Cocaine Dependence
Conditions
Keywords
Cocaine Dependence, Cocaine Addiction
Brief summary
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
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.
Interventions
DRUGCocaine Self-adminstration
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.
BEHAVIORALPsychiatric and Cognitive Testing
Interviews, questionnaires, and computer testing.
RADIATIONPositron Emission Tomography
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.
OTHERMagnetic Resonance Imaging
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.
Sponsors
National Institute on Drug Abuse (NIDA)
Yale University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Following 2-5 days of cocaine abstinence | 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. |
| Functional Brain Network Engagement Associated With Response Inhibition | Following 2-5 days of cocaine abstinence. | 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). |
| Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF) | Following 2-5 days of cocaine abstinence. | 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. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the New Haven, CT community, through current/past enrollment in similar research at the Cocaine Research Clinic and Yale PET Center as well as through community advertising (e.g., flyers). The first participant was enrolled on February 26, 2018 and the last participant was enrolled on June 30, 2022.
Pre-assignment details
Of 32 enrolled individuals, 17 met inclusion criteria for participants with cocaine-use disorder and 8 met criteria as healthy-comparison participants. Twenty historical healthy-comparison participants were not considered enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Adults With a Cocaine-use Disorder (CUD) Non-treatment-seeking, medically healthy adults meeting DSM-5 criteria for a moderate or severe cocaine-use disorder. | 17 |
| Healthy Comparison Adults, MRI (HC-MRI) Medically and psychologically healthy adults enrolled in this study to complete the magnetic resonance imaging (MRI) procedures as part of a comparison Group to examine MRI Outcome Measures. | 8 |
| Historical Healthy Comparison Adults, PET (HHC-PET) A historical sample of medically and psychologically healthy adults completing positron emission tomography (PET) procedures. This sample was compiled uniquely for this study from a larger set of historical data to form a comparison Group to examine PET Outcome Measures. | 20 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Technical failure | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Adults With a Cocaine-use Disorder (CUD) | Healthy Comparison Adults, MRI (HC-MRI) | Historical Healthy Comparison Adults, PET (HHC-PET) | Total |
|---|---|---|---|---|
| Age, Continuous | 49.3 years STANDARD_DEVIATION 6.5 | 36.6 years STANDARD_DEVIATION 4.8 | 49.0 years STANDARD_DEVIATION 7.4 | 46.5 years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 8 Participants | 19 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Positive toxicology screen indicating recent cocaine use | 17 Participants | 0 Participants | 0 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 1 Participants | 8 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 5 Participants | 12 Participants | 26 Participants |
| Region of Enrollment United States | 17 participants | 8 participants | 20 participants | 45 participants |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 12 Participants | 7 Participants | 13 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 8 |
| other Total, other adverse events | 0 / 17 | 0 / 8 |
| serious Total, serious adverse events | 0 / 17 | 0 / 8 |
Outcome results
Primary
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).
Time frame: Following 2-5 days of cocaine abstinence.
Population: All participants who performed a Go/NoGo task during MRI procedures. Functional MRI data of Go/NoGo performance was not collected on the Group historical healthy comparison adults who had completed PET procedures (HHC-PET).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Adults With a Cocaine-use Disorder (CUD) | Functional Brain Network Engagement Associated With Response Inhibition | Right frontoparietal network | 0.409 Unitless beta coefficient | Standard Error 0.103 |
| Adults With a Cocaine-use Disorder (CUD) | Functional Brain Network Engagement Associated With Response Inhibition | Left frontoparietal network | 0.349 Unitless beta coefficient | Standard Error 0.159 |
| Adults With a Cocaine-use Disorder (CUD) | Functional Brain Network Engagement Associated With Response Inhibition | Basal ganglia network | 0.175 Unitless beta coefficient | Standard Error 0.103 |
| Adults With a Cocaine-use Disorder (CUD) | Functional Brain Network Engagement Associated With Response Inhibition | Cingulo-insula network | 0.103 Unitless beta coefficient | Standard Error 0.121 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Functional Brain Network Engagement Associated With Response Inhibition | Cingulo-insula network | -0.271 Unitless beta coefficient | Standard Error 0.183 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Functional Brain Network Engagement Associated With Response Inhibition | Right frontoparietal network | 0.125 Unitless beta coefficient | Standard Error 0.156 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Functional Brain Network Engagement Associated With Response Inhibition | Basal ganglia network | -0.240 Unitless beta coefficient | Standard Error 0.156 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Functional Brain Network Engagement Associated With Response Inhibition | Left frontoparietal network | 0.037 Unitless beta coefficient | Standard Error 0.241 |
p-value: 0.024Mixed Models Analysis
Primary
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.
Time frame: Following 2-5 days of cocaine abstinence
Population: Standard analysis of PET data requires a high-resolution MRI image for anatomical localization; thus only participants with a CUD completing both PET and MRI procedures(N=14 CUD) were analyzed. PET data was not collected on the Group healthy comparison adults completing only MRI procedures (HC-MRI).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Adults With a Cocaine-use Disorder (CUD) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Caudate | 25.67 mL*cm^3 | Standard Deviation 7.29 |
| Adults With a Cocaine-use Disorder (CUD) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Ventromedial prefrontal cortex | 33.95 mL*cm^3 | Standard Deviation 7.21 |
| Adults With a Cocaine-use Disorder (CUD) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Orbitofrontal cortex | 30.40 mL*cm^3 | Standard Deviation 6.13 |
| Adults With a Cocaine-use Disorder (CUD) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Inferior frontal gyrus | 28.42 mL*cm^3 | Standard Deviation 6.08 |
| Adults With a Cocaine-use Disorder (CUD) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Putamen | 30.31 mL*cm^3 | Standard Deviation 5.84 |
| Adults With a Cocaine-use Disorder (CUD) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Middle frontal gyrus | 28.37 mL*cm^3 | Standard Deviation 6.94 |
| Adults With a Cocaine-use Disorder (CUD) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Anterior cingulate cortex | 32.54 mL*cm^3 | Standard Deviation 6.88 |
| Adults With a Cocaine-use Disorder (CUD) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Superior frontal gyrus | 27.55 mL*cm^3 | Standard Deviation 6.33 |
| Adults With a Cocaine-use Disorder (CUD) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Ventral striatum | 36.48 mL*cm^3 | Standard Deviation 8.05 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Superior frontal gyrus | 23.65 mL*cm^3 | Standard Deviation 4.3 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Ventral striatum | 32.19 mL*cm^3 | Standard Deviation 5.58 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Caudate | 22.41 mL*cm^3 | Standard Deviation 4.75 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Putamen | 26.06 mL*cm^3 | Standard Deviation 5.26 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Orbitofrontal cortex | 26.36 mL*cm^3 | Standard Deviation 4.61 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Anterior cingulate cortex | 28.73 mL*cm^3 | Standard Deviation 5.54 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Ventromedial prefrontal cortex | 29.41 mL*cm^3 | Standard Deviation 5.34 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Inferior frontal gyrus | 24.78 mL*cm^3 | Standard Deviation 4.25 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5) | Middle frontal gyrus | 24.95 mL*cm^3 | Standard Deviation 4.36 |
Comparison: Outcome Measure Data were tested using a single linear mixed effects model. The 9 regions of interest (i.e., all 9 Rows of the Outcome Measure Data) were included in the model as a within-subjects factor for the fixed-effect of region. Group (i.e., CUD, HHC-PET) was included in the model as a between-subjects factor for the fixed-effect of group. The model also included the region-by-group interaction term and a factor to model the random-effect of participant.p-value: 0.035Mixed Models Analysis
Primary
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.
Time frame: Following 2-5 days of cocaine abstinence.
Population: Participants who completed resting-state functional MRI procedures. Two the 16 CUD participants completing MRI were excluded from analysis due to insufficient data and poor image quality resulting from excessive head motion. Resting-state functional MRI data were not available on the Group historical healthy comparison adults who had completed PET procedures (HHC-PET).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Adults With a Cocaine-use Disorder (CUD) | Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF) | Right frontoparietal network | 0.749 Unitless ratio | Standard Error 0.019 |
| Adults With a Cocaine-use Disorder (CUD) | Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF) | Basal ganglia network | 0.636 Unitless ratio | Standard Error 0.036 |
| Adults With a Cocaine-use Disorder (CUD) | Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF) | Left frontoparietal network | 0.739 Unitless ratio | Standard Error 0.021 |
| Adults With a Cocaine-use Disorder (CUD) | Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF) | Cingulo-insula network | 0.707 Unitless ratio | Standard Error 0.029 |
| Adults With a Cocaine-use Disorder (CUD) | Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF) | Default-mode network | 0.747 Unitless ratio | Standard Error 0.021 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF) | Cingulo-insula network | 0.726 Unitless ratio | Standard Error 0.041 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF) | Default-mode network | 0.726 Unitless ratio | Standard Error 0.03 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF) | Right frontoparietal network | 0.772 Unitless ratio | Standard Error 0.026 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF) | Left frontoparietal network | 0.734 Unitless ratio | Standard Error 0.03 |
| Historical Healthy Comparison Adults, PET (HHC-PET) | Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF) | Basal ganglia network | 0.590 Unitless ratio | Standard Error 0.051 |
Comparison: Outcome Measure Data were tested using a single linear mixed effects model. The 5 brain networks of interest (i.e., all 5 Rows of the Outcome Measure Data) were included in the model as a within-subjects factor for the fixed-effect of network. Group (i.e., CUD, HC-MRI) was included in the model as a between-subjects factor for the fixed-effect of group. The model also included the network-by-group interaction term and a factor to model the random-effect of participant.p-value: 0.87Mixed Models Analysis