Combining Neuro-Imaging and Non-Invasive Brain Stimulation for Clinical Intervention in Opioid Use Disorder

Study Overview
=================
Brief Summary
-----------------
The overarching goal of this project is to expand the traditional expertise in non-invasive neuromodulation at the University of Minnesota towards developing novel paired-neuromodulation approaches using transcrancial direct current stimulation (tDCS) for new addiction treatments that support long-term abstinence. This study will investigate whether the pairing of dorsolateral prefrontal cortex (DLPFC) stimulation and cognitive training can enhance functional connectivity between DLPFC and nucleus accumbens (NAcc). We have identified higher functional connectivity between DLPFC and NAcc in alcoholics that have successfully maintained abstinence for extended periods of time (7 years). This paired-neuromodulation approach can potentially be used as a therapeutic intervention to decrease substance use probability in addiction (e.g. opioid use disorder). The long term goal is to develop new addiction treatments that support long-term abstinence in opioid use disorder. The overall objective of this proposal is to enhance functional connectivity between DLPFC and NAcc as a therapeutic intervention to enhance cognition and reduce substance use rates in opioid use disorder.

Official Title
-----------------
Combining Neuro-Imaging and Non-Invasive Brain Stimulation for Clinical Intervention in Opioid Use Disorder

Conditions
-----------------
Opioid-Related Disorders, Heroin Dependence, Morphine Dependence

Intervention / Treatment
-----------------
* Device: Transcranial Direct Current Stimulation (tDCS)
* Device: Sham Transcranial Direct Current Stimulation (tDCS)
* Behavioral: Cognitive Training


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Current diagnosis of opioid use disorder Enrolled in a methadone treatment program for at least 2 months in Hennepin Healthcare and be clinically stable. Meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnostic criteria for opioid use disorder Participants may have current comorbid drug use, but their primary substance use disorder diagnosis must to be based on opioid use. Participants must have the intention to remain in the methadone treatment program until the end of the intervention portion of the study. Exclusion Criteria: Any medical condition or treatment with neurological sequelae (i.e. stroke, tumor, loss of consciousness>30 min, HIV) Head injury resulting in a skull fracture or a loss of consciousness exceeding 30 minutes (i.e., moderate or severe TBI) Any contraindications for tDCS or MRI scanning (tDCS contraindication: actively receiving treatment for seizures or epilepsy; MRI contraindications; metal implants, pacemakers or any other implanted electrical device, injury with metal, braces, dental implants, non-removable body piercings, pregnancy, breathing or moving disorder) Current active psychosis or mania Presence of a condition that would render study measures difficult or impossible to administer or interpret (e.g. current mania, active psychosis) Primary current substance use disorder diagnosis on a substance other than opioid except for caffeine or nicotine Current stimulant use disorder (need to be free of stimulant use for at least 1 month) History of electroconvulsive therapy or cortical energy exposure within the past 12 months, including participation in any other neuromodulation studies incarceration

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tDCS with Cognitive Training<br>DLPFC stimulation with tDCS with simultaneous cognitive training | Device: Transcranial Direct Current Stimulation (tDCS)<br>* Participants receive 10 sessions (2 5-visit blocks of 46 minutes) of active tDCS to DLPFC (dorsolateral prefrontal cortex)<br>Behavioral: Cognitive Training<br>* Executive functioning tasks<br>|
| Active Comparator: Sham tDCS with Cognitive Training<br>Sham tDCS with simultaneous cognitive training | Device: Sham Transcranial Direct Current Stimulation (tDCS)<br>* Participants receive 10 sessions (1 5-visit block of 46 minutes of active tDCS and 1 5-visit block of sham tDCS)<br>Behavioral: Cognitive Training<br>* Executive functioning tasks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in circuit-based target engagement | Participants will complete MRI sessions on a 3T scanner located in the Center for Magnetic Resonance Research (CMRR) at the University of Minnesota. Participants will undergo resting-state MRI over an 8-minute scan in order to gather resting state functional connectivity. Significant within-subject increase (p<.05, 1-tailed) in signal intensity (unitless measure) resting state functional connectivity (rsFC) of at least one frontally mediated network (frontal-striatal, frontal-insular, frontal-thalamic) in Active and Sham arms. | baseline; mid-test (week 2±1); post-test (week 3±1) | 
| Change in D-KEFS Trails T-Score | The Trails subtest measures switching. The participant is presented with a sheet with several letters or numbers and is asked to follow the prompts (e.g. connect alternating numbers and letters). The time and number of errors for each of the 5 sheets is recorded and a T-score (range: 1-20) is calculated from this information. A higher T-score indicates higher capacity for switching, i.e., a better outcome. | baseline; mid-test (week 2±1); post-test (week 3±1); Follow-up 1 (post-test + 1 month), Follow-up 2 (post-test + 2 months) | 
| Change in D-KEFS Verbal Fluency T-Score | The Verbal Fluency subtest measures executive control. Participants have to produce as many words as possible from a category in 60 seconds. The number of words produced and the number/position/type of errors are recorded. A T-score (range: 1-20) is calculated from this information. A higher T-score indicates higher executive control, i.e., a better outcome. | baseline; mid-test (week 2±1); post-test (week 3±1); Follow-up 1 (post-test + 1 month), Follow-up 2 (post-test + 2 months) | 
| Change in D-KEFS Color Word T-Score | The Color-Word subtest measures switching capacity. The participant is presented with words demonstrating a mismatch between the name of a color (e.g., blue, green, or red) and the color it is printed on (i.e., the word red printed in blue ink instead of red ink). The participant must follow the prompts (e.g. Say the color of the ink this time) when responding. The number of correct answers and the time taken to complete the task are recorded, generating a T-score (range: 1-20). A higher T-score indicates higher capacity for switching i.e., a better outcome. | Time Frame: baseline; mid-test (week 2±1); post-test (week 3±1); Follow-up 1 (post-test + 1 month), Follow-up 2 (post-test + 2 months) | 
| Change in WAIS Digit Span T-Score | The Digit Span subtest measures working memory. The participant is prompted to recall the order of digits they just heard (e.g., same order, backwards order, sequential order). There are two trials per item. Each item increases the difficulty by adding one digit. The total number correct generates a T-score (range: 1-20). A higher T-score indicates higher capacity for working memory, i.e., a better outcome. | baseline; mid-test (week 2±1); post-test (week 3±1); Follow-up 1 (post-test + 1 month), Follow-up 2 (post-test + 2 months) | 
| Change in WAIS Coding T-Score | The Coding subtest measures switching capacity. The participant is presented with a symbol for each digit 1-9 (e.g., an upside-down T represents the number 2). The participant must translate the numbers into symbols, as fast as they can, for 120 seconds. The number of correctly-drawn symbols generates a T-score (range: 1-20). A higher T-score indicates higher capacity for switching, i.e., a better outcome. | baseline; mid-test (week 2±1); post-test (week 3±1); Follow-up 1 (post-test + 1 month), Follow-up 2 (post-test + 2 months) | 
| Change in Timeline Follow Back (TLFB) Score | The TLFB questionnaire measures substance use disorder severity. The questionnaire asks the participant about substance use in the past 30 days. The participant reports on a binary scale as to whether or not they have used a given substance. A greater number of days with drug use in the past month the participant used a substance equals a higher score. A higher score equals greater substance use disorder severity. | baseline; mid-test (week 2±1); post-test (week 3±1); Follow-up 1 (post-test + 1 month), Follow-up 2 (post-test + 2 months) |