Investigation of Cocaine Addiction Using mGluR5 PET and fMRI

Study Overview
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Brief Summary
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The proposed research program will investigate the changes in brain chemistry and circuitry that 're-wire' the brain during chronic cocaine use, promote relapse, and complicate treatment efforts. Currently-using and non-treatment-seeking individuals with a cocaine use disorder will undergo a cocaine self-administration paradigm 2-5 days prior to completing positron emission tomography (PET) and functional magnetic resonance imaging (fMRI).

Detailed Description
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Cocaine use disorder (CUD) remains a significant public health concern that is resistant to current treatments. Challenges to treating CUD include an imbalance in neurobiological systems that 're-wire' the brain such that appetitive and habitual processes influence decision-making and behavior. This research project aims to provide insight into this reorganized circuitry in CUD by investigating neurofunctional systems related to glutamatergic plasticity and functional brain networks during initial (2-5 days) abstinence. To target this potentially critical period of recovery, currently-using and non-treatment-seeking individuals with CUD will undergo a cocaine self-administration paradigm 2-5 days prior to completing [18F]FPEB positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Healthy comparison (HC) subjects that have participated in [18F]FPEB PET as part of other Yale approved protocols will be recruited to participate in the fMRI portion of this study. Aim 1: To determine the availability of mGluR5 using [18F]FPEB PET during initial abstinence in individuals with CUD. The investigators hypothesize individuals with CUD, relative to HC, will exhibit concurrently and regionally specific increases (e.g., in the striatum) and decreases (e.g., in the prefrontal cortex) in mGluR5 availability. Aim 2: To determine patterns of resting-state, response-inhibition, an automaticity related connectivity within and between large-scale functional networks using fMRI during initial abstinence in individuals with CUD. The investigators hypothesize network-based analyses of fMRI will reveal lower frontoparietal and greater limbic network modulation in CUD as compared to HC. Aim 3: To explore the relationships between mGluR5 availability and functional network activity during initial abstinence in individuals with CUD. The investigators will perform multi-modal analysis of PET and fMRI data to examine links between molecular and functional systems in CUD using emerging 'fusion' approaches. While exploratory in nature, the investigators expect to find links between alterations in mGluR5 systems and functional reorganization in CUD (e.g., greater dorsostriatal mGluR5 may be linked to blunted frontoparietal inhibition). Aim 4: To explore the relationships between mGluR5 availability, functional network activity (and their linkages) with cocaine self-administration, disease severity and chronicity, and psychometric assessments of impulsivity and compulsivity. While exploratory in nature, the investigators expect more substantial neurofunctional alterations during initial abstinence will be associated with greater cocaine self-administration, disease severity, impulsivity and compulsivity in individuals with CUD.

Official Title
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Investigation of Cocaine Addiction Using mGluR5 PET and fMRI

Conditions
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Cocaine Dependence

Intervention / Treatment
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* Behavioral: Psychiatric and Cognitive Testing
* Drug: Cocaine Self-adminstration
* Radiation: Positron Emission Tomography
* Other: Magnetic Resonance Imaging


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All participants: Age 21 - 60 years Provide voluntary, written, informed consent Physically healthy by medical history, physical, neurological, ECG, and laboratory examinations For females: non-lactating, no longer of child-bearing potential or agreeing to practice effective contraception during the study (e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device [IUD] or intrauterine system [IUS]; barrier methods: condom or occlusive cap [diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository; male partner sterilization; true abstinence when this is in line with the preferred and usual lifestyle of the subject), and a negative serum pregnancy test Participants with a cocaine use disorder: DSM-5 criteria for moderate or severe cocaine-use disorder Recent street cocaine use in excess of quantities used in the current study Intravenous and/or smoked (crack/freebase) cocaine use Positive urine toxicology screen for cocaine Healthy comparison participants: Successful completion of an [18F]FPEB scan as part of another Yale approved protocol as a healthy control/comparison subject Exclusion Criteria: All participants: Any condition that, in the opinion of investigators, would prevent compliance with the study protocol A history of significant medical or neurological illness (e.g., coronary artery disease, significant anemia, seizures) Current use of psychotropic and/or potentially psychoactive medications Physical or laboratory evidence of pregnancy Meet any additional PET/MR imaging-related exclusion criteria, including: Presence of MRI incompatible implants and other contraindications for MRI (e.g., pacemaker, artificial joints, non-removable body piercings, etc.) Participation in other research studies involving ionizing radiation within one year of the PET scans that would cause the participant to exceed the yearly dose limits History of a bleeding disorder or are currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto). Claustrophobia Severe motor problems that prevent the subject from lying still for PET/MR imaging Complaints of chronic pain (e.g., as the result of rheumatoid arthritis) Current, past or anticipated exposure to radiation in the work place Participants with a cocaine use disorder: Other drug use disorder (except for tobacco-use disorder) Less than 1 year of cocaine use disorder A DSM-5 major psychiatric diagnosis (schizophrenia, bipolar disorder, etc.) unrelated to cocaine Healthy comparison participants: Any DSM-5 major psychiatric diagnosis (schizophrenia, bipolar disorder, etc.), except tobacco-use disorder Positive drug screen

