Marisa M. Silveri - US grants

DESCRIPTION (provided by applicant): The aim of our proposed study is to examine the effects of binge alcohol consumption on brain metabolites and cognitive function in 18-24 year olds using magnetic resonance spectroscopy (MRS) and neuropsychological assessment. The final stages of fine-tuning in frontal and association cortices that occur during this period of emerging adulthood permit notable improvements in frontally mediated decision-making and response inhibition abilities, while decreasing impulsive behavior. Previous work has identified that heavy alcohol consumption is associated with structural and functional brain abnormalities, and altered cerebral metabolites. These alterations, which are particularly prominent in the prefrontal cortex, likely contribute to alcohol-related executive function deficits, supporting a frontal dysfunction hypothesis in alcohol use disorders. This proposal will use specialized proton (1H) MRS techniques to quantify and compare proton metabolites in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) of 18-24 year old male and female binge (BD) and light alcohol drinkers (LD). A novel component of this proposal is the ability to reliably detect and quantify GABA and glutamate, central targets of alcohol action, in the prefrontal cortex using MEGAPRESS and 2D-JPRESS. N-acetyl-aspartate (NAA), choline, and myo-inositol (myo-I), reported to show alterations in heavy alcohol users, will also be examined in this proposal. Spectroscopic data will be examined relative to cognitive performance, with a focus on executive functioning, a frontally mediated area of cognition most widely reported to show deficits in alcohol use disorders. The results of this study will have significant relevance for public health concern, as identification of neurobiological correlates associated with binge alcohol consumption during emerging adulthood will help fill a gap in the existing literature on brain alcohol effects in a population that demonstrates not only the highest rate of binge drinking, but also the highest rate of alcohol abuse and dependence.

DESCRIPTION (provided by applicant): In vivo magnetic resonance spectroscopy (MRS) has been used to examine alterations in cellular health, integrity and metabolism across a variety of alcoholic populations, although almost no MRS studies have included sufficient numbers of women to examine sex differences in the impact of alcohol on cerebral metabolites. This novel proposal aims to compare GABA and glutamate metabolite levels in a region of the medial temporal lobe (MTL) that contains the hippocampus, and spatial and verbal memory function in 22-45 year old alcohol dependent (ALC) men and women examined in early abstinence (5-10 days), and healthy age- and sex-matched comparison subjects (NALC) reporting a minimal alcohol use history. To investigate the effects of menstrual cycle phase on brain metabolites, NALC women will be tested longitudinally, in both follicular and luteal phases of their menstrual cycle (confirmed by salivary hormone assays). Furthermore, a subset of NALC men will be scanned twice to assess MRS test-retest reliability. We will apply single voxel proton (1H) MRS at 4.0 Tesla to measure MTL metabolites using MEGAPRESS and 2D-JPRESS, sequences optimized for detection and quantification of GABA and glutamate, respectively, to minimize methodological challenges associated with peak overlap and susceptibility of the MTL to field inhomogeneities. Metabolite data will be examined relative to hippocampal-mediated memory function, an area of cognition that has not only demonstrated sex differences, but also is impaired in alcoholic populations. The results of this study will establish profiles of neurochemical correlates of memory function in healthy NALC adults, which may be menstrual cycle dependent (Specific Aims 1,2). Inclusion of ALC patients, especially those who are recently detoxified, will provide baseline data (Exploratory Aim) that will be used to design a future longitudinal study in alcoholics that examines MTL GABA and glutamate changes and associated improvements in cognitive function. Those findings could not only establish neurochemical correlates associated with successful recovery, but also identify potential markers of increased risk for relapse. PUBLIC HEALTH RELEVANCE: The overall aim of our proposed study is to compare GABA and glutamate metabolite levels in a region of the medial temporal lobe (MTL) that contains the hippocampus, and spatial and verbal memory function in 22-45 year old alcohol dependent (ALC) men and women examined in early abstinence, and healthy age- and sex-matched comparison subjects (NALC) by applying high field (4.0 Tesla) in vivo magnetic resonance spectroscopy (MRS) techniques in conjunction with neuropsychological assessment of verbal and spatial learning and memory. To investigate the effects of menstrual cycle phase on brain metabolites, NALC women will be tested longitudinally, in both follicular and luteal phases of their menstrual cycle (confirmed by salivary hormone assays). The results of this study will establish profiles of neurochemical correlates of memory function in healthy NALC adults, which may be menstrual cycle dependent, but also inclusion of ALC patients will provide baseline data that will be used to design a future longitudinal study in alcoholics that examines MTL GABA and glutamate changes and associated improvements in cognitive function, findings that could not only establish neurochemical correlates associated with successful recovery, but also identify potential markers of increased risk for relapse.

DESCRIPTION (provided by applicant): This revised R01 A1 proposal (AA022493), Consequences of Adolescent Alcohol Use on Brain Development, responds to the need to understand the impact of initiating alcohol consumption on adolescent brain maturation. We have teamed with the Center for Adolescent Substance Abuse Research (CeASAR) and Boston Children's Hospital to implement an innovative strategy that combines multiple neuroimaging and neuropsychological approaches to identify neurodevelopmental vulnerabilities associated with early and escalating alcohol use during adolescence. Adolescents will be recruited from general pediatrician offices and adolescent medicine clinics comprising the New England Partnership for Substance Abuse Research (NEPSAR), a practice-based research network of primary care offices. Adolescents will be enrolled into the study prior to the initiation of alcoho use or other drug use, and examined longitudinally, at baseline (13-14 yrs old) and again at two annual follow-up visits. To provide a comprehensive longitudinal profile of brain function, structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and task and resting state blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) will be paired with magnetic resonance spectroscopy (MRS) to measure GABA and glutamate levels in the anterior cingulate cortex (ACC) and medial temporal lobe (MTL, containing hippocampus). In addition, arterial spin labeling (ASL) will be used to measure quantitative perfusion, which will be used to calibrate the magnitude of BOLD fMRI signal changes during response inhibition and spatial memory fMRI tasks. Magnetic resonance measures will be integrated with measures from clinical assessments and an extensive neuropsychological battery, designed to detect and further characterize developmental changes and the influence of adolescent alcohol use. The incorporation of complementary multi-modal measures of brain function and neuroplasticity could offer valuable insight into the dynamic processes of brain maturation and help identify neural signatures associated with the onset and escalation of alcohol use, which will provide a foundation for informing prevention and intervention efforts aimed at reducing adolescent alcohol consumption.

PROJECT SUMMARY I am a clinical researcher and Director of the Neurodevelopmental Laboratory on Addictions and Mental Health at McLean Hospital. I also am an Associate Professor in Psychiatry at Harvard Medical School. I have been continuously funded as a principal investigator (PI) to conduct NIAAA-sponsored patient-oriented research (POR) since 2004 and have been a collaborator and consultant on several additional NIH-sponsored grants. My research has focused on understanding adolescent brain development, and risk for and underlying neurobiology of addiction and psychiatric disorders. I currently serve as PI on one NIAAA R01 grant and one Foundation grant, and am Co-Investigator on 3 R01s (NIMH, NCCAM, NIDA) and 1 R21 (NIAAA). I mentor a growing group of junior investigators, including 3 mentees on K01 grants. I work in a rich environment for clinical research, which is ideal for training junior faculty in POR. However, I receive no institutional support for mentoring and will be required to curtail mentoring efforts to assume significant non-research responsibilities beginning in 2017. The K24 award will protect time that would permit an increase in intensive mentorship to junior investigators and attract researchers to POR. My immediate and long-term career objectives are to characterize neurobiological markers in addiction and psychiatric disorders, which will inform the development of new and effective treatments for alcohol use disorders and for patients with dual diagnoses, and to train the next generation of investigators to develop the skills they require to effectively conduct POR. I also remain committed to disseminating research findings (through publications, scientific lectures and public outreach) that will help prevention efforts and that will inform treatment interventions, to aid in the reduction of suffering due to alcohol use and abuse. The specific aims to be accomplished during the period of the award are to 1) provide substantive mentoring of junior investigators in POR (35%), 2) continue and extend involvement in my POR (10%), and 3) develop specific new content expertise in the areas of adolescent comorbid psychopathology, clinical approaches in adolescent treatment settings, and epigenetics (5%). I am committed to training a remarkable group of mentees, who are the future of addiction and psychiatry POR. Through intensive mentoring I will, in turn, enhance my POR by increasing my clinical perspectives, and by incorporating treatment and epigenetic components into new POR initiatives.