Indirect frontocingulate structural connectivity predicts clinical response to accelerated rTMS in major depressive disorder

Abstract

Background: Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for major depressive disorder (MDD), but its clinical efficacy remains rather modest. One reason for this could be that the propagation of rTMS effects via structural connections from the stimulated area to deeper brain structures (such as the cingulate cortices) is suboptimal. Methods: We investigated whether structural connectivity-derived from diffusion MRI data-could serve as a biomarker to predict treatment response. We hypothesized that stronger structural connections between the patient-specific stimulation position in the left dorsolateral prefrontal cortex (dlPFC) and the cingulate cortices would predict better clinical outcomes. We applied accelerated intermittent theta burst stimulation (aiTBS) to the left dlPFC in 40 patients with MDD. We correlated baseline structural connectivity, quantified using various metrics (fractional anisotropy, mean diffusivity, tract density, tract volume and number of tracts), with changes in depression severity scores after aiTBS. Results: Exploratory results (p < 0.05) showed that structural connectivity between the patient-specific stimulation site and the caudal and posterior parts of the cingulate cortex had predictive potential for clinical response to aiTBS. Limitations: We used the diffusion tensor to perform tractography. A main limitation was that multiple fibre directions within voxels could not be resolved, which might have led to missing connections in some patients. Conclusion: Stronger structural frontocingular connections may be of essence to optimally benefit from left dlPFC rTMS treatment in MDD. Even though the results are promising, further investigation with larger numbers of patients, more advanced tractography algorithms and classic daily rTMS treatment paradigms is warranted.

Cortical Thickness in the Right Anterior Cingulate Cortex Relates to Clinical Response to Left Prefrontal Accelerated Intermittent Theta Burst Stimulation: An Exploratory Study

“…Second, longitudinal changes in cortical thickness between T1 and T2 were significantly correlated with the direct clinical responses and these changes in thickness showed predictive potential for the delayed clinical effects, measured at T4. The caudal part of the cingulate cortex has previously been linked to the response to MDD treatment ( 11 , 31 , 32 ). Interestingly, using the same dataset, it was shown that indirect structural connections (derived from diffusion weighted MRI data) between the stimulation site in the left DLPFC and the right cACC was significantly correlated with the direct clinical responses ( 11 ).…”

“…The high interindividual heterogeneity of clinical effectiveness underscores the pressing need for biomarkers to predict treatment outcome. Previous studies showed promising results using measures derived from resting‐state functional MRI (rs‐fMRI) ( 8 , 9 , 10 ) or diffusion weighted MRI (dMRI) ( 11 ). However, these biomarkers require extensive imaging protocols that are not always available in clinical settings, need specialized data processing, and are costly.…”

“…For example, greater functional activity was found in the rostral ACC in meditators compared to healthy controls, which might reflect stronger processing of distracting events ( 17 ). Functional connectivity between the subgenual part of the ACC and the stimulation site in the left DLPFC ( 8 , 18 ) and indirect structural connections between the DLPFC and the caudal part of the ACC ( 11 ) were previously related to the effectiveness of rTMS treatment for depression.…”

Adverse events of repetitive transcranial magnetic stimulation in older adults with depression, a systematic review of the literature

“…Finally, stimulation intensity, location of stimulation, position of stimulation and number of sessions and stimuli potentially influence the occurrence of (serious) AE. In addition, patients specific factors like age, medication use, and brain morphology (e.g., functional connectivity and neurodegeneration) will also influence the occurrence of (serious) AE 35 . Consistent reports on AE are needed to describe such potential relationships.…”

“…In addition, patients specific factors like age, medication use, and brain morphology (e.g., functional connectivity and neurodegeneration) will also influence the occurrence of (serious) AE. 35 In a study population with 472 adults receiving HF-rTMS at the DLPFC, 9.7% reported headache, 9.3% experienced scalp discomfort, 1.9% facial twitching, 1.5% tears in their eyes, 1.3% local erythema, 2.5% drowsiness, and 4.7% reported other AE. These percentages were lower in the study population of 109 adults receiving LF-rTMS at the DLPFC of the meta-analysis of Slotema and colleagues.…”