Cocaine use disorder (CUD) remains a significant public health problem given that many patients fail to respond to existing therapies (Dutra et al., 2008). Treatment refractory CUD may be explained, in part, by abnormal neurocircuitry. The medial prefrontal cortex (mPFC) and dorsal anterior cingulate cortex (dACC) have demonstrated altered functioning in CUD (Hanlon et al., 2016). Compared to controls, participants with CUD show consistent changes to the mPFC/dACC, including hypoactivation during cognitive and attentional tasks (Bolla et al., 2003; Kaufman et al., 2003; Kubler et al., 2005), hyperactivation during drug cue exposure (Garavan et al., 2000; Grant et al., 1996), and lower grey matter volumes (Ersche et al., 2011; Matochik et al., 2003).
Imaging studies also show that these alterations in the mPFC/dACC are associated with an impaired response to treatment. Hypoactivation of the mPFC/dACC region of the fronto-cingular network during the Color-Word Stroop task, a measure of cognitive interference and response inhibition, is associated with faster relapse rates (Brewer et al., 2008). Greater activation of the fronto-cingular network during incongruent stimuli on the Stroop task is also associated with poorer outcomes in CUD participants receiving cognitive behavioral therapy (CBT) (Worhunsky et al., 2013). When using the Drug Stroop task, better performance was associated with a longer duration of cocaine abstinence during CBT (DeVito et al., 2018). Thus, processing deficits across these brain regions likely contribute to the limited success of behavioral interventions for CUD, resulting in high dropout rates and a lack of treatment response.
Our goal is to target the mPFC/dACC with repetitive transcranial magnetic stimulation (rTMS) to investigate its impact on neurocognitive function and response to treatment in CUD. We will use the H7-coil, which targets the mPFC/dACC and has been FDA-cleared as a treatment for obsessive-compulsive disorder (Carmi et al., 2019). Previous work by our group showed that high-frequency (10 Hz) rTMS with the H7-coil led to a significant reduction in choices for cocaine in the human laboratory setting (Martinez et al., 2018). Additional studies using rTMS for CUD have targeted the dorsolateral or ventromedial PFC and demonstrated reduction in craving and drug cue reactivity (Ekhtiari et al., 2019; Antonelli et al., 2021; Kearney-Ramos et al., 2018; Kearney-Ramos et al., 2019).
Despite these promising findings, sham-controlled clinical trials investigating the effect of rTMS on abstinence and cocaine consumption are lacking. In this trial, our goal is to investigate rTMS as a potential treatment for CUD. Treatment-seeking volunteers with moderate/severe CUD will undergo three weeks (15 daily sessions) of outpatient, randomized, double-blinded, sham-controlled, high-frequency (10 Hz) rTMS to the mPFC/dACC with the H7-coil followed by standardized CBT. We will evaluate feasibility, safety, and the effect of rTMS on the mPFC/dACC using functional magnetic resonance imaging (fMRI) and clinical outcome measures (cocaine use). This outcome data will inform a larger clinical trial to evaluate rTMS as an augmentation for CBT outcomes in moderate/severe CUD and further explore the associated neural mechanisms of rTMS in this clinical population.