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Psychiatric and Cognitive Testing<br>All participants will complete psychiatric assessment and cognitive testing. | Behavioral: Psychiatric and Cognitive Testing<br>* Interviews, questionnaires, and computer testing.<br>|
| Active Comparator: Cocaine Self-adminstration<br>This arm plans to assess the subjective (e.g., euphoric) and behavioral effects (e.g., self-administration) of cocaine in experienced, non-treatment seeking users of the drug in a human laboratory study of self-regulated cocaine administration. | Drug: Cocaine Self-adminstration<br>* The intervention will include a training and safety session that consists of physician/nurse-administered cocaine followed by a self-regulated cocaine administration period under carefully controlled and closely monitored conditions.<br>* Other names: cocaine hydrochloride;|
| Active Comparator: Positron Emission Tomography<br>All participants will complete a PET scan to assess mGluR5 receptors using [18-F]FPEB | Radiation: Positron Emission Tomography<br>* PET scans will be performed on a High Resolution Research Tomograph (HRRT), the highest resolution human brain scanner available. Antecubital venous catheters will be used for IV administration of the radiotracer and for venous blood sampling. A radial artery catheter may also be inserted by an experienced physician before the PET scan. At the beginning of each scan, the participants's head will be immobilized and a 6-minute transmission scan, using an orbiting 137Cs point-source, is obtained and used for attenuation correction. PET scans will be acquired using bolus or bolus plus constant infusion administration of [18F]FPEB.<br>* Other names: PET;|
| Active Comparator: Magnetic Resonance Imaging<br>All participants will complete one MRI scan to assess brain structure and function. | Other: Magnetic Resonance Imaging<br>* Structural and functional MRI data will be acquired using a Siemens Trio TIM 3.0T system at the Yale Magnetic Resonance Research Center. High-resolution structural MRI data will be acquired to facilitate analysis of PET data and may be used in additional analysis of tissue volume and brain structure. Resting-state and task-based functional MRI data will be acquired using state-of-the-art multiband echo-planar imaging (EPI) gradient-echo sequences. Diffusion-weighted MRI data will also be acquired using multiband imaging sequences to investigate anatomical connectivity.<br>* Other names: MRI, functional MRI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Receptor availability assessed as the volume of distribution (VT) of [18F]FPEB radiotracer, measured using positron emission tomography (PET). Higher [18F]FPEB VT values indicate a greater availability of mGluR5 receptors. | Following 2-5 days of cocaine abstinence | 
| Functional Brain Network Engagement Associated With Response Inhibition | Independent component analysis (ICA) of functional MRI data separates brain activity associated with distinct functional networks. Comparing the activity in these networks to the fMRI task events using a regression analysis produces a beta-weight where a larger beta indicates the network was more activated or 'engaged' in processing the task demands. In this study, participants completed a Go/NoGo task to assess brain processing associated with infrequent-stimulus response inhibition (i.e., correct NoGo's) compared to frequent-stimulus responses (i.e., correct Go's). | Following 2-5 days of cocaine abstinence. | 
| Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF) | Independent component analysis (ICA) of functional MRI data separates brain activity associated with distinct functional networks. The fractional amplitude of low-frequency fluctuations (fALFF) during resting-state reflects a measure of the general health status of a network, comprised of both the strength of network activity and within-network connectivity absent of any specific cognitive demands. | Following 2-5 days of cocaine abstinence. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cocaine Dependence, Cocaine Addiction