Background Motor cortex localization and motor threshold determination often guide Transcranial Magnetic Stimulation (TMS) placement and intensity settings for non-motor brain stimulation. However, anatomic variability results in variability of placement and effective intensity. Objective Post-study analysis of the OPT-TMS Study reviewed both the final positioning and the effective intensity of stimulation (accounting for relative prefrontal scalp-cortex distances). Methods We acquired MRI scans of 185 patients in a multi-site trial of left prefrontal TMS for depression. Scans had marked motor sites (localized with TMS) and marked prefrontal sites (5 cm anterior of motor cortex by the “5 cm rule”). Based on a visual determination made before the first treatment, TMS therapy occurred either at the 5 cm location or was adjusted 1 cm forward. Stimulation intensity was 120% of resting motor threshold. Results The “5 cm rule” would have placed stimulation in premotor cortex for 9% of patients, which was reduced to 4% with adjustments. We did not find a statistically significant effect of positioning on remission, but no patients with premotor stimulation achieved remission (0/7). Effective stimulation ranged from 93–156% of motor threshold, and no seizures were induced across this range. Patients experienced remission with effective stimulation intensity ranging from 93–146% of motor threshold, and we did not find a significant effect of effective intensity on remission. Conclusions Our data indicates that individualized positioning methods are useful to reduce variability in placement. Stimulation at 120% of motor threshold, unadjusted for scalp-cortex distances, appears safe for a broad range of patients.

The standard clinical technique for using repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD) is associated with limited efficacy to date. Such limited efficacy may be due to reliance on scalp-based targeting rather than state-of-the-science methods which incorporate fMRI-guided neuronavigation based on a specific model of neurocircuit dysfunction. In this review, we examine such a specific model drawn from regulatory focus theory, which postulates two brain/behavior systems, the promotion and prevention systems, underlying goal pursuit. Individual differences in these systems have been shown to predict vulnerability to MDD as well as to comorbid generalized anxiety disorder (GAD). Activation of an individual's promotion or prevention goals via priming leads to motivational and affective responses modulated by the individual's appraisal of their progress in attaining the goal. In addition, priming promotion vs. prevention goals induces discriminable patterns of brain activation that are sensitive to the effects of depression and anxiety: MDD is associated with promotion system failure, anhedonic/ dysphoric symptoms, and hypoactivation in specific regions in left prefrontal cortex, whereas GAD is associated with prevention system failure, hypervigