Healthy
Conditions
Keywords
Reward Circuitry, Impulsivity, Family History of Alcoholism, NMDA/DA Interactions
Brief summary
This project compares Family History Positive (FHP) for alcoholism subjects to matched Family History Negative (FHN) subjects derived from the project Principal Investigator's National Institute on Alcohol Abuse and Alcoholism-funded longitudinal study of drinking behavior in a 2000 college freshman population (known as the Brain and Alcohol Research in College Students study (BARCS)). The age of these subjects is a valuable one at which to capture the transition from harmful use to abuse/dependence. This project explores the effects of memantine in a double-blind, randomized, counterbalanced manner on alcoholism risk-relevant tasks. More specifically, this project studies functional MRI tasks related to different aspects of reward and/or impulsivity-related behavior in different contexts, compares the underlying neural circuitry across tasks, and uses a pharmacologic probe of the glutamatergic system to examine NMDA/DA interactions. The combined measures provide the opportunity to advance our understanding of specific aspects of brain function related to familial alcoholism vulnerability in an already well-characterized population as some members evolve into alcohol abuse. In addition to conventional within-task analyses, functional network connectivity and allied approaches will be used to examine brain networks across tasks. The investigators will study adult male and female subjects in equal numbers who are either offspring of an alcoholic parent or are FHN matched controls. The investigators will recruit and assess a total of 84 (42 FHP and 42 matched FHN) subjects between the ages of 18-21 years on initial BARCS contact. The investigators will use 4 cognitive tasks during the functional MRI (fMRI) which include: 1) a Monetary Incentive Delay Task that distinguishes networks engaged in motivational (anticipation) and consummatory (outcome) components of reward processing; 2) a Go/No-Go Task that measures the ability to inhibit response to a pre-potent stimulus; 3) an Alcohol Cue Reactivity Task that examines Nucleus Accumbens response to alcohol-related versus matched soft drink stimuli; and 4) a Pavlovian-to-Instrumental Transfer (PIT) Task that dissects a component of the Monetary Incentive Delay (MID) Task, and provides an imaging assay of a transfer-like process that can be related to real-world drinking behavior, thus informing upon and extending the key findings from CTNA-2.
Interventions
DRUGMemantine
Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered.
DRUGPlacebo
Identically appearing sugar pill, given orally
Sponsors
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Intervention model description
All subjects received both the study drug and placebo. Family history was the main variable of interest, and randomization was stratified by this variable.
Eligibility
Sex/Gender
ALL
Age
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
* Biological father with a history of Alcoholism * A least 1 other first- or second-degree relative with a history of Alcoholism.
Exclusion criteria
* Cannot be an only child * A diagnosis of DSM-IV-TR Axis I psychotic disorders screened with the Mini International Neuropsychiatric Interview (MINI), done in the BARCS study (with the exception of Alcohol Abuse) * Report of psychotic disorder in a 1º relative * Prenatal exposure to alcohol (mother reported to drink 3 or more drinks on an occasion or more than 3 times per month during pregnancy * Not speaking English fluently or being a non-native English speaker, or being educated in a primary language other than English \>grade 1 * Mental retardation (Full Scale IQ\<70) * Traumatic brain injury with loss of consciousness \> 30 minutes or concussion in last 30 days * Presence or history of any medical/neurologic illness that may affect brain physiology (e.g., epilepsy, Multiple Sclerosis), including focal brain lesion seen on structural MRI (all structural scans are read by a licensed radiologist) * Current pregnancy (all females will be tested with urine screens on the day of MRI) * Any positive alcohol screen will result in exclusion * Inability to comprehend the consent form appropriately * Other specific fMRI exclusions include metal devices, clips or fragments in body (orbital x-ray performed if needed) * Female participants under 125 pounds will be excluded from participating due to the strength and side effects in this segment of the population.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Blood Oxygenation Level Dependent (BOLD) Activation in the Amygdala During Win Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | 4 hours post intervention on each study day, separated by 1 week to 1 month | All participants completed the fMRI Monetary Incentive Delay task on each study day. During the task, participants needed to select the correct response during win and lose conditions by pressing a button on a button box in the MRI. Participant's BOLD activation response (A measurement of oxygen level that is released to neurons since areas of the brain that are thought to be more active or involved in certain tasks require more oxygen to perform the tasks.) was measured while they performed the task in MRI scanner. |
| Change in Blood Oxygenation Level Dependent (BOLD) Activation in Anterior Cingulate Cortex During Loss Condition of Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | 4 hours post intervention on each study day, separated by 1 week to 1 month | All participants completed the fMRI Monetary Incentive Delay task on each study day. During the task, participants needed to select the correct response during win and lose conditions by pressing a button on a button box in the MRI. Participant's BOLD activation response (A measurement of oxygen level that is released to neurons since areas of the brain that are thought to be more active or involved in certain tasks require more oxygen to perform the tasks.) was measured while they performed the task in MRI scanner. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Impulsive Behavior as Measured on the Balloon Analog Risk Task (BART) Computerized Task Between Placebo and Study Medication | 3 hours post intervention on each study day, separated by 1 week to 1 month | All participants completed the BART task approximately 3 hours post drug administration on both study visits. Study days were approximately 1 week to 1 month a part. BART is a computer decision-making task that measures risk taking. Participants are presented with a series of balloons. The object is to earn as much money as possible by pumping the balloon without popping it. The point of explosion varies from trial to trial and costs participants the money they have earned in that trial. |
| Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | 3 hours post intervention on each study day, separated by 1 week to 1 month | All participants completed the EDT task approximately 3 hours post drug administration on both study visits. Study days were approximately 1 week to 1 month a part. EDT is a delay-discounting task that exposes participants to choice consequences during test administration. The EDT involves multiple blocks of choices, one for each delay. Choices are made between a standard amount that is delivered immediately and is certain and a probable amount that is delayed and uncertain. |
Countries
United States
Participant flow
Recruitment details
82 participants were screened for eligibility and then were consented at the Olin Research Center. However, after consent and prior to group randomization, 11 participants were excluded from the study due to follow-up eligibility paperwork (i.e. psychiatric interview, family history review, etc.) for a total of 71 randomized.
Participants by arm
| Arm | Count |
|---|---|
| Family History Positive (FHP) People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism. | 35 |
| Family History Negative (FHN) People who have no affected first- or second-degree relatives. | 36 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Family History Negative (FHN) | Family History Positive (FHP) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 36 Participants | 35 Participants | 71 Participants |
| Age, Continuous | 22.09 years | 24.70 years | 23.42 years |
| Region of Enrollment United States | 32 participants | 33 participants | 65 participants |
| Sex: Female, Male Female | 20 Participants | 28 Participants | 48 Participants |
| Sex: Female, Male Male | 12 Participants | 5 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 36 |
| other Total, other adverse events | 24 / 35 | 26 / 36 |
| serious Total, serious adverse events | 0 / 35 | 0 / 36 |
Outcome results
Primary
Change in Blood Oxygenation Level Dependent (BOLD) Activation in Anterior Cingulate Cortex During Loss Condition of Monetary Incentive Delay (MID) Task Between Placebo and Study Medication
All participants completed the fMRI Monetary Incentive Delay task on each study day. During the task, participants needed to select the correct response during win and lose conditions by pressing a button on a button box in the MRI. Participant's BOLD activation response (A measurement of oxygen level that is released to neurons since areas of the brain that are thought to be more active or involved in certain tasks require more oxygen to perform the tasks.) was measured while they performed the task in MRI scanner.
Time frame: 4 hours post intervention on each study day, separated by 1 week to 1 month
Population: The number of subjects analyzed differs from the overall number of subjects because analyses for this measure occurred about 48 months into recruitment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FHN - Memantine | Change in Blood Oxygenation Level Dependent (BOLD) Activation in Anterior Cingulate Cortex During Loss Condition of Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | -0.5980 voxel wise BOLD signal | Standard Deviation 2.9465 |
| FHN - Placebo | Change in Blood Oxygenation Level Dependent (BOLD) Activation in Anterior Cingulate Cortex During Loss Condition of Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | 1.2368 voxel wise BOLD signal | Standard Deviation 2.8177 |
| FHP - Memantine | Change in Blood Oxygenation Level Dependent (BOLD) Activation in Anterior Cingulate Cortex During Loss Condition of Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | .7498 voxel wise BOLD signal | Standard Deviation 3.1314 |
| FHP - Placebo | Change in Blood Oxygenation Level Dependent (BOLD) Activation in Anterior Cingulate Cortex During Loss Condition of Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | 3.4762 voxel wise BOLD signal | Standard Deviation 2.3169 |
p-value: 0.356t-test, 2 sided
p-value: 0.009t-test, 2 sided
Primary
Change in Blood Oxygenation Level Dependent (BOLD) Activation in the Amygdala During Win Monetary Incentive Delay (MID) Task Between Placebo and Study Medication
All participants completed the fMRI Monetary Incentive Delay task on each study day. During the task, participants needed to select the correct response during win and lose conditions by pressing a button on a button box in the MRI. Participant's BOLD activation response (A measurement of oxygen level that is released to neurons since areas of the brain that are thought to be more active or involved in certain tasks require more oxygen to perform the tasks.) was measured while they performed the task in MRI scanner.
Time frame: 4 hours post intervention on each study day, separated by 1 week to 1 month
Population: The number of subjects analyzed differs from the overall number of subjects because analyses for this measure occurred about 48 months into recruitment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FHN - Memantine | Change in Blood Oxygenation Level Dependent (BOLD) Activation in the Amygdala During Win Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | -0.6994 voxel wise BOLD signal | Standard Deviation 3.8049 |
| FHN - Placebo | Change in Blood Oxygenation Level Dependent (BOLD) Activation in the Amygdala During Win Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | 1.7115 voxel wise BOLD signal | Standard Deviation 3.9355 |
| FHP - Memantine | Change in Blood Oxygenation Level Dependent (BOLD) Activation in the Amygdala During Win Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | 0.3683 voxel wise BOLD signal | Standard Deviation 3.9475 |
| FHP - Placebo | Change in Blood Oxygenation Level Dependent (BOLD) Activation in the Amygdala During Win Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | 4.0298 voxel wise BOLD signal | Standard Deviation 5.6935 |
p-value: 0.032t-test, 2 sided
p-value: 0.125t-test, 2 sided
Secondary
Change in Impulsive Behavior as Measured on the Balloon Analog Risk Task (BART) Computerized Task Between Placebo and Study Medication
All participants completed the BART task approximately 3 hours post drug administration on both study visits. Study days were approximately 1 week to 1 month a part. BART is a computer decision-making task that measures risk taking. Participants are presented with a series of balloons. The object is to earn as much money as possible by pumping the balloon without popping it. The point of explosion varies from trial to trial and costs participants the money they have earned in that trial.
Time frame: 3 hours post intervention on each study day, separated by 1 week to 1 month
Population: Participants with a family history of alcoholism (family history positive) and without a history of alcoholism (family history negative) who completed BART task.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FHN - Memantine | Change in Impulsive Behavior as Measured on the Balloon Analog Risk Task (BART) Computerized Task Between Placebo and Study Medication | -0.12839 total pumps | Standard Deviation 1.001 |
| FHN - Placebo | Change in Impulsive Behavior as Measured on the Balloon Analog Risk Task (BART) Computerized Task Between Placebo and Study Medication | -0.04331 total pumps | Standard Deviation 1.033 |
| FHP - Memantine | Change in Impulsive Behavior as Measured on the Balloon Analog Risk Task (BART) Computerized Task Between Placebo and Study Medication | 0.2727 total pumps | Standard Deviation 0.91 |
| FHP - Placebo | Change in Impulsive Behavior as Measured on the Balloon Analog Risk Task (BART) Computerized Task Between Placebo and Study Medication | -0.0789 total pumps | Standard Deviation 1.022 |
Secondary
Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication
All participants completed the EDT task approximately 3 hours post drug administration on both study visits. Study days were approximately 1 week to 1 month a part. EDT is a delay-discounting task that exposes participants to choice consequences during test administration. The EDT involves multiple blocks of choices, one for each delay. Choices are made between a standard amount that is delivered immediately and is certain and a probable amount that is delayed and uncertain.
Time frame: 3 hours post intervention on each study day, separated by 1 week to 1 month
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FHN - Memantine | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times delayed pressed in Delay Condition | 13.58831 responses | Standard Deviation 6.838454 |
| FHN - Memantine | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times immediate pressed in Delay Condition | 10.85871 responses | Standard Deviation 6.97291 |
| FHN - Memantine | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times delayed pressed in Immediate Cond. | 11.44094 responses | Standard Deviation 3.890267 |
| FHN - Memantine | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times immediate pressed in Immediate Cond. | 18.57818 responses | Standard Deviation 12.316437 |
| FHN - Placebo | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times immediate pressed in Delay Condition | 11.84 responses | Standard Deviation 7.133 |
| FHN - Placebo | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times delayed pressed in Immediate Cond. | 11.94 responses | Standard Deviation 4.096 |
| FHN - Placebo | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times immediate pressed in Immediate Cond. | 17.74 responses | Standard Deviation 10.847 |
| FHN - Placebo | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times delayed pressed in Delay Condition | 14.13 responses | Standard Deviation 7.414 |
| FHP - Memantine | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times delayed pressed in Immediate Cond. | 11.77072 responses | Standard Deviation 4.882568 |
| FHP - Memantine | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times immediate pressed in Delay Condition | 10.34057 responses | Standard Deviation 5.995089 |
| FHP - Memantine | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times immediate pressed in Immediate Cond. | 14.82459 responses | Standard Deviation 9.884165 |
| FHP - Memantine | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times delayed pressed in Delay Condition | 15.41029 responses | Standard Deviation 8.256729 |
| FHP - Placebo | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times immediate pressed in Immediate Cond. | 14.39 responses | Standard Deviation 10.431 |
| FHP - Placebo | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times immediate pressed in Delay Condition | 10.22 responses | Standard Deviation 5.873 |
| FHP - Placebo | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times delayed pressed in Delay Condition | 13.64 responses | Standard Deviation 7.504 |
| FHP - Placebo | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | # of times delayed pressed in Immediate Cond. | 11.50 responses | Standard Deviation 4.159 |