Cortical and subcortical connections change after repetitive transcranial magnetic stimulation therapy in cocaine use disorder and predict clinical outcome

Abstract

Cocaine use disorder (CUD) is a worldwide public health condition which is suggested to induce pathological changes in macro- and microstructure. Treatments with psychosocial and pharmacological approaches achieve only low to moderate effects on dealing with cocaine clinical symptomatology. Novel approaches such as repetitive transcranial magnetic stimulation (rTMS) have gained attention to induce a reduction in CUD symptoms, yet its mechanisms remain partially understood. Here, we sought to elucidate whether rTMS induces changes on white matter (WM) microstructure in frontostriatal circuits after two weeks of therapy in patients with CUD, and to test whether baseline WM microstructure of the same circuits has an effect on clinical improvement. This study consisted of a 2-week, parallel group, double-blind, randomized controlled clinical trial (acute phase) (sham [n = 23] and active [n = 27]), in which patients received two daily sessions of rTMS on the left dorsolateral prefrontal cortex (lDLPFC) as an add-on treatment. We acquired T1-weighted and HARDI-DWI 2-shell sequences at baseline and at two weeks. To elucidate the effects from active rTMS on frontostriatal WM tracts, we extracted NODDI metrics and performed a linear mixed model. We further evaluated the relationship between clinical outcomes in craving and impulsivity and the baseline white matter microstructure. After 2 weeks, active rTMS showed a significant increase in neurite density (ICVF or the density of axons and dendrites) compared to sham rTMS in WM tracts connecting left DLPFC with left (B = 0.038, d = -0.278) and right vmPFC (B = 0.034, d = -0.112). Similarly, rTMS showed reduction in orientation dispersion (OD or axon organization) in WM tracts connecting left DLPFC with left caudate nucleus (B = 0.009, d = -0.087), left thalamus (B = 0.006, d = -0.489) and left vmPFC (B = 0.027, d = 0.024). Results also show a greater reduction in craving VAS after 2 weeks rTMS when baseline ICVF was low in WM tracts connecting left caudate nucleus with substantia nigra (B = 22.61, d = 0.729), left pallidum (B = 21.13, d = 0.738), and those connecting left thalamus with substantia nigra (B = 16.30, d = 0.649) and left pallidum (B = 21.92, d = 0.723). Our results suggest that rTMS induced white matter microstructural changes between fronto-striato-thalamic regions after 2 weeks. rTMS-induced microstructural changes may depend on the baseline integrity of the connections between the striatum, thalamus, and the substantia nigra. Connections that predicted clinical improvement in CUD. The current results support the efficacy of rTMS as a therapeutic tool in the treatment of CUD. However, the individual clinical improvement may rely on each patient state of structural connections integrity. Keywords: Cocaine use disorder; Imaging; Transcranial magnetic stimulation; Diffusion MRI; NODDI

Lower cortical thickness and increased brain aging in adults with cocaine use disorder

“…While the relatively large sample size (74 patients with CUD and 62 HC) enhances the generalizability of our findings, the current sample is biased toward patients with CUD with less severe sequelae, as individuals with stronger craving and more cognitive deficits were less likely to participate in an MRI scan or continuation in the study's clinical and cognitive assessments. Additionally, the original cohort excluded subjects older than 50 years (31). Therefore, our results are rather conservative estimates, as age differences might be larger at older ages, which needs further investigation.…”

“…A detailed description of the evaluated cross-sectional Mexican Substance Use Disorder neuroimaging dataset (SUDMEX_CONN) can be found in: (9,31,32). Briefly, 145 participants (patients with CUD and HC between 18 and 50 years of age) were enrolled in the study between March 2015 and October 2016.…”

The Mexican dataset of a repetitive transcranial magnetic stimulation clinical trial on cocaine use disorder patients: SUDMEX TMS

“…A participants checklist with the specific MRI sequences acquired can be found in supplementary material. To date, the present dataset has been used to examine the short and long-term clinical benefits of rTMS and their impact on functional connectivity 10 , to identify cognitive deficits of CUD participants by machine learning algorithms 11 , to improve diffusion MRI segmentation methods using deep learning 12 , to predict clinical outcomes using microstructural changes 13 , and to identify a generalizable functional connectivity signature characterizes brain dysfunction in cocaine use disorder 14 . Altogether, this dataset could serve for the study of the longitudinal impact of rTMS as a promising add-on treatment for CUD, as well as to test new neuroimaging algorithms and analysis techniques.…”

“…Its content focuses on the behavior of depression, with vegetative, cognitive, and anxiety symptoms having the greatest weight in the total calculation of the scale. The cutoff points to define severity are no depression (0-7); mild depression (8)(9)(10)(11)(12)(13)(14)(15)(16); moderate depression (17)(18)(19)(20)(21)(22)(23); and severe depression (≥24) 40 .…”

A generalizable functional connectivity signature characterizes brain dysfunction and links to rTMS treatment response in cocaine use disorder

“…In the active rTMS treatment phase, the stimulation with 5000 pulses at 5 Hz per-day was delivered to the left dorsolateral prefrontal cortex. For the patients in active rTMS treatment arm, a relevance vector machine model 32 was then trained with these selected FCs to predict changes in the visual analog scale (VAS) score which is designed to evaluate the participants' craving of cocaine 33 . To determine the relationship between the discriminative FC features and treatment response to rTMS, we used the identified connectivity signature as a mask to select the FCs of baseline CUD patients who were assigned rTMS treatment in the clinical trial cohort (SUDMEX-TMS dataset).…”