Neural Substrates of Emotion: Impact of Cocaine Dependence
Condition: Cocaine Use Disorder
MeSH terms: Cocaine-Related Disorders
Study type: Interventional
Phase: Phase 2

Summary: 
      Over one million individuals in the United States meet criteria for cocaine use disorders.
      Relapse rates are highest among cocaine-dependent (CD) populations. Social stress is a
      significant risk factor for relapse. Data from human neuroimaging studies suggest that
      "top-down" prefrontal cortical inhibition of amygdala activity controls emotional responses
      to social stimuli. A growing literature suggests that hypoactivity in the medial prefrontal
      cortex coupled with increases in amygdala activity underscore the vulnerability of CD
      individuals to relapse. Neuroimaging studies of corticolimbic network activity (functional
      connectivity) have been conducted in CD subjects at rest. Compared with healthy controls, CD
      subjects exhibited lower corticolimbic connectivity and the degree of corticolimbic
      uncoupling was associated with time to relapse. Studies measuring corticolimbic connectivity
      during exposure to a social stress task in CD subjects could provide critical insight into
      the neurobiologic mechanisms that underscore the sensitivity of CD individuals to social
      stress. Moreover interventions that improve corticolimbic connectivity in CD subjects may be
      effective therapeutic strategies for preventing relapse in CD populations. Oxytocin (OT) is
      an anxiolytic neuropeptide that attenuates amygdala responses to aversive social cues. In
      order to better understand the neurobiologic mechanisms that control emotion-related behavior
      in CD populations, we propose a double-blind placebo (PBO) controlled study using blood
      oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to measure (1)
      corticolimbic functional connectivity during the Montreal Imaging Stress Task (MIST) and (2)
      amygdala activity in response to an implicit facial affect recognition paradigm in groups of
      CD individuals (CD n=80) and healthy non-dependent controls (HC, n=80). Prior to the scanning
      session, participants will receive either intranasal OT (24 IU) or PBO spray (n=40 per
      treatment group). The order of the tasks will be counterbalanced.
    

Detailed description: 
      Individuals will be screened for eligibility over the telephone by a trained research
      assistant during which major inclusion/exclusion criteria will be assessed. Individuals who
      appear eligible will be invited for an in-person interview with a member of the research
      team. Prior to any study procedures, the individual will sign an Institutional Review Board
      (IRB) approved informed consent form. Following consent, a battery of standardized
      assessments will be delivered (described below). A general medical history and physical exam
      will also be performed to ensure that the subject is eligible to participate. The exam will
      also include a metal screening questionnaire that will be reviewed by clinical staff. If a
      patient is ineligible to participate, he or she will be given a referral for medical care
      and/or an appropriate treatment program.

      C3e. Assessments Screening and Diagnostic Instruments Quick Screen: This assessment will
      quickly determine whether an individual meets study inclusion or exclusion criteria. The
      instrument is designed to assess for substance dependence and obvious psychiatric, medical,
      and logistic exclusions.

      Mini-International Neuropsychiatric Interview (MINI): The MINI is a brief structured
      interview that was designed to assess Diagnostic and Statistical Manual (DSM) IV diagnoses
      using a series of questions in dichotomous format (yes/no). To date the MINI has not been
      revised to assess DSM V criteria. Earlier studies have found that the MINI is similar in
      sensitivity, specificity, and inter-rater reliability to other more lengthy diagnostic
      interviews, such as the SCID-I/P.

      Structured Clinical Interview for DSM-IV (SCID-I/P): The SCID-P is a structured diagnostic
      interview that assesses each of the criteria for DSM-IV diagnoses. To date the SCID has not
      been revised to assess DSM-5 criteria. The alcohol and drug use disorder modules will be used
      to thoroughly assess both current and lifetime diagnostic status for abuse and dependence. It
      has excellent inter-rater and test-retest reliability.

      Childhood Trauma Questionnaire (CTQ): Since childhood trauma has been shown to affect
      corticolimbic brain activity and corticolimbic brain activity following OT administration we
      will use the CTQ to assess childhood trauma exposure in each of the study participants. The
      CTQ is a 25-item self-report questionnaire used to assess the extent to which individuals
      have childhood abuse and neglect. Subjects answer each question using a 5-point Likert scale
      ranging from (1) never true to 5 (very often true). The reliability and validity of the CTQ
      have been tested in both healthy and substance-dependent populations.

