A Randomized Controlled Trial of Medial Prefrontal Cortex Theta Burst Stimulation for Cocaine Use Disorder: A Three-Month Feasibility and Brain Target Engagement Study.

A Randomized Controlled Trial of Medial Prefrontal Cortex Theta Burst Stimulation for Cocaine Use Disorder: A Three-Month Feasibility and Brain Target-Engagement Study - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Biol Psychiatry Cogn Neurosci Neuroimaging . Author manuscript; available in PMC: 2026 Jun 1. Published in final edited form as: Biol Psychiatry Cogn Neurosci Neuroimaging. 2024 Dec 10;10(6):616–625. doi: 10.1016/j.bpsc.2024.11.022 A Randomized Controlled Trial of Medial Prefrontal Cortex Theta Burst Stimulation for Cocaine Use Disorder: A Three-Month Feasibility and Brain Target-Engagement Study Daniel M McCalley 1, 2, †, * , Kaitlin R Kinney 3, † , Navneet Kaur 3 , Julia P Wolf 1, 2 , Ingrid E Contreras 1, 2 , Joshua P Smith 1, 2 , Sarah W Book 1, 2 , Colleen A Hanlon 1, 2, 3, 4 Author information Article notes Copyright and License information 1. Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC 2. Department of Neurosciences, Medical University of South Carolina, Charleston, SC 3. Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC 4. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC † Designates co-first authors Author contribution statements: Daniel M. McCalley : Writing - Original Draft, Data Curation, Formal analysis, Validation, Visualization, Kaitlin R. Kinney : Writing - Original Draft, Data Curation, Formal analysis, Validation, Visualization, Navneet Kaur : Writing - Original Draft, Data Curation, Formal analysis, Visualization, Julia P. Wolf : Investigation, Curation, Resources, Ingrid E. Contreras : Investigation, Curation, Resources, Joshua P. Smith : Conception, Methodology, Supervision, Sarah W. Book : Conception, Methodology, Supervision, Colleen A. Hanlon : Conceptualization, Methodology, Writing - Original Draft, Funding acquisition, Supervision * Correspondence: Daniel M. McCalley, Ph.D., Postdoctoral Fellow, Department of Psychiatry and Behavioral Sciences, Stanford University, 3801 Miranda Ave, Palo Alto, CA 94304-5797, 650-493-5000 (fax) Issue date 2025 Jun. PMC Copyright notice PMCID: PMC13151909  NIHMSID: NIHMS2065715  PMID: 39667495 The publisher's version of this article is available at Biol Psychiatry Cogn Neurosci Neuroimaging Abstract Background: Cue-induced craving precipitates relapse in drug and alcohol use disorders. Theta burst stimulation (TBS) to the left frontal pole of the medial prefrontal cortex (MPFC) has previously been shown to reduce drinking and brain reactivity to alcohol cues. This randomized, double-blind, sham-controlled target-engagement study aimed to assess whether TBS has similar effects in individuals with cocaine use disorder (CUD). Methods: Thirty-three participants in intensive outpatient treatment received either real or sham TBS over 10 sessions across 3 weeks (36,000 pulses total; continuous TBS, 110% resting motor threshold, 3600 pulses/session). TBS was administered on days of behavioral counseling. Twenty-five individuals completed all 10 TBS sessions. Brain reactivity to cocaine cues was measured using fMRI at baseline, 1-month, 2-months, and 3-months. Results: Cocaine abstinence during the 3-month follow-up period was greater in the real TBS group (1-month: 92.0%, 2-month: 100.0%, 3-month: 85.0%) compared to sham (1-month: 66.6%, 2-month: 66.6%, 3-month: 66.6%), though not statistically significant [1-month: 6.00, p=0.14; 2-month OR=:14.30, p=0.09, and 3-month OR=2.75, p=0.30]. However, there was a significant effect on cocaine cue reactivity (treatment effect: F 1,365 = 8.92, p=0.003; time*treatment interaction: F 3,365 =12.88, p<0.001). Real TBS reduced cocaine cue reactivity in the MPFC (F 3,72 =5.46, p=0.02) overall, and in the anterior cingulate (F 3,72 =3.03, p=0.04), and insula (F 3,72 =3.60, p=0.02). Conclusions: This early-stage trial demonstrates TBS to the MPFC reduces brain reactivity to cocaine cues in key nodes of the Salience Network in treatment-seeking cocaine users. Future, well-powered trials are warranted to evaluate clinical efficacy outcomes. Keywords: Cocaine dependence, cocaine use disorder, cue-reactivity, transcranial magnetic stimulation, theta burst stimulation, frontopolar cortex Introduction Cocaine dependence is a chronically relapsing disorder that is associated with harm for users, their families and communities, and the health care system. Nearly 40 million Americans age 12 and older have tried cocaine or crack ( 1 ) and nearly 4 million are regular users. Relative to other drugs of abuse, cocaine use is resistant to behavioral or pharmacologic treatment. Relapse rates following treatment programs are often as high as 75% only 60 days post-treatment ( 2 ). Drug-cue associated craving is one of the strongest predictors of relapse ( 3 – 5 ). Cue-induced craving is related to elevated activity in the frontal-striatal circuits involved in limbic arousal and habitual drug taking. Converging evidence from human neuroimaging studies have identified the frontal pole of the medial prefrontal cortex (MPFC) as a brain region consistently activated by cocaine cues, which may contribute to relapse ( 6 ). Subsequently, both basic science and clinical studies have demonstrated that altering this circuit alters drug-intake ( 7 ). To date, however, there are no FDA-approved treatments directly designed to modulate the neural circuitry involved in cocaine cue-reactivity. There has been recent interest in the use of transcranial magnetic stimulation (TMS) as a noninvasive neural-circuit based therapeutic tool for cocaine use disorder ( 8 – 12 ). Recognized by the Food and Drug Administration for depression, OCD and smoking cessation treatment, TMS is a noninvasive technique leveraging electromagnetic induction to elicit neural activity in the cortex and subcortical regions through monosynaptic afferent projections. Theta burst stimulation (TBS), a patterned form of rTMS, induces plasticity in preclinical models and selectively modulates cortical excitability in humans ( 13 ). Research from our laboratory revealed that single TMS pulses to the left frontal pole induces significant alterations in brain activity, as measured by the blood oxygen level–dependent signal, in the MPFC and striatum. This effect was observed using interleaved TMS and functional magnetic resonance imaging (fMRI) in healthy individuals ( 14 , 15 ), and those with cocaine ( 15 , 16 ) and alcohol dependence ( 16 ). Moreover, when continuous TBS (cTBS) is applied to the MPFC in cocaine users, there is a specific reduction in TMS-evoked activity ( 17 ) as well as cocaine cue-reactivity ( 18 ). There are now many studies which have demonstrated that the frontal pole is a viable, transdiagnostically relevant target for TMS ( 19 , 20 ). A recent study in 50 individuals with alcohol use disorder (AUD), for example, demonstrated that 10 sessions of cTBS to the frontal pole during an intensive outpatient treatment program decreased alcohol drinking, increased retention in the treatment program, and decreased brain reactivity to alcohol cues for 3 months ( 21 ). The goal of the present study was to evaluate a similar protocol as a treatment tool for individuals with cocaine dependence. Methods and Materials Experimental Procedures: Participants. Thirty-three treatment-seeking individuals with cocaine dependence participated in this randomized sham controlled, double-blind target-engagement study ( NCT03238859 ). Participants were recruited from the Intensive Outpatient Programs at the Ralph H. Johnson Department of Veterans Affairs Medical Center and the Center for Drug and Alcohol Problems at the Medical University of South Carolina (MUSC) in Charleston, South Carolina. All protocols were approved by MUSC and VA institutional review boards and were performed in accordance with the Declaration of Helsinki on Ethical Practices for Medical Research. Participants gave written informed consent. Exclusion criteria: current/prior dependence on prescription/psychoactive drugs other than cocaine, alcohol, or nicotine, history of head injury with loss of consciousness, pregnancy or breast feeding, unstable medical illness, ferromagnetic metal in the body, or history of seizures ( Table 1 ). No individuals within this study were actively receiving treatment for post-traumatic stress disorder. Table 1. Participant Demographics. There was no difference in demographic variables between the real and sham group, with the exception of resting motor threshold. Values represent mean ± SD unless otherwise specified. Real cTBS (n=17) Sham cTBS (n=16) p-value Demographics Sex 15 M; 2 F 14 M; 2 F 0.95 Age (years) 51.41 ± 10.91 51.63 ± 9.89 0.95 Education (years) 13.65 ± 2.26 13.19 ± 1.52 0.50 Race 7 C, 10 AA 3 C, 13 AA 0.75 Treatment-Related Measures Resting motor threshold (% MSO) 56.35 ± 7.95 46.07 ± 14.37 (n=14) 0.02 Cocaine Use and Craving Age of first use (years) 24.47 ± 8.40 25.88 ± 7.06 0.61 Total duration of use (years) 20.38 ± 14.04 20.97 ± 13.44 0.90 Days since last use 21.53 ± 17.33 19.56 ± 14.86 0.73 Cocaine craving score 12.29 ± 4.52 14.31 ± 7.31 0.35 Other Substance Use Cigarette smoker 13 13 0.74 Current marijuana use 7 7 0.88 AUDIT score 12.82 ± 12.83 17.44 ± 10.65 0.27 Days since last drink 36.18 ± 27.10 25.56 ± 18.61 0.33 Drinking days in last month 13.23 ± 24.38 12.36 ± 11.63 0.45 Alcohol Dependence 7 8 0.61 Alcohol Abuse 6 7 0.62 Mental Status Beck’s Depression Inventory (BDI) 16.00 ± 15.45 9.19 ± 9.74 0.14 State-Trait Anxiety Inventory (State) 39.06 ± 10.04 33.50 ± 9.16 0.11 State-Trait Anxiety Inventory (Trait) 44.76 ± 10.47 37.88 ± 9.58 0.06 Barratt Impulsivity Scale (BIS) 70.50 ± 13.20 (n=16) 70.50 ± 11.33 1.00 Open in a new tab AA, African American; AUDIT, Alcohol Use Disorders Identification Test; BDI, Beck Depression Inventory-II; BIS, Barratt Impulsiveness Scale; C, Caucasian; cTBS, continuous theta burst stimulation; F, female; M, male; MSO, machine stimulator output; RMT, resting motor threshold. Study Design. After written informed consent, participants completed an MRI scan along with clinical assessments before receiving ten cTBS treatment sessions (3600 pulses per visit) on consecutive business days. They then had three follow-up MRI visits. The first MRI scan was during the first week of the intensive outpatient treatment program (baseline visit). The second scan was 4-6 weeks following the first scan, coinciding with the last week of the intensive outpatient program (1 month follow-up). There was also a 2- and 3-month follow-up visit where participants received an MRI scan and return to cocaine use was assessed (see Figure 1 ). Figure 1. Experimental design. Open in a new tab All participants were enrolled in the study during the first week of Intensive Outpatient Programming. During weeks 2 and 3 of this program, participants were randomized to receive 10 days of real or sham theta burst stimulation. A At each visit, standard safety measurements were performed including the Clinical Institute Withdrawal Assessment, urine screening for other drugs of abuse that might affect the motor threshold, and changes in medical history. Transcranial magnetic stimulation tolerability and any adverse events were also collected. B Self-reported cocaine use was collected at each study visit for all days since the previous study visit, including the follow-up periods. C Cocaine craving questionnaire, Beck’s Depression Inventory-II, State-Trait Anxiety Inventory, and Barratt Impulsiveness Scale. D Left MPFC, 1 session/10 days, continuous theta burst stimulation, 3600 pulses/session, cue provocation before and during session, 110% resting motor threshold. MRI, magnetic resonance imaging. Clinical Assessments. Assessments included the Structured Clinical Interview for DSM-IV ( 22 ), Timeline Followback ( 23 ), Fagerström Test for Nicotine Dependence ( 24 ), Cocaine Craving Questionnaire ( 25 , 26 ), Alcohol Use Disorders Identification Test ( 27 ), Beck’s Depression Inventory-II ( 28 ), State-Trait Anxiety Inventory ( 29 ), and Barratt Impulsivity Scale ( 30 ) (see Table 1 ). [Note: Because the DSM-IV was used in this study, we use the term cocaine dependence throughout this manuscript]. Structural and Functional Neuroimaging. A Magnetom Prisma 3T high-speed scanner (Siemens Medical Systems, Erlangen, Germany) with a 32-channel gradient head coil was used. High-resolution, T1-weighted structural scans were obtained using a 3D magnetization-prepared rapid acquisition gradient echo (MPRAGE) sequence (TR=1900 ms; TE=2.26 ms; voxel size: 1.0 x 1.0 x 1.0 mm; field of view: 256 mm; resolution: 256). Functional Blood Oxygen Level Dependent (BOLD) signal was acquired during the cocaine cue-reactivity task using a multi-slice gradient echo-planar T2*weighted sequence (TR= 2200 ms; TE= 35.0 ms; voxel size: 3.0 x 3.0 x 3.0 mm; field of view= 192 mm; resolution: 64). Cocaine Cue Reactivity fMRI Task. The cue-reactivity task has been extensively used by our group and was administered using E-Prime 2 software (Psychology Software Tools, Inc., Sharpsburg, PA). The task was set up as a block design that was a total of 12 minutes and consisted of 6, 120-second epochs. Each epoch included 24-second blocks of four conditions presented in a pseudorandom order: cocaine images (e.g., crack pipe), neutral images (e.g., chair), blur images (e.g., matching cocaine images in color and hue), and rest (fixation cross). Each block contained 5 images of one of these image types (4.8 seconds/image). Transcranial Magnetic Stimulation. Resting motor threshold was determined via the standardized Parameter Estimation by Sequential Testing (PEST) procedure, an automated algorithm used to determine TMS thresholds ( 31 ). cTBS was delivered to the left frontal pole of the medial prefrontal cortex (FP1, EEG 10-20 system) at 110% resting motor threshold (B-65 A/P coil (Magventure, Farum, Denmark). Two scalp electrodes (Natus Inc.) were placed on the left frontalis muscle under the coil 2 centimeters apart from edge to edge. The TMS coil was positioned at FP1 using the standard EEG 10-20 landmark location (X displacement: 5% of head circumference; Y displacement: 10% of nasion-inion distance). Participants received 3600 pulses of cTBS. To allow the coil to cool, cTBS was delivered in two, 2-minute trains (one train=120 seconds; 1800 pulses/train; 60-second intertrain interval). To enhance the tolerability, stimulation intensity was ramped up over 30 seconds at the beginning of each train by 5% increments. We have previously demonstrated that the perceived painfulness of this protocol is comparable to standard 10Hz TMS to the left dorsolateral prefrontal cortex ( 32 ). TMS was delivered once per day for 10 days, over two weeks (Monday-Friday). For safety purposes, we collected urine drug screens prior to TMS stimulation at each visit. In the event an individual was positive for cocaine, TMS was delayed until a negative urine drug screen was provided. Participants who were currently taking medications which alter seizure threshold (stimulants such as Adderall, barbiturates, opiates, and benzodiazipines) were not enrolled. Participants were required to maintain a steady dosing regimen of any medication throughout the trial. The Clinical Institute Withdrawal Assessment – Alcohol was administered prior to TMS sessions to ensure individuals were not undergoing alcohol withdrawal. Sham cTBS was performed using the Magventure MagPro system’s integrated sham function. Identical to active cTBS, the coil was placed over FP1 in addition to two scalp electrodes on the left frontalis muscle under the coil. The coil was then flipped 180 degrees such that the active side faced away from the scalp. In this configuration, the sound and pressure of the coil remained constant, and the scalp electrodes were active, thus mimicking the multi-sensory experience of cTBS without CNS stimulation. Both during real and sham cTBS, participants were given the instruction “please view the cues and stay focused on cocaine, especially the negative aspects of how it makes you feel”. During cTBS, participants were presented with a series of visual cocaine cues ( 18 ). Behavioral Analysis: Return to cocaine use. Daily, self-reported cocaine use (Timeline Followback) was collected at all study visits. Urine drug screens were collected before all study visits, and on a random basis within the intensive outpatient program. In the event self-report and urine drug screen results were inconsistent (3 instances), results from the urine drug screen were used for analyses of cocaine abstinence. The odds of returning to cocaine use were calculated using standard odd’s ratios. To deal with missing data, the last observation carry forward method was used ( 21 , 33 ). We performed our primary analysis of sobriety using a sample of individuals who completed all 10 TMS sessions (per-protocol, n=25). Clinical Assessments. Self-report scores for cocaine craving, STAI, BDI, and BIS were each analyzed using a 2 (treatment type: real TMS, sham TMS) x 4 (time: pre-TMS, post-TMS, 1 month follow-up, 2-month follow-up) mixed-model analysis of variance (ANOVA). Treatment type was a between-subjects factor and time was a within-subjects factor. Neuroimaging analysis: fMRI preprocessing. Consistent with previous publications from our group ( 21 , 34 ), fMRI data were preprocessed and analyzed with Statistical Parametric Mapping (SPM) version 12 (Wellcome Department of Cognitive Neurology, London, UK). Preprocessing steps included structural segmentation, bias correction, brain masking and normalization to MNI-152 space. A field map derived voxel displacement map was generated and coregistered to the functional images. Subsequent preprocessing steps included realignment, unwarping (using voxel displacement map), co-registration (through mean T2* image), skull-stripping and non-linear normalization to MNI-152 space. Finally, the functional skull-stripped images were smoothed with an 8mm FWHM kernel to enhance signal-to-noise ratio and reduce inter-subject variability. MRI data were available from a total of 27 participants. Of these participants, 14 received real TMS and 13 received sham TMS, with mean (SD) age of 51.1 (11.4) and 52.0 (9.7) years, respectively. Six participants in this study were not scanned due to factors beyond our control (e.g., hurricanes, MRI maintenance). Electrical field modeling and scalp-to-cortex distance measurement. Patient-tailored electrical fields were modeled to reflect the chosen TMS coil and the rate of change in coil current (110% of individual rMT) using simNIBs v.3.2.1. Scalp-to-cortex (STC) distance was extracted from simNIBS( 21 ). Cocaine cue-reactivity: Primary, region-of-interest approach. Mean BOLD signal intensity during cocaine cue presentation within the fronto-striato-limbic network was extracted from a priori-defined anatomical regions-of-interests (ROIs) using MarsBaR 0.44 in SPM12 ( 18 , 35 ). A custom region-of-interest reflecting the stimulation site was constructed by merging left-sided ROIs from the Automated Anatomical Labeling Atlas (AAL) Frontal_Sup_Orb, Frontal_Mid_Orb, and Rectus. Other regions of interest included: the bilateral anterior cingulate cortex (AAL: Cingulum_Ant_L, Cingulum_Ant_R), the left and right insula (AAL: Insula_L, Insula_R) and the ventral and dorsal striatum (Oxford-GSK_Imanove connectivity atlas). To assess the change in BOLD signal magnitude throughout the experiment, a univariate generalized linear model was conducted using IBM SPSS Statistics (v26) with factors including treatment type (real or sham TMS), time (pre-TMS, 1, 2 and 3-month follow-ups), and ROI. STC distance was included as a covariate. Hedge’s g was calculated to evaluate the magnitude of change in cocaine-cue reactivity and to power future clinical trials in this field. In post-hoc analyses, we evaluated the influence of mood and behavioral variables, as well as stimulation intensity (% machine stimulator output) on change in cocaine cue-reactivity. Univariate models were constructed using anxiety, depression, impulsivity, cocaine craving scores, and stimulation strength (110% rMT) as covariates. Cocaine cue-reactivity: Exploratory, whole-brain approach. Functional data from each condition (neutral, cocaine, blur, rest) were concatenated. A first-level GLM was created with 3 regressors for the neutral, cocaine, and blur task conditions, 6 regressors for motion (x,y,z, pitch, roll, yaw) and 1 constant regressor. Motion-adjusted contrast maps were created for each task condition. To assess response to cocaine cues on a group level, a full factorial design matrix was created for treatment type (real TMS, sham TMS) and time (pre-TMS, post-TMS, 1 month follow-up, 2-month follow-up). Statistical parametric maps were calculated according to a GLM to assess BOLD signal to cocaine cues for real and sham TMS across time (voxel-wise threshold, p<0.05; cluster-level threshold, p<0.05, uncorrected). Cocaine cue-reactivity: Exploratory, functional connectivity approach. Individualized functional connectivity change scores between the stimulation site (MPFC) and downstream regions (cingulate, insula, ventral striatum, dorsal striatum, thalamus, and occipital cortex [control region]) were calculated ( 21 ). Change scores were analyzed via univariate linear modeling – fixed factors: treatment type (real or sham cTBS), time (1, 2 and 3-months); covariates: individual scalp-to-cortex distance. Results Baseline demographic and behavior. At baseline, participants receiving real (n=17) and sham (n=16) left frontal pole cTBS demonstrated no significant difference in cocaine craving, AUDIT scores, age of first use, duration of use, days since last use, severity of co-morbidities, and use of nicotine and marijuana (see Table 1 ). Retention and return to cocaine use. The CONSORT (Consolidated Standards of Reporting Trials) diagram ( Figure 2 ) describes enrollment and retention in the study. Eight individuals (4 real, 4 sham TBS) did not complete all 10 cTBS visits (75.8% retention). Among those who did not complete cTBS, 7 withdrew from the intensive outpatient treatment program. One individual withdrew from our study and remained enrolled in intensive outpatient programming to completion. Ten individuals were not retained for follow up visits: Real cTBS: 4 lost to follow up, 2 moved out of state; sham cTBS: 3 lost to follow up, 1 moved out of state. Figure 2. CONSORT diagram of study participants. Open in a new tab CONSORT diagram showing flow of participants through the theta burst stimulation (TBS) experiment. A total of 10 participants were excluded after consent and screening. Among the 8 individuals who did not complete all 10 cTBS sessions, 7 withdrew from the intensive outpatient treatment program entirely. Only 1 individual (randomized to receive real cTBS) withdrew from our study and remained enrolled in intensive outpatient programming to completion. 10 individuals were not retained for all three follow up visits: Real cTBS: 4 lost to follow up, 2 moved out of state; sham cTBS: 3 lost to follow up, 1 moved out of state. ^Real cTBS: 4 participants did not complete cTBS visits – 3 withdrew after 1 cTBS session, 1 withdrew after 3 cTBS sessions. Sham cTBS: 4 participants did not complete cTBS visits – 1 withdrew after baseline visit, 1 withdrew after 3 cTBS sessions, and 1 withdrew after 4 cTBS sessions. Within the per-protocol sample of individuals who completed all 10 TBS sessions, there was not a statistically significant difference in cocaine abstinence rates between real TMS (n=13) and sham TMS (n=12). However, a greater portion of individuals who received real TBS remained abstinent (1 mo: 92.0%, 2Mo: 100.0%, 85.0%), relative to sham (1mo: 66.6%, 2mo: 66.6%, 3 mo: 66.6%) at the 1 month (OR: 6.00 , z=1.48 , p=0.14), 2 month (OR: 14.3, z=1.71 , p=0.09), and 3 month follow-up visits (OR: 2.75, z=1.03 , p=0.30), which may be clinically meaningful ( Figure 3 ). There was no difference in study retention between groups (real TBS: 1 mo: 100.0%, 2 mo: 80.0%, 3 mo: 60.0%; sham TBS: 1 mo: 100.0%, 2 mo: 89.0%, 3 mo: 78.0%). These results were robust using intent-to-treat and modified per-protocol analysis approaches ( Figure S1 ). Figure 3. Cocaine abstinence rates following theta burst stimulation. Open in a new tab Abstinence to cocaine following real vs. sham theta burst stimulation (TBS). Individuals in the real TBS group (black lines, circles) were more likely to abstain from cocaine use than the sham group (gray lines, squares). Cocaine craving and other clinical assessments. For anxiety scores, there was an effect of treatment (F 1,84 =4.05, p=0.05) and time (F 3,84 =2.75, p=0.05). There was no significant treatment x time interaction (F 3,84 =0.38, p=0.77). Individuals receiving sham stimulation had slightly lower anxiety scores at baseline, a trend that was maintained throughout the study. Average anxiety scores within our sample were below 40, indicating low to moderate anxiety on the STAI. There was no main effect of treatment type, time, or a time x treatment interaction in cocaine craving, depression, or impulsivity scores ( Figure S2 ). Sham integrity. Participants correctly guessed the received treatment (real or sham cTBS) in 142 out of 330 survey responses (43.03% accuracy). On a scale of 0 to 10 (0= least confident; 10=most confident), participants endorsed strong confidence in their decision, irrespective of guess accuracy (8.09 ± 1.90, all survey responses; 8.21 ± 1.92, n=142, correct guesses; 7.97 ± 1.89, n=188, incorrect guesses). Cocaine cue-reactivity: Primary, region-of-interest approach. Within the network of regions-of-interest, there was a main effect of treatment (F 1,365 =8.92, p=0.003), time (F 3,365 =4.25, p=0.006), and time x treatment (F 3,365 =12.88, p<0.001) interaction. Scalp-to-cortex distance was a significant covariate (F 1,365 =10.77, p=0.001). Smaller scalp-to-cortex was associated with a greater decrease in cocaine cue-reactivity (β=0.014, t=3.122, p=0.002). Cocaine cue-reactivity within the network as a whole was significantly lower at the 2-month (t 13 =3.23, p=0.007, Hedge’s g=−1.67) and 3-month (t 10 =4.893, p=0.0006, Hedge’s g=2.82) follow-up visits ( Figure 4 ). There was a significant main effect of treatment within the MPFC stimulation site (F 1,73 =5.46,p=0.02), as well as time*treatment interactions within the ACC (F 3,73 =3.03, p=0.04), the left insula (F 3,73 =3.67, p=0.02), and the right insula (F 3,73 =4.00, p=0.01). Reductions in cue-reactivity were largest within the MPFC (2 months, Hedge’s g=−1.52; 3 months, Hedge’s g=−1.77), the bilateral cingulate cortex (3 months, Hedge’s g=−1.64) and the left and right insula (Left. 3 months, Hedge’s g=−1.34; Right, 3 months, Hedge’s g=−1.23) ( Figure 5 ). See supplement for change in cocaine cue-reactivity within the ventral and dorsal striatum, DLPFC and IFG ( Figs S3 – S4 ). Figure 4. Influence of real vs. sham theta burst stimulation over time. Open in a new tab Estimated marginal means across time is plotted with respect to treatment (real TBS: black lines, circles; sham TBS: gray lines, squares). The general linear model assessing change in region-of-interest BOLD signal across the network of regions included a covariate for scalp-to-cortex distance. Across all regions of interest, BOLD signal during cocaine cues was consistently lower in the group receiving real TBS relative to sham. Error bars represent SEM. ACC, anterior cingulate cortex; B, bilateral; DS, dorsal striatum; Ins, insula; L, left; R, right; VS, ventral striatum. Figure 5: Longitudinal change in regional response to cocaine cues. Open in a new tab Longitudinal change in fMRI BOLD signal to cocaine cues. There was a substantial reduction in cocaine cue-reactivity following real (black lines, circles, top left) vs. sham (gray lines, squares) theta burst stimulation within the MPFC (green, stimulation site, top left), the bilateral ACC (salmon, top right), and the left insula (purple, bottom left) and right insula (purple, bottom right) for three months. Generalized linear model statistics for change in each ROI are below each graph. Significant (p<0.05) effects are bolded. Associated effect sizes (Hedge’s g) reflecting the magnitude of difference in BOLD signal during cocaine cues within each region are presented at the bottom middle. Blue bars indicate a decrease in cocaine-cue reactivity, relative to sham, red indicates an increase relative to sham. Error bars represent SEM. ACC, anterior cingulate cortex; B, bilateral; L, left; MPFC, medial prefrontal cortex; R, right; cTBS, continuous theta burst stimulation. Relationship between change in brain reactivity to cocaine cues and behavioral variables: Baseline cocaine craving was a significantly related to change in cocaine cue reactivity throughout the entire network of ROIs (F 1,408 =7.63, p=0.006). Greater baseline cocaine craving scores were associated with a greater decrease in cocaine cue-reactivity within the network of ROIs (β=0.007, t=2.762, p=0.006). Baseline anxiety, depression, and impulsivity scores, however, were not significant covariates. Stimulation intensity (110% of rMT) was also not a significant covariate (See supplement for expanded statistics). Cocaine cue-reactivity: Exploratory, whole-brain approach. While not surviving stringent, multiple comparisons correction, there was a more pronounced decrease in whole-brain cocaine cue-reactivity following real, relative to sham cTBS. Specifically, cocaine cue-reactivity was consistently reduced at the 2- and 3-month follow up within the thalamus, middle and posterior cingulate cortices, and the orbitofrontal cortex. ( Figure S5 ). Cocaine cue-reactivity: Exploratory, functional connectivity approach. While not statistically significant, there was a relative attenuation of functional connectivity between the stimulation site and striato-limbic regions following real cTBS, relative to sham ( Figure S6 ). TMS electrical field modeling, clinical outcome, and change in cocaine cue-reactivity. As previously reported ( 36 ), there was a high degree of individual variability in realized TMS electrical field strength at the cortical target ( Figure 6 ). There was no obvious relationship between TMS electrical field strength, clinical outcome, and change in cue-reactivity ( Figure 6 ). Figure 6: Relationship between TMS electrical field strength, clinical outcome, and change in cocaine cue-reactivity. Open in a new tab Individual TMS electrical fields are organized by strongest (top row) to lowest (bottom row) voltage/meter within the top 99.99 percentile of tetrahedra within each model. Positive (retained at follow up and remained abstinent) and negative (lost to follow up, relapsed) clinical outcome are denoted in green and red, respectively. Change in cocaine cue-reactivity from baseline for each individual are plotted for the entire ROI network, and for each ROI independently. Change scores were computed using the most recent available fMRI BOLD data. Darker blue and darker red colors represent greater increases of decreases in BOLD signal, respectively. We did not observe any obvious relationship between these variables. Discussion There is urgent need to develop effective treatments for individuals with cocaine use disorder (CUD). TMS is a neural-circuit specific, therapeutic tool that may show promise in modulating brain circuits associated with relapse in CUD. A limited number of studies, however, have explored the therapeutic effects of TMS in treating CUD. Notably, these studies have all delivered stimulation to the left dorsolateral prefrontal cortex (DLPFC) ( 37 – 43 ). Convergent evidence suggests that the MPFC may be a fruitful, transdiagnostic target for substance use disorders ( 19 , 20 ). Our group has recently demonstrated that a single session of frontal pole cTBS reduces brain response to cocaine cues ( 16 , 18 ), and that 10 sessions of frontal pole cTBS enhances treatment outcomes in AUD ( 21 ). To extend this work, we present the first target-engagement study including a longitudinal, randomized, double-blind evaluation of the impact of 10 sessions of left frontal pole cTBS in a population of treatment-seeking Veterans with cocaine dependence. The primary conclusions are that 10 days of left frontal pole TBS is feasible and tolerable among individuals with cocaine dependence and an effective approach to reduce brain response to cocaine cues within a network of brain regions related to relapse. Moving forward, these early target-engagement data suggest that future trials powered for clinical efficacy are warranted. Feasibility and Tolerability. There is growing interest in developing high-potency forms of brain stimulation that can be delivered quickly. We have now demonstrated that this high-density, continuous protocol is well-tolerated among individuals with Alcohol Use Disorder ( 21 ) and cocaine dependence. A recent study of 240 individuals from our laboratory demonstrated that patient self-reported pain during cTBS over the frontal pole was not statistically different than DLPFC stimulation ( 32 ). The integrity of our sham condition was sound, with participant guesses regarding the received condition at near-chance levels. There were no significant adverse events within this study related to TMS. Impact on cocaine abstinence. There are no FDA-approved pharmacotherapies available for cocaine dependence. Several groups have recently shown that TMS, delivered to the DLPFC reduces cocaine craving and relapse ( 37 – 43 ). Evidence from neuroimaging research leveraging cocaine cue reactivity ( 44 ) and lesion network mapping ( 20 ) have consistently pointed to the MPFC as a fruitful neuromodulation target for substance use disorders. While the results presented within this manuscript did not reach statistical significance, we observe a pattern of prolonged abstinence rates following real, relative to sham TBS. Notably, these outpatient individuals also received program-sponsored housing which was contingent upon total cocaine abstinence, a well-documented tool known to enhance treatment outcomes. The strength of this technique is reflected in the overall cocaine abstinence rates following sham stimulation (~66%) relative to relapse rates following other treatment approaches (~25%) in a similar timeframe ( 2 ). In the context of this already-effective technique, it is perhaps more surprising that real TMS appears to confer additional benefit to treatment outcomes. In other words, it is promising that these results were not masked by a relative floor effect. Taken together, these results suggest that TMS is an effective tool that can be combined with housing-based recovery programs. fMRI BOLD signal magnitude in response to cocaine cues. Elevated brain response to cocaine cues within the MPFC, cingulate, insula, and striatum has been associated with relapse ( 3 , 4 ). Here, we aimed to reduce cocaine cue-reactivity within these fronto-striato-limbic circuits. We demonstrate that cocaine cue-reactivity is reduced within the MPFC stimulation site following real cTBS. There was also a time*treatment interaction within the ACC and anterior insula, wherein cocaine cue-reactivity was lower following real, relative to sham, cTBS. This work builds upon existing evidence from our laboratory wherein 1 ( 18 ) or 6 sessions ( 17 ) of cTBS delivered to the same target reduced drug cue-reactivity within the same fronto-striato-limbic regions. Here, we demonstrate that this TMS protocol reduced brain reactivity to cocaine cues suggesting this is a promising approach to reduce relapse ( 3 – 5 ). These results are largely consistent with those reported in our recently published trial among patients with AUD, which used the same TMS protocol ( 21 ). Together, these results support the use of left frontal pole TMS as a strategy to reduce brain response to cocaine cues. Cocaine craving: We did not observe a change in cocaine craving following TMS. Within this preliminary trial, we collected self-reported craving data using the Cocaine Craving Questionnaire-Brief ( 25 , 26 ). The field’s understanding of craving has rapidly evolved to recognize drug craving as a dynamic process wherein features of peak craving intensity, frequency of cravings, duration of craving episodes influence relapse, and compulsion or habitual drive to use cocaine ( 45 ). These variables may not be adequately captured within one questionnaire. We did, however, observe that greater baseline craving scores were associated with a greater reduction in cocaine cue-reactivity, indicating that cocaine craving may be an important variable to consider in TMS trials for CUD. Future work may consider using measures of cocaine craving which capture the temporal dynamics and magnitude of cocaine craving. Limitations and Future Directions. There are limitations of the current study that should be considered. As with many longitudinal studies in substance use disorder there was attrition throughout the study that resulted in data loss and reduced our ability to detect direct relationships between clinical behavior and brain reactivity. Odd’s ratios may be more sensitive to relatively small differences in proportions when sample sizes are small ( 46 ). We encourage the reader to consider these data as qualitatively positive trends and improvements in abstinence rates. Well-powered, future work is warranted to evaluate the precise magnitude of effect of frontal pole TBS on reducing relapse. Additionally, as is common among studies recruiting from the Veteran’s Affairs hospital, we enrolled relatively few women. Given emerging sex differences in TMS clinical outcomes ( 47 ), we encourage the field to implement strategies that recruit balanced samples of males and females. Lastly, there is need for future discovery regarding the impact of brain state on outcomes in CUD. In this study, participants were exposed to cues and told to think about the negative aspects of drug use. There are, however, other approaches, such as combining TMS with cognitive regulation of drug use ( 48 ). Conclusions. 10 days of real cTBS delivered to the frontal pole of the medial prefrontal cortex led to sustained reductions in cocaine cue-reactivity within brain regions associated with relapse. While not reaching statistical significance, a greater portion of those who received real TBS remained abstinent, relative to sham – providing a strong foundation for a future trial adequately powered for clinical efficacy. This was the first randomized, double-blind, sham-controlled clinical trial to deliver TMS to the frontal pole of the MPFC in individuals with cocaine dependence. Cocaine cue-reactivity was reduced within the medial prefrontal cortex, ACC, and the anterior insula at the 3 months follow-up visit after real, but not sham, cTBS. Given the absence of FDA-approved pharmacotherapy for CUD, cTBS to the MPFC is a promising neural circuit-based intervention that warrants further exploration. The observed decrease in cocaine cue reactivity underscores the potential of cTBS as a powerful tool in reducing craving and cocaine use, providing a new avenue for intervention in the challenging landscape of cocaine use disorder. Supplementary Material 1 NIHMS2065715-supplement-1.pdf (1.7MB, pdf) Support: This work was supported by NIH grant R21DA041610. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Financial Disclosures: Daniel M. McCalley has a financial interest in Nudge Neuromodulation, a low-intensity focused ultrasound company. Nudge Neuromodulation equipment or resources were not used in this experiment. Colleen A. Hanlon has a financial interest in BrainsWay, a TMS device manufacturer. BrainsWay equipment was not used in this experiment. 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