements of the HPCR. More specifically the HPCR provides knowledge to fill common gaps in training about addiction, including the neuroscience of addiction, evidence-based AUD therapy and medications, and the varied paths to recovery. It also provides quick, validated alcohol screening and assessment tools that address time constraints while providing a definitive picture of drinking levels and AUD symptoms and clarity about what constitutes heavy drinking, AUD severity levels, and recovery to build confidence in providing brief advice and collaborating on recovery plans. The HPCR outlines steps to reduce stigma surrounding alcohol-related problems and encourage greater patient acceptance of alcohol treatment when needed.

Discussion. Dr. O’Dell inquired about how to improve medical education about alcohol and drugs. Dr. Koob, with input from Dr. Goldman, responded that the good news is that the American College of Academic Addiction Medicine (ACAAM) now offers a credentialed fellowship training program in addiction medicine that can lead to Board certification that is recognized by every state. The bad news, however, is that there has been little impact on medical school curricula and little impact on other forms of training, e.g., psychology programs. Making progress in this area is a priority for NIAAA in the coming year, using parts of the HPCR as a launching point. Dr. Jones-Webb asked about the types of metrics that have been developed to measure DEIA. Dr. Koob responded that metrics have not yet been developed but will be developed. The new NIAAA Scientific Diversity Officer will be addressing this issue as it is an NIH-wide priority. His observation is that younger people in the field are much more diverse than previously. Dr. Witkiewitz thanked NIAAA for the development of the resources Dr. Koob outlined in his report, noting that her institution, the University of New Mexico, has used CollegeAIM to evaluate its program. She asked if NIAAA collects data on the use of these resources. Dr. Williams-Simmons responded that NIAAA is limited in the amount of data that it can collect, i.e., it can measure downloads and web pages viewed, but cannot conduct surveys about use. Dr. Lewis commented that DEIA metrics are needed, agreeing with Dr. Koob that more young people are interested in addiction research. Dr. Koob observed that more women are also entering the field.

 Council Member Presentation: Brain Function and Network Flexibility in a Family History of AUD

Dr. Koob introduced Council Member Dr. David Kareken, Indiana University School of Medicine, who summarized findings from his laboratory’s research, noting that it draws on investigations at the Indiana Alcohol Research Center which has a long history of studying brain-centered genetic vulnerabilities to alcohol. Dr. Kareken’s research focuses on the role of the brain in appetitive function and executive control function.

Appetitive drive (subcortical and medial prefrontal areas). Dr. Kareken came to the alcohol research field with an interest in the chemical senses of olfaction and gustation. At the time, a much of the imaging of the alcohol use reward system was conducted with visual stimuli. He experimented instead with smell (aromas) and taste (flavors), both of which can be tailored to an individual’s personal alcohol preferences. His first foray into this approach was via olfaction using a computer-controlled olfactometer in a functional magnetic resonance imaging (fMRI) study. Odorants from the subject’s two most preferred alcohol drinks when seeking to become intoxicated were placed outside the MRI bore. These aromas were compared to appetitive control aromas of grape and chocolate. Thus, both conditions had appetitive reward with one leading to intoxication. The brain images of heavy drinkers who had a family history of AUD compared to heavy drinkers without such a history indicated that those with a family history of AUD had more activation of the medial prefrontal areas in response to the alcohol aromas than did those without a family history. Disappointingly, however, there was not much striatal activation in this investigation.

Dr. Kareken’s next study examined positron emission tomography (PET) scans among 49 heavy beer drinkers. PET provides a good approximation of striatal dopamine release in humans by using a carbon-labelled raclopride which is a D2/D3 antagonist. This radio tracer can be displaced by endogenous dopamine release. Thus, if the individual is appetitively excited and releases striatal dopamine, there is a reduction in binding potential. In this study, Dr. Kareken and his colleagues provoked dopamine release by using subjects’ own most used beer when seeking to become intoxicated, using a gustometer with syringes loaded with the preferred beer or Gatorade (controls). Subject in the treatment condition received 15 small squirts (a milliliter each) of beer over 15 minutes during tracer uptake. Although not pharmacologically significant, the Pavlovian stimulus of the beer flavor alone was sufficient to release dopamine laterally in the right ventral striatum in these heavy drinkers. This effect was driven largely by those with a family history of AUD (first-degree relative) compared to those with second-degree relatives with AUD and those with no family history. Like the earlier fMRI study, these findings suggest that family history may prime the reward system’s response to alcohol’s conditioned stimuli.

Twenty-eight of the PET subjects also had an fMRI in a closely matched fMRI stimulation paradigm with subjects exposed to beer and Gatorade scans. Here again, there was right lateralized ventral striatal activity. Activation from beer taste in the medial prefrontal cortex subjective reward value area also correlated with the number of beers wanted.

Dr. Kareken and his colleagues then designed experiments to study dopamine transmission when subjects are given the opportunity for alcohol self-administration. In this experiment, the investigators used a gustometer and the computer-assisted alcohol infusion system (CAIS) that uses a pharmacokinetic model to model alcohol distribution and elimination to precisely control brain exposure; this cannot be done with oral administration nor during imaging. In the study, subjects underwent three PET scans in which they were exposed to a parametric combination of flavors and ethanol. During the scans, subjects saw an image of three beer glasses that would slowly drain each time they pushed a button that administered the flavor (i.e., a small spritz of beer). At the same time, they were exposed to a carefully controlled ascending limb of alcohol in the brain via infusion which was then clamped at 60 mg percent and held steady to eliminate variation across subjects (or the equivalent time course using saline). The findings revealed that after controlling for ethanol exposure and looking only at the conditioned stimulus (beer flavor), once again dopamine release in the right ventral striatum was observed. When flavor was controlled using Gatorade, a left ventral dopamine release from the ethanol was noted. When subjects were exposed to the “natural condition” (beer flavor and ethanol infusion compared to Gatorade and saline solution), bilateral dopamine release occurred in the ventral striatum.

Sweet Preference. There is a body of research identifying a preference for sweet taste among humans at risk for AUD and those in recovery. Rodents selectively bred for alcohol preference also have a correlated trait of increased sucrose/sweet intake. The human response to sucrose/sweet has not been adequately studied. In a recently published study from Dr. Kareken’s laboratory, a sample of 140 individuals balanced in family history and recent drinking underwent an fMRI during stimulation with a high- or low-intensity sucrose (primary reward), as well as a monetary incentive delay task (secondary reward). Then, between a few days to two weeks later, the subjects returned to complete a free-access intravenous alcohol self-administration session. Prior to the session, subjects experienced a brief, standardized 30 mg. percent alcohol prime using the computerized alcohol infusion system (CAIS). After 30 minutes, subjects were permitted to self-administer ad lib (up to 150 mg. percent, for safety reasons). Because of variability in the self-administration phase, the researchers concentrated on participants’ subjective responses during the peak of prime compared to baseline at the beginning of infusion. The dependent variable was “enjoyable intoxication,” derived by principal component analysis and comprised four highly inter-related components: intoxication, perceived number of drinks, enjoyment, and perceived stimulation. Results showed areas of the brain that are stimulated by high intensity sucrose, including gustatory regions in the insula posteriorly and the attentional salience areas anteriorly, and in parts of the ventral striatum. But the key focus was the correlation between the activation to sucrose and the perceived “enjoyable intoxication” that subjects experienced from the alcohol prime several days to two weeks later. The activation to sucrose predicted the subjects’ subsequent response to the alcohol. Both sucrose and the monetary anticipation activated the insula, but neither monetary reward anticipation nor receipt were related to the subjective response to the alcohol prime, despite the fact that they are both robust activators of the insula. Rather, the salience areas of the dorsal anterior insula and the presupplementary/supplementary motor area (those involved in the attentional salience network) were the regions where sucrose activation predicts the experience from the alcohol prime. This is important, as the positive rewarding aspects of alcohol on the rising limb are a risk factor for future AUDs and binge drinking.

Executive Control. Previous research (Acheson et al. [2014], ACER) examining go/no go paradigms (motor inhibition or restraint), a common approach to studying executive control, showed greater activation in some areas of the brain among those who were family history positive for AUD (FHA) compared to those who were family history negative (FHN). But the results were not straightforward, as in both the “Go” control condition and the targeted Go/No-Go motor inhibition periods, Acheson et al. observed “greater activation” in what appear to be regions of the default mode network (DMN), a network that is less evident with cognitive task engagement and more prominent at rest. Dr. Kareken reexamined earlier data he had collected using a Stop Signal task and found similar results, i.e., greater apparent activation under both Go and Stop conditions in a prominent node in the precuneus posterior cingulate area. Further analyses of these data showed this to be greater deactivation in family history negative individuals, with family history positive individuals showing less changing activation in this area between Go and Stop trials in the DMN. Thus, those with FHA changed less between the two states in the DMN.

These findings led to a new study that was less focused on executive control per se and more focused on the alternation between the two brain states of task engagement and rest. Researchers in Dr. Kareken’s lab began a collaboration with the CONNplexity Lab at Purdue University that offered expertise in network science. In the new study, the investigators were less concerned with nodes of activation and more interested in the functional reconfiguration of connectivity in the whole brain across the seven canonical networks (visual, somatomotor, dorsal attention, ventral attention, limbic, frontoparietal, and default mode). The study design consisted of two fMRI scans, the first one relatively short (8 minutes) and the second one long (12 minutes). The first scan consisted of two 4-minute resting connectivity periods. The second scan was divided into three 4-minute segments. During the first segment, subjects performed the Stop Signal task which required either Go responses or the need to quickly withdraw a Go when the Go signal was followed by a Stop signal. This was followed by two 4-minute resting periods.

During each 4-minute segment in the two scans, brain connectivity matrices were decomposed via independent component analysis into subcomponents of connectivity, with each subject having a loading indicating how much of a given subcomponent is present in that individual. Thus, the investigators could determine specific subcomponents that differentiated those with a family history of AUD from those who did not. They tested 15 empirically determined components across each 4-minute fMRI segment. Only one component across all five segments differentiated those with FHA. This component appeared in the first period of the second scan, after subjects stopped performing the Stop signal task.

Normally, the components that appear in the frontoparietal area that are involved in executive control are anti-related to the DMN; these networks tend to alternate with one another. But in this component, they are positively correlated. There is also some involvement in the visual and sensorimotor networks that are typically not considered in alcohol research. Notably, those with no family history of AUD had a greater loading of this component compared to those who were family history positive. This suggests that as subjects are transitioning from an activated state and entering a rest period, there exists some transient functional reconfiguration involving the visual, sensorimotor, frontoparietal, and default mode, and how they interact. Further, there is less of this reconfiguration in those with a family history of AUD. This remained true when the investigators controlled for sex (which was significantly related to the component), as well as for subject motion in the scanner, stop signal reaction time, AUDIT, and recent drinking. A subset of the sample (n=46) also completed a delayed discounting task to measure reward impatience. In this subjective analysis, both delay discounting and depressive symptoms (as measured by the Center for Epidemiological Studies Depression Scale, CESD) inventory were related to this component of functional connectivity reconfiguration. These characteristics were all related to the connectivity component in the same direction as considered risks for AUD: Those individuals who were male, had more negative affect, were more reward impatient, and family history positive all had less network reconfiguration.

In summary, Dr. Kareken emphasized the following key points:

• Those without a family history of AUD transiently “reconfigured” how brain areas/networks communicated when changing mental states, moving from task to rest.
• Those with a family history of AUD experienced less of this reconfiguration, as did: 1) Men; 2) People with greater depressive symptoms; and 3) People with less “delay of gratification.”
• FHA-related brain signatures may therefore be less related to the task itself, and more related to transitions between tasks.

These are some of the concepts that Dr. Kareken’s research team is now pursuing on two projects on AUD diagnosis, family history risk, and cognitive capacity.

Discussion: Dr. Koob commented that he found Dr. Kareken’s research on the role of family history and the impact of sucrose fascinating as it reminded him of a past discussion with the late Dr. Enoch Gordis, former NIAAA Director, who was convinced there was a relationship between the neural control of eating and neural control of alcohol. He inquired if there was any link between genetics and family history of AUD. Dr. Kareken responded that his laboratory has genotyped dried blood samples for the research participants and have not yet found a link, noting, however, that there are only 140 people in the sample. There may be a stronger connection with the gut and vagus nerve. Dr. Goldman interjected that polygenic scores are becoming predictive, allowing researchers to define who may be at genetic risk vs. familial risk. He asked Dr. Kareken to comment on the differences between those types of risk. Dr. Kareken said that familial risk is an aggregate proxy risk that also involves shared environment, which cannot be ignored. He is interested in further exploration of the new polygenic risk scores currently being published. However, they may be harder to apply in smaller studies such as his, which include subjects of multiple ancestries. Dr. Goldman replied that polygenetic scores are still not fully predictive. He acknowledged the validity of Dr. Kareken’s points but observed that there are large source datasets for summary statistics to compute the polygenic scores for Dr. Kareken’s datasets as a resource for the future. Dr. Lovinger asked which subcortical networks, if any, were considered in these studies. Dr. Kareken responded some subcortical areas were involved, but that the subcortical parcellation used in the studies reported here are less optimal than desired. The investigators plan to refine these areas more in future studies. Dr. Witkiewitz inquired about how the heterogeneity of responses from people in the family history positive group shown at the end of the presentation were considered, noting the high level of variability in the sample. Dr. Kareken responded that the study was a target of opportunity so subjects may be more variable than usual, both within and across sub-samples. Usually when his laboratory recruits subjects prospectively, the investigators seek to match subjects on variables that are known to appear frequently among individuals with a family history of AUD.

Intramural Presentation: Understanding the Interplay of Oxidative Stress, Inflammation, Cell Death, and Lipid Signaling in Tissue Injury and AUD-related Pathologies and Identification of New Therapeutic Targets

Dr. Koob introduced Dr. Pal Pacher, Senior Investigator, Laboratory of Cardiovascular Physiology and Tissue Injury, Division of Intramural Clinical and Biological Research, NIAAA, who explained that his laboratory is trying to understand the mechanisms of various types of tissue injury, including those induced by alcohol. There is increasing recognition that people with chronic or acute liver disease (including alcohol associated liver disease) are dying not only from liver disease but also from cardiovascular and renal complications. His laboratory is very interested in trying to understand the inter-organ communication that is driving the development of these life-threatening complications of liver disease. For example, an early study he led demonstrated that attenuation of liver inflammation and fibrosis via an endocannabinoid receptor 2 agonist improved hepatic cardiomyopathy (Matyas C. et al. Hepatology 2020; 71(4):1391-1407. doi: 10.1002/hep.30916). His presentation today focused on two ongoing projects that have been conducted over the past 10 years.

PCSK9. The first study described by Dr. Pacher concerns the identification of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a potential biomarker and therapeutic target for cardiovascular and liver aging, i.e., an example of heart and liver communication.

Age is an independent risk factor for cardiovascular and metabolic diseases. The phenotype of healthy aging includes decreased heart rate, increased likelihood of arrythmias, endothelial dysfunction and increasing stiffness of the vasculature, as well as increased levels of cholesterol and atherosclerosis, increased likelihood of hypertension (not always), diastolic and later systolic dysfunction, and impaired ventricular-arterial coupling. These reduce the reserve capacity of the heart and vasculature. The proposed mechanisms, all hallmarks of aging, include mitochondrial dysfunction, reactive oxygen and nitrogen species generation and impaired calcium handling, DNA injury, inflammation, cell death/senescence, diminished regenerative capacity, vascular and cardiac remodeling/fibrosis, and interorgan crosstalk (kidney-heart, liver-heart).

PCSK9 is key regulator of cholesterol metabolism that promotes low density lipoprotein receptor (LDLR) degradation and decreases LDL-cholesterol uptake with consequent increased serum total and LDL (low-density lipoprotein) cholesterol levels. The investigators became interested in PCSK9 because their prior pilot studies had indicated elevated blood (plasma/serum) PCSK9 levels in aging rats and humans. PCSK9 inhibitors are drugs approved by the U.S. Food and Drug Administration for the treatment of dyslipidemia and atherosclerosis and have been shown to have beneficial effects (decreased cardiovascular [CV] morbidity/mortality) beyond their primary mode of action (lowering cholesterol). Little was known about the role of PCSK9 in cardiovascular and liver aging.

The investigators’ first task was to determine the source of PCSK9. Using multiple transcriptomics approaches, they found that it is highly expressed in the liver, but not in the heart as documented in both animal and human studies (Arif M. et al. Geroscience 2023 Sept 20 doi: 10.1007/s11357-023-00928-w; Matyas et al. JACC: Basic to Translational Science Sept 13, 2023, in press https://doi.org/10.1016/j.jacbts.2023.06.005). In contrast to PCSK9, troponin T (TNNT2), an established cardiomyocyte gene marker (positive control), was highly expressed in heart and was released during ischemic injury, as confirmed by single cell and spatial transcriptomics analysis. Based on these studies, the researchers then focused on a transcriptomic profile of the aging liver. They studied the differentially expressed genes (both up and down regulated) in the aging liver. The aging liver also showed greater mitochondrial dysfunction, oxidative stress and cell death/senescence, impairment of lipid metabolism, which were accompanied by elevated plasma/serum cholesterol levels. There was also enhanced inflammation in the liver in aging rats, and numerous metabolic pathways were downregulated, particularly in tryptophan metabolism and valine, leucine, and isoleucine degradation, among others. The scientists validated their model using public rat and human liver data.

Next, using NIH supercomputing resources, the researchers conducted a gene co-expression network analysis, examining over 2300 genes with 200,000+ links. In the analysis, cluster 14 was the most prominent and thus hypothesized to be most important. The genes in cluster 14 are most involved in cholesterol biosynthesis and metabolism, lipid biosynthesis and regulation of lipid metabolism, and sterol biosynthesis. Focusing on the 43 genes in cluster 14, the scientists found that 29 were upregulated in aging. Of these, PCSK9 was one of the three central (i.e., most connected) genes in the cluster. This finding was then validated in both rat and human validation cohorts. Next, using single cell transcriptomics, the researchers confirmed that PCSK9 is primary expressed in all hepatocytes, particularly in more metabolically active ones, and that PCSK9 levels are elevated in aging livers.

The NIAAA investigators then selected healthy subjects over 65 years of age and divided them into two groups based on their level of PCSK9 expression. Those in the higher-expressing group showed greater signs of age-related pathology, including lipid metabolism alteration, mitochondrial dysfunction, inflammation, and metabolic impairment (Arif et al. Geroscience in press: doi: 10.1007/s11357-023-00928-w). While this was an exciting finding, the researchers still needed to prove that PCSK9 played an important role in the development of aging-associated liver disease. To do so, they conducted an animal study comparing young and old Fisher rats that develop age-associated cardiovascular dysfunction similarly to humans. They treated the rats with a monoclonal antibody against PCSK9 (alirocumab) for six weeks and collected morphometric data and histopathology, performed cardiac function analyses, and collected tissue for proteomics and transcriptomics analysis. In parallel, they began studying human subjects, comparing healthy individuals younger than 35 with those 65 and older, measuring their serum/plasma PSCK9 levels and cardiovascular function. They found in both the rat and human studies that the PSCK9 levels increased with aging and correlated positively with cardiovascular dysfunction, both systolic and diastolic. In the rat study, PCSK9 inhibition improved serum cholesterol and serum oxidized LDL in aging animals. With less PCSK9, there was an increase in LDL receptors in the liver which decreased serum cholesterol levels. Surprisingly, PCSK9 inhibition not only met the primary endpoint, but it also attenuated liver inflammation, metabolic dysregulation, and oxidative stress. In terms of cross-organ communication, they also found that the liver fat content correlated with the left ventricle mass and the liver inflammatory score, i.e., liver triglyceride content and the non-fatty liver disease activity score (NAS) positively correlated with aging-associated cardiac dysfunction (both systolic and diastolic). This suggests that PCSK9 plays an important role in the liver aging process that contributes to cardiovascular dysfunction in aging.

Next, the research team investigated the hallmarks of aging in the aging hearts, specifically mitochondrial dysfunction, oxidative stress, and inflammation. There are many genes associated with mitochondria involved in the assembly of mitochondrial complexes. The dominant ones related to aging involve oxidative phosphorylation and related to diabetic cardiomyopathy. This aging-associated mitochondrial dysfunction was improved by PCSK9 inhibition. Overall, aging-associated myocardial oxidative stress, inflammation, and cell death were all improved by PCSK9 inhibition. Furthermore, aging-associated myocardial remodeling/fibrosis, as well as cardiac dysfunction, was improved by PCSK9 inhibition.

In conclusion, Dr. Pacher emphasized the following points.1) Age-associated development of non-alcoholic fatty liver disease (NAFLD) is associated with elevated liver/blood PCSK9 level and correlates with cardiovascular dysfunction. 2) Increased age is one of the strongest predictors of blood PCSK9 levels, while blood PCSK9 level positively correlates with CV dysfunction and is an independent predictor of left ventricular (LV) diastolic dysfunction both in humans and experimental animals.3) PCSK9 inhibition attenuates the progression of CV disease and NAFLD progression in aging animals.4) PCSK9 may emerge as a novel target and potential biomarker for age-related cardiovascular disease. 5) The primary source of increased age-associated blood PCSK9 level is the liver, not the heart (consistent with recent FDA approval of Leqvio® (inclisiran), a drug which selectively inhibits the PCSK9 synthesis in the liver). Matyas et al. JACC: Basic to Translational Science Sept 13, 2023, in press https://doi.org/10.1016/j.jacbts.2023.06.005)

Effect of Alcohol Dose on Cardiovascular Aging. Alcohol consumption is seen as having an impact on cardiovascular pathology. Alcohol may have direct toxic effects including atrial fibrillation, hypertension, malnutrition, chronic pancreatitis, and liver cirrhosis, leading to alcoholic cardiomyopathy, including sudden cardiac death. Potential mediators and/or confounders include genetics, diet, social determinants of health, smoking, and polysubstance use disorder. The proposed mechanisms of alcoholic cardiomyopathy (nonischemic dilated CMP) include mitochondrial dysfunction and inhibition of oxidative phosphorylation; free radical damage; inhibition of calcium-myofilament interaction; disruption of the cell membrane structure; inhibition of protein synthesis; activation of the renin-angiotensin system; synergy with concomitant conditions; and Interorgan crosstalk between the liver and kidney).

Investigators in Dr. Pacher’s laboratory set out to study the effect of chronic ethanol exposure on rats. Their study compared young (3-4 months old) and old (24-26 months old) F344/Brown Norway rats who were put on a 0.5 percent or 5 percent Lieber-DeCarli alcohol liquid diet or isocaloric control liquid diet for six months. After six months, the rats were subjected to hemodynamic measurements and sacrificed, and their hearts were studied (biochemistry, etc.). Measurements included mitochondrial complex activities since mitochondrial dysfunction is a known hallmark of aging. They found complex 2 and 4 activities were impaired only in the aging animals and were also impaired by alcohol in aging. Thus, chronic alcohol feeding induced myocardial mitochondrial dysfunction. Chronic alcohol feeding also enhanced cardiac oxidative and nitrative stress. Cardiomyopathy is characterized by the expression of angiotensin II receptors type 2 (AGTR2) that was increased with alcohol, especially in the aging animals. The same pattern was seen in Inducible nitric oxide synthase (iNOS) levels, again indicating enhanced oxidative/nitrative stress. Other key findings were that chronic alcohol feeding promoted myocardial DNA injury and cell death; enhanced myocardial inflammation; promoted myocardial fibrosis (only in aging rats); promoted serum lipid abnormalities and endothelial dysfunction/reactive oxygen species (ROS) production as well as increased total peripheral resistance (TPR); promoted systolic dysfunction and diastolic dysfunction (the latter only in aging); and impaired ventricular-arterial coupling (VAC), a predictor of cardiovascular mortality.

In conclusion, Dr. Pacher summarized the following key findings. 1) Chronic ethanol consumption (high dose, 5 percent) in young rats triggers myocardial oxidative/nitrative stress with predominant systolic dysfunction. 2) Chronic ethanol consumption (high dose) induces ventricular-arterial uncoupling in both young and aging animals which may increase risk of cardiovascular death.3) Chronic ethanol consumption (high dose) markedly amplifies the aging-associated pathological processes (oxidative/nitrative stress, cell death, fibrosis, inflammation, and vascular and cardiac dysfunction (both systolic and diastolic) promoting accelerated cardiovascular aging. 4) Moderate (low dose, 0.5 percent) alcohol consumption, either in young or aging animals, is not associated with notable cardiovascular effects.5) Consumption of alcohol should be avoided in the aging population, particularly in subjects with cardiovascular disease and diabetes.

Discussion: Dr. Koob emphasized the findings that alcohol produces pathology. He asked Dr. Pacher if he had looked at transgenic animals that are models for Alzheimer’s Disease to see if there is any brain-cardiovascular interaction influenced by aging. Dr. Pacher responded that this is a very good idea because the brain is largely composed of cholesterol and water. There are more and more studies indicating that cholesterol metabolism in the brain could be responsible for some neurodegenerative diseases. Dr. Koob noted imaging research using PET scans by Dr. Nora Volkow, NIDA, that indicates that cholesterol in the brain may be interfering with measures of inflammation. Dr. Pacher replied that the role of cholesterol is very important; the human brain only started to develop when people began to eat meat. Dr. Lang inquired about the length of time the PCSK9 inhibitor treatment was implemented; Dr. Pacher explained that it was administered for almost two months Dr. Lang observed that it is surprising that cardiovascular dysfunction which takes years to develop could be reversed in a such a relatively short time. Dr. Pacher said that the findings did surprise him, and he was skeptical; however, the results were very clear-cut (notable the 6 weeks treatment in Fisher rats is close to 5% of their expected lifespan, which would correspond to years of treatment in humans). There are now many clinical studies on monoclonal antibodies against PCSK9 coming out, liver specific PCSK9 inhibition received FDA approval, and there is an oral PSCK9 inhibitor in the clinical development too. The beneficial effects of these inhibitors go beyond reducing serum/plasma cholesterol levels. For example, a recent study demonstrated that COVID patients administered PCSK9 inhibitor had improved outcomes. Scientists still don’t understand what PCSK9 by itself is doing, which may include impacting various processes in different cell types, but the good news is that there are clinically efficient ways to deploy PCSK9 inhibitors. Dr. Goldman commented that PCSK9 is a hot topic in science. He asked if the spatial transcriptomic analysis indicated if gene network 14 activity is happening in specific cells in the heart. Dr. Pacher answered that that his team used various methods and examined transcriptomic data from various areas, but there is practically no PCSK9 in the heart.

DEIA at NIAAA: September Council Briefing

Dr. Koob introduced Dawn M. Wayman, Scientific Diversity Officer in the Office of the Director, NIAAA. Ms. Wayman noted that she is currently in her 11^th week at NIAAA so that her presentation serves as an introduction to her, and her initial 6-month plans for implementation of DEIA at NIAAA.

Background. Ms. Wayman shared her personal history with academic training in infectious diseases at John Hopkins University and experience as an epidemiologist at a local health department prior to joining NIH as an intramural research coordinator focusing on clinical decision making related to race and extramural program analyst. Subsequently, she joined the Office of the Director working in human resources related to diversity, equity, and inclusion. Ms. Wayman joined NIAAA because senior leadership supports the work. She cautioned that, as a small IC, NIAAA’s quantifiable indicators may not reflect immediate significant progress, but noted that the Institute is small enough that DEIA efforts can make a difference.

What is DEIA? NIH’s work is guided by President Joseph Biden’s Executive Order on Diversity, Equity, Inclusion, and Accessibility in the Federal Workforce (June 25, 2021) that defined DEIA: 1) Diversity: The practice of including the many communities, identities, races, ethnicities, backgrounds, abilities, cultures, and beliefs of the American people, including underserved communities; 2) Equity: The consistent and systematic fair, just, and impartial treatment of all individuals, including individuals who belong to underserved communities that have been denied such treatment; 3) Inclusion: The recognition, appreciation, and use of the talents and skills of employees of all backgrounds. 4) Accessibility: The design, construction, development, and maintenance of facilities, information and communication technology, programs, and services so that all people, including people with disabilities, can fully and independently use them.

NIAAA’s Six-Month DEIA Plan (August 2023-February 2024): NIAAA’s initial six-month plan addresses the internal, external, and future workforces, as well as review and enhancement of NIAAA’s Racial and Ethnic Equity Plan (REEP) to improve diversity in its internal workforce and Management Directive (MD)-715 that supports equal employment opportunities. Developing the external workforce will include intentional connections with academic institutions, a grant application workshop series, and a webinar series. To address the development of the future workforce, plans include building relationships with colleges and universities, campus tours and laboratory visits, and a webinar series.

Discussion: Dr. Koob emphasized the importance of grant application training, noting that young minority applicants receive a score that veteran researchers would consider a “come back in” score and instead simply give up instead of revising their applications. Dr. Jones-Webb cited the importance of connections in building the future workforce. She recommended considering the T32 training programs for intentional connections. Dr. O’Dell invited Ms. Wayman to visit her institution, The University of Texas at El Paso, where the student body is 90 percent Hispanic. She also asked about the status of the NIAAA diversity work group that was previously active. Dr. Koob responded that there are plans underway to restart the work group.

Concept Clearance. Data Science Tools for Alcohol Research

Dr. Koob introduced Dr. Elizabeth Powell, Division of Neuroscience and Behavior, who presented a concept clearance on data science tools for alcohol research that was initially presented to Council in June 2018 and now needs to be reissued. The updated concept reflects NIH policy on data management that considers environmental factors such as ethics and policy in the data science workflow. The new NIH Data Management and Sharing Policy addresses the stages in the data life cycle (acquisition, cleaning, use/reuse, publication, and preservation/destruction) and integrates experimental design with data life cycle in the data management and sharing plan.

Since the concept clearance presentation in June 2018, data science activities at NIAAA have included the following. SBIR contract awards for new machine learning algorithms using data from previously funded NIAAA projects, one for identification of new genes in bioinformatics data and one for prediction of drinking patterns in human behavioral data are currently in Phase II. The algorithms and tools they developed were made publicly available, through open-source code in Jupyter notebooks and in scientific publications. Using the search strategy of the keyword ‘machine learning’ as a surrogate for data science, a portfolio analysis shows a 60 percent increase in applications and funded projects, with an overall 90 percent increase in funding. The NIAAA Data Archive, a repository for human data from NIAAA funded projects, was established and will soon be available to the alcohol research community. Increased data governance at NIAAA and NIH via an NIAAA Data Access Committee and the new NIH Data Management and Sharing policy have been implemented; new FOAs will be published 5) A Data Science Working for Group for NIAAA staff was established. A subcommittee of the Data Science Working Group is implementing the Final Policy on Data Management and Sharing. In addition, NIAAA is participating in NIH-wide and Institute/Center (IC)-specific workforce development initiatives for extramural staff.

Nonetheless, data science gaps persist at NIAAA, notably as follows.

1) How much data do we have? Access?

2) How do we better harmonize data? Common data elements?

3) What are the data sharing capabilities at NIAAA? How to use NIH Enterprise GitHub?

4) Are we collaborating across NIH with data science projects? Across HHS? Other federal agencies, including NSF?

5) What is NIAAA’s representation in the data science community and workforce development?

6) What are the NIAAA efforts in Ethics and policy?

Future data science directions at NIAAA  should include.

 1) To generate intellectual property, analytical tools and methods for alcohol research that interface within modern data ecosystems for use by the entire scientific community.

2) To promote harmonization of data sets within specific disciplines of alcohol research to improve scientific reproducibility and increase sharing of data across multiple scientific teams.

3) To transform fragmented sets of individual data components into a coordinated ecosystem.

4) To explore ethics and privacy considerations for data access and use.

5) To enable multiscale analysis of clinical and basic science datasets, employ modern data science techniques of artificial intelligence, machine learning and deep learning.

6) To promote interdisciplinary collaborations and training between alcohol researchers and data scientists

) To adapt NIH data science tools and tactics for use in alcohol research.

 Action. Endorsed by Dr. O’Dell.

Concept Clearance. Sleep Dysfunction in Alcohol-induced Hyperkatifeia

Dr. Koob introduced Dr. Shailesh Kumar, Division of Neuroscience and Behavior, who presented a concept clearance on sleep dysfunction as a core feature and intervention target in alcohol-induced hyperkatifeia.

Background. Alcohol-induced withdrawal involves a range of physiological and psychological symptoms known as “hyperkatifeia.” The heightened emotional distress sensitivity experienced during alcohol withdrawal in hyperkatifeia amplifies relapse risk and sustains alcohol misuse in recovery. Sleep disturbances during alcohol withdrawal are part of these symptoms and contribute to discomfort and dissatisfaction. Sleep disruption plays a pivotal role in alcohol withdrawal-induced hyperkatifeia, disrupting both physiological and psychological processes, and thereby amplifying allostatic load, i.e., the cost the body may have to pay to adapt to an adverse psychological or physical situation, thus overburdening the operation of the regulatory system.

Purpose. The purposes of the proposed concept are to examine sleep disturbances, hyperkatifeia, and AUD interactions to develop interventions targeting sleep dysfunction and improving treatment outcomes. An additional purpose is to explore the influence of sleep disturbances on hyperkatifeia during alcohol withdrawal and gain a comprehensive understanding of hyperkatifeia’s features and its connection with sleep disruptions. A third purpose is to develop targeted interventions to alleviate symptoms, enhance emotional regulation, and improve well-being for individuals with hyperkatifeia.

Research Goals. Goals for the research include 1) Characterize the specific disruptions in sleep stages experienced by individuals with alcohol withdrawal-induced hyperkatifeia and examine their association with hyperkatifeia severity; 2) Investigate the impact of altered sleep architecture on emotional dysregulation, cognitive function, and stress reactivity in individuals with AUD and hyperkatifeia; 3) Identify the neural circuits, neuroendocrine pathways, and brain regions involved in sleep disturbances, stress circuitry dysregulation, and hyperkatifeia; and 4) Develop and refine targeted interventions that address specific sleep stage disruptions, including pharmacological approaches and behavioral interventions.

Research Plan. The following methodologies are proposed as follows.

1) Cross-sectional and longitudinal studies are encouraged to assess sleep disturbances and hyperkatifeia symptoms

2) Objective measures like polysomnography (PSG), actigraphy, and electroencephalography (EEG), coupled with subjective assessments are encouraged.

3) Neuroimaging studies to investigate the neurobiological correlates of sleep dysfunction and hyperkatifeia are encouraged.

4) Molecular approaches to study the underlying neurobiology of sleep disturbances and hyperkatifeia by exploring neurochemical signaling pathways, genetic influences, and circuit-level interactions; are encouraged

5) Long-term follow-up assessments are encouraged to examine the sustained effects of interventions on sleep outcomes, hyperkatifeia symptoms, and alcohol relapse rates in individuals with AUD.

Justification. The proposed concept is justified because it addresses a knowledge gap by exploring sleep dysfunction's impact on hyperkatifeia in AUD withdrawal. The proposed concept also represents an uncharted and unfunded area of research, highlighting an unexplored area and allows for targeted interventions, examining sleep stages, hyperkatifeia, and allostatic load for evidence-based solutions. In addition, the concept enhances well-being by aiming to improve overall health in alcohol-induced hyperkatifeia cases;  and advances recovery, which is vital for improved stress regulation and emotional well-being during alcohol withdrawal-induced hyperkatifeia. Finally, the concept provides neurobiological Insights by uncovering mechanisms and targets for symptom relief and treatment enhancement.

Discussion. Dr. Lang recommended that the concept’s emphasis on human clinical studies be specified so that animal researchers do not waste time considering it. Dr. Koob observed that the proposed concept addresses priorities within the Division of Treatment Recovery (DTR) which has expertise in human studies, as well as within the Division of Neuroscience and Behavior (DNB) and should not be siloed within DNB. Dr. Litten, DTR Director, commented that his division provided comments on a workshop agenda related to the topic and will continue interacting with DNB on the topic. He noted that one issue is the heterogeneity of the population. Dr. O’Dell emphasized that behavioral interventions as well as pharmacological ones be addressed.

Action. Endorsed by Dr. Lang, Dr. Lewis, Dr. Kareken, and Ms. Davidson.

Concept Clearance: Comprehensive Alcohol-HIV/AIDS Research Center

Dr. Koob introduced Dr. Kendall Bryant, Director of Alcohol and HIV Research, Office of the NIAAA Director, who presented a concept clearance for a Comprehensive Alcohol-HIV/AIDS Research Center (P60 Clinical Trial Optional) (RFA – AA-23-004). This is a reissue of RFA-AA-19-003. The Center, in existence for 30 years, is now located at Louisiana State University.

Purpose. This Notice of Funding Opportunity (NOFO) (RFA – AA-23-004) uses the NIH Comprehensive Research Center (P60) mechanism to support research center grants to conduct a range of basic and behavioral cross-cutting, intervention, and translational research in alcohol and HIV/AIDS. NIAAA supports a broad-based Alcohol Research Centers program to foster and conduct interdisciplinary, collaborative research. The Office of AIDS Research also supports multiple Centers for HIV and AIDS Research (CFAR) to advance the prevention and treatment of HIV/AIDS under multiple NIH and National HIV/AIDS Strategic Plans.

Center Objectives. The Comprehensive Alcohol-HIV/AIDS Research Center grant provides a mechanism for fostering interdisciplinary cooperation within a group of established investigators conducting exceptional Alcohol-HIV/AIDS research The Center must 1) provide support for shared resources; 2) support a full range of basic, developmental, clinical, and/or applied research components; 3) allow for growth and development through pilot projects; 4) provide state-of-the-art leadership in the Alcohol-HIV/AIDS field; and 5) translate and disseminate research findings.

Primary Research Scope: Cross-cutting Research. Given the significant overlap between alcohol use-associated susceptibility of infections and chronic conditions in multiple organ/systems and HIV-related comorbid conditions, research topics for the center core components should advance cross-cutting research identified in the National HIV/AIDS Strategy. An example of a cross-cutting area of research is basic and translational research measuring the possible role of alcohol in accelerated aging among people living with HIV, including the following.

1. The impact of alcohol use on HIV-related chronic disease/conditions and the underlying organ injury (Epidemiological and Natural History) will be explored.
2. The impact of alcohol use on organ/system that could adversely affect HIV-related comorbidities including immune and gastrointestinal tract barrier function, dysbiosis and immune activation and chronic inflammation (Etiology and Pathogenesis) will be explored.
3. The impact of alcohol use on susceptibility to HIV infection, including relevant defects in mucosal barrier and immune compartments and/or HIV latency/persistence in viral reservoirs (Prevention and Cure) will be explored.

Advancing Integrative Analytic Strategies. The Center will also advance integrative analytic strategies by facilitating the following,

1. Data will be analyzed from multiple longitudinal studies and randomized clinical trials in well-defined patient cohorts (Persons with HIV [PWH] and AUD) to obtain fundamental knowledge about pathogenic changes.
2. Datasets from clinical cohorts (PWH and AUD) will allow development of systems/synergistic biology approaches supported by state-of-the art machine learning, artificial intelligence (AI) bioinformatic and biostatistical analyses to integrate metagenomic, genomic, and metabolomic metadata.

Action. Endorsed by Dr. Larimer, Dr. Jones-Webb, and Ms. Kane-Davidson.

Council Discussion/Public Comments

Dr. Robert Huebner, retiring Chair of the Friends of NIAAA, introduced new Chair Dr. William Wieczorek, Chief Executive Officer and President of the Pacific Institute for Research and Evaluation (PIRE). In his remarks, Dr. Huebner emphasized the Friends of NIAAAs’ goal of promoting the excellent research supported by NIAAA to both members of Congress and the public. Dr. Koob asked for a round of applause recognizing Dr. Huebner’s four years of outstanding support. Dr. Wieczorek introduced himself, acknowledged Dr. Huebner’s leadership to date, and pledged continuing support to NIAAA.

Consideration of the NCAA and CRAN May Meeting Minutes and Future Meeting Dates

The May 9, 2023, Council meeting minutes and the May 10, 2023, Collaborative Research on Addiction at NIH (CRAN) meeting minutes were approved unanimously. Dr. Srinivas announced upcoming Council meeting dates. In 2024, Council will meet on February 8, May 7, and September 12; the 2024 CRAN meeting is scheduled for May 8. In 2025, Council will meet on February 6, May 6, and September 11; the 2025 CRAN meeting is scheduled for May 7.

Society for Sober Liver Survival

Dr. Koob reviewed the purpose of the new Society for Sober Liver Survival founded by Jenn Jones: Sober Living’s purpose is to provide a safe space to engage and empower people to activate their agency by developing their unique alcohol recovery pathway through peer group and mentor support, education, and external resources. Additionally, through the support of Sober Living’s Whole Health Advisory Council, the organization will actively ensure medical providers, health organizations, and communities have the latest AUD and alcoholic liver disease (ALD) information on early detection, treatment, and patient and care partner support options.

Dr. Koob shared a video developed by Ms. Jones. In the video, she noted that this summer the American Association for the Study of the Liver (AASLD) and the European Association for the Study of the Liver (EASL) announced a change in nomenclature for fatty liver disease, now known as steatotic liver disease (SLD). Non-alcoholic fatty liver disease will now be identified as metabolic dysfunction associated steatotic liver disease (MASLD). A new and much-needed category, MASLD and increased alcoholic intake, was denoted as MetALD. Ms. Jones also noted that serving those with ALD is a missing programmatic piece in the work of the major fatty liver disease organizations. The Society for Sober Liver Survival will work with the Fatty Liver Foundation to address this gap. Ms. Jones advocated for the implementation of an integrative model to treat ALD and AUD simultaneously, as well as for the reduction of stigma associated with ALD. The Society seeks to partner with NIAAA through grants to establish Sober Living programs and through inclusion in clinical trials.

Dr. Koob noted that the integration of AUD and ALD treatment is an ongoing area of investigation and implementation science at NIAAA.

Council Discussion

Dr. Koob asked if there were any questions from those attending the meeting online. Dr. Gonzales, Dr. Nagy, and Dr. Lewis commented on the excellence of the meeting. Dr. Carpenter lauded Ms. Wayman’s DEIA presentation and noted that he will be joining the Sex and Gender Minority Research Office (SGMRO) at Council of Councils. Dr. Chambers concurred on the excellence of the meeting, noting her particular interest in PCSK9 and the role of cholesterol, citing its increasing prominence in pregnancy-related research. Dr. Koob observed that PCSK9 is a burgeoning area of interest; NIAAA and NIDA have several researchers who have been publishing in this area. Dr. Larimer commented that it was great to see the uptake of CollegeAIM; Dr. Koob noted that women are surpassing men in binge drinking in college and that NIAAA would like to find a way to reach the non-college population of young people. Dr. Hingson agreed. Dr. O’Dell commented favorably on the Society for Sober Liver Survival video, wondering how it can be connected to other organizations. Dr. Koob responded that Friends of NIAAA may be able to help make such connections. Dr. Kareken emphasized the need to make providers aware of the new Society and its message. Dr. Witkiewitz commented on the importance of combatting stigma about ALD. Dr. Koob noted that NIAAA needs to update the nomenclature on old slides and manuscripts to make sure it is correct and current. Ms. Kane-Davidson commented on the importance of translating the science and disseminating resources so that patients can be adequately supported by their providers. Dr. Koob reminded Council to draw NIAAA’s attention to grant applications that deserve attention, as well as those that should be considered low priority.

Adjournment

Dr. Koob adjourned the meeting at 4:20 p.m.

CERTIFICATION

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