      Within Session Rating Scale: A modification of the Within Session Rating Scale will be used
      to assess craving and mood during the procedures. This scale is anchored with the adjectival
      modifiers ("not at all and extremely"). There are four items assessing domains of craving
      (want/need/craving/ability to resist). For the market value item, the individual will be
      asked to name the dollar amount they would be willing to pay for cocaine if they could have
      it "now". Other items include anxiety and mood. These data will be collected prior to
      treatment, prior to MIST1, and immediately after each run of the MIST.

      Menstrual History Diary: Drug craving mood and affect have been associated with menstrual
      cycle phase and ovarian hormone status. Subjects will be asked to estimate the timing of
      their cycle for the 90-days prior to study entry and to track their cycle during study
      participation. Daily Hassles Scale: The Daily Hassles Scale consists of a list of 117
      irritating, frustrating or distressing events that characterize everyday interactions with
      the environment. Subjects rate intensity for the past month. The Daily Hassles Scale is
      positively correlated with adaptational outcomes and is a good predictor of psychological
      symptoms. Data from the daily hassles will be used to explore the relationship between stress
      related corticolimbic brain activity and sensitivity to daily hassles.

      Metal Screening Questionnaire (MSQ): The MSQ is a list of 18 "yes or no" questions regarding
      pacemakers, shrapnel, bullets, implants, tattoos, hairpieces, insulin pumps, cochlear
      implants, staples and metal clips, false eyes, nerve stimulators, dental bridges, replacement
      valves, intrauterine devices (IUDs), dentures, trans-dermal nicotine patches, surgery, metal
      in the eyes, claustrophobia, and current pregnancy. In addition the MSQ asks "have you ever
      been shot at or received treated for metal in your eyes?" The questionnaire is anchored by
      "Is there any possibility of metal, metal pieces, or metal implants in your body?" Each study
      participant will be asked to fill-out the MSQ at the assessment visit and the clinician will
      review the MSQ with the participant during the physical exam.

      Minnesota Nicotine Withdrawal Scale (MNWS): Nicotine withdrawal could have a significant
      impact on our study outcomes. The MNWS is a 15-item self-report scale of behaviors associated
      with nicotine withdrawal. Subjects answer each question using a 5-point Likert scale ranging
      from (0) none to 4 (severe). Smokers will be asked to fill-out the questionnaire both before
      (prior to medication administration) and after the scanning sessions. Group differences in
      the severity of nicotine withdrawal may be used as covariates in the analysis.

      The Connor-Davidson Resilience Scale (CD-RISC): The CD-RISC is a 25-item self-report measure
      that assesses the ability to cope with stress and adversity. Participants will be asked to
      complete the CD-RISC at the assessment visit.

      Interpersonal Support Evaluation List Short Form (ISEL-SF): The ISEL-SF is a 12-item
      self-report form that measures perceived availability of four domains of social support
      (belonging, self-esteem, appraisal and tangible). Individuals rate each item using a
      four-point scale ranging from definitely false (1) to definitely true (4). Participants will
      be asked to complete the ISEL-SF at the assessment visit.

      Urine Pregnancy Test: Female participants will be asked to provide a urine sample which will
      be tested for the presence of human chorionic gonadotropin (hCG) using the QuickVue One-Step
      urine hCG pregnancy test (Quidel Corporation, San Diego, CA). The test provides a qualitative
      measure of hCG in urine (≥ 25 milli-Intenational unit (mIU/mL); 99% sensitivity; 99%
      specificity). The urine pregnancy test will be performed at screening and on the day of the
      study visit, prior to the urine drug screen and breathalyzer test. If the pregnancy test is
      positive, the subject will be excluded and no further testing will take place.

      Blood Sample Collection and Assays: Baseline saliva samples for estradiol, progesterone and a
      baseline blood sample for OT will be collected from each participant 15-30 minutes prior to
      the OT/PBO administration. Blood will be collected in tubes containing
      ethylenediaminetetraacetic acid (EDTA). Tubes will be centrifuged at 1500 rpm at 4˚C. Plasma
      will be stored at -70˚C. Determination of OT will be performed using a commercial ELISA kit
      (Enzo Life Sciences). Intra-assay coefficients of variation for OT average ~3-5% and
      inter-assay variation is typically less than 10%.

      Substance Related Instruments Form 90: The Form 90, an assessment instrument commonly used in
      addiction studies, is similar in concept to the Time Line Follow back. This is a
      calendar-based instrument designed to assess daily substance consumption. Study participants
      will be asked to estimate the amount of substance consumed with the aid of visual cues
      designed to accurately quantify consumption. Cocaine will be recorded in dollar value as well
      as quantity in order to standardize for different types of cocaine use (crack, IV, nasal,
      etc.). The data will be summarized in three ways: (a) percent of abstinent days (i.e., no
      use); (b) amount of use per day and (c) days since last use.

      Urine Drug Screening: Drug screens will be performed using the On Track Test Cup (Roche
      Diagnostics), an in vitro diagnostic test for the qualitative detection of drug or drug
      metabolite in the urine. The On Track Test Cup profile (cut off) consists of amphetamines
      (1000ng/ml), cocaine (300 ng/ml), tetrahydrocannabinol (THC) (50 ng/ml), morphine (300
      ng/ml), and benzodiazepines (200 ng/ml). Results will be used to ascertain abstinence prior
      to initiation of test session and to substantiate self-report.

      Breathalyzer: To ascertain abstinence from alcohol during the study period, subjects will
      have their breath sampled for the presence of alcohol (Alco-Sensor III, Intoximeters Inc.,
      St. Louis, MO). The Alco-Sensor III can accurately detect breath alcohol levels between
      .000-.400 blood alcohol concentration (BAC).

      Session Procedures Study Visit: Participants will be instructed to arrive at MUSC's Addiction
      Sciences Division (ASD) on the morning of the study visit. Participants will be informed that
      they will be expected to remain abstinent from cocaine and other drugs for the three-day
      period prior to the study visit in order to minimize the impact of recent drug/alcohol use on
      brain activity and subjective responses to the MIST. Participants will be asked to avoid
      caffeinated beverages on the morning of the study visit since caffeine may introduce
      variability in stress reactivity. If a participant is nicotine-dependent (s)he will be
      provided with a nicotine patch. Upon arriving at the ASD, the participant will be
      breathalyzed and will provide a urine sample, which will be tested for the presence of
      cocaine, opiates, barbiturates, benzodiazepines, and stimulants; if female, a urine pregnancy
      test will also be administered prior to the drug test. If the pregnancy and urine drug tests
      are negative,with the exception of marijuana, the session will proceed. In the event a
      participant tests positive for drugs or alcohol, the study visit will be rescheduled. Saliva
      samples will be collected, and the participant will be escorted to the Clinical Neurobiology
      Laboratory at the Institute of Psychiatry for a blood draw. Participants will then be
      escorted to the on-campus Center for Biomedical Imaging (CBI) facility by approved study
      personnel.

      Medication Administration Intranasal OT and matching PBO (saline spray) will be compounded by
      MUSC's Investigational Drug Services (IDS) which has extensive experience in extemporaneous
      OT preparation and quality control monitoring. Randomization will be done by IDS, who will
      keep a record of the blind. The record will be available should unblinding be required. To
      achieve balance in sample size with respect to gender, smoking status, age, and race, a block
      randomized design with randomly varying block sizes will be used. OT or PBO sprays will be
      administered at the CBI and under the supervision of the study staff at 11:30 a.m.,
      approximately 45-minutes prior to the scanning session. First the participant will be asked
      to blow their nose. The vial will be primed to ensure that each puff contains OT or placebo
      spray and not air. The participant will be instructed to exhale through their nose and then
      spray into one nostril while inhaling. Nostrils will be alternated and the participant will
      be asked to repeat the procedure for each nostril. Participants will self-administer three
      puffs of the nasal spray per nostril (4 IU of OT/puff) for a total of 24 IU. This dose and
      timing of administration were selected based on similar fMRI studies demonstrating BOLD
      signal changes in the amygdala 45-50 minutes post-administration.

      MRI Data Acquisition All MRI data will be acquired on a Siemens Trio 3 Tesla (T) scanner
      (Siemens Medical, Erlangen, Germany). Participants will be screened for metal using a
      handheld metal detector. Study personnel will position subjects on the scanner bed with foam
      padding placed around their head to prevent motion. Participants will wear
      earplugs/headphones and the task will be projected on a wide screen located at the end of the
      scanner bore and viewed via a back-projected mirror that will be mounted on 12-channel head
      coil. Participants will use a non-ferrous optical hand pad to submit their answers to the
      arithmetic task. The hand pad will be connected via an optical cable to a computer outside
      the scanner room. Their ability to view the projection screen and use of the hand pad will be
      assessed prior to scanning. During initial scanner tuning, localizing, and structural
      scanning, participants will be shown "relaxing" images (i.e., 20 scenic pictures, each
      displayed for 30 seconds). A high resolution T1-weighted MPRAGE anatomical scan (TR = 8.1 ms,
      echo time (TE) (TE = 3.7 ms, flip angle = 8°, field of view = 256 mm, 1.0 mm) covering the
      entire brain and positioned using a sagittal scout image will be acquired for co-registration
      and normalization of functional images. T2*-weighted gradient echo planar imaging (EPI)
      images will be acquired with the following parameters: TR = 2500 ms, TE = 27 ms, flip angle =
      77º, 40 axial slices (FOV = 224 x 224 mm, thickness = 3.5 mm voxels with 0.5 mm gap, in
      interleaved order. The scanning planes will be oriented parallel to the anterior
      commissure-posterior commissure line.

      Implicit Facial Affect Recognition Task The amygdala response to emotional faces that are
      presented outside the focus of attention (i.e. implicit tasks) is significantly greater than
      that observed during overt (explicit) presentation of the same stimuli. Emotional adult faces
      will be selected from a variety of sources are standardized in size and enclosed in the same
      oval surround. Dr. Joseph (Co-I) has developed a corpus of faces for a recent project, "A
      comparative developmental connectivity study of face processing") that will be used for the
      present project. The faces will depict male and female Caucasian, Asian and African Americans
      expressing three different categories of emotion; fear, anger, and happiness. Neutral faces
      will also be presented. Because the participants will also be from different ethnic
      categories, it is important to include a mixture of races. In a block design, participants
      will view a series of faces (for 27.5 sec) within a block and report on the gender of those
      faces at the end of the block (for 5 sec). Each block will present 56 faces that depict the
      same emotion and same gender so there will be 6 pseudorandomly ordered task blocks (3
      emotions x 2 genders) and 7 rest blocks (27.5 sec each) that present a crossbar to be
      fixated. In each task block, each emotional face will be presented for 33 msec. followed by a
      neutral face mask (from a different individual) for 167 msec. followed by a blank screen for
      291 msec. At the end of the block participants will report the gender using two buttons on a
      response pad. Assignment of face sets to sessions will be counterbalanced across subjects.

      The Montreal Imaging Stress Task The study will use a block design of three, six-minute runs
      separated by two-minutes of rest for feedback, for a total of 24-minutes. During each run,
      participants will be exposed to 40-second blocks of three different conditions (rest,
      control, and stress). Prior to the task, a research assistant will meet with each participant
      and described the parameters of the task. The participants will be shown images of what the
      screen will look like during each condition. The participants will be instructed to relax
      during the rest condition and focus on the screen. During the control condition, the
      participants will be asked to answer math problems as accurately as possible but will also be
      told that their responses will not be recorded. During the stress condition, the participants
      will be asked to perform the math task as quickly and accurately as possible. They will be
      given immediate feedback about their performance and will be able to see the performance
      level of an "average" person through a performance bar that will be located at the top of the
      screen. A strict time limit will be enforced throughout the stress condition. The
      participants will be told that the average person would answer about 85% of the questions
      correctly, while in reality, the program's algorithm limits the participants' performance
      rate to between 35-45%. At the end of runs one and two, the participants will be given
      negative feedback from the investigator and will be urged to improve their performance so
      that their data may be included in the study. To minimize the effects of scanner drift, the
      beginning condition will be counterbalanced between participants. However, the sequence of
      conditions will be constant (i.e. control condition will follow the rest condition and the
      stress condition will follow the control condition).
    

Intervention name(s): Oxytocin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Nasal spray based on naturally occurring hormone, oxytocin.
Other intervention name(s): Pitocin
Intervention MeSH terms: Oxytocin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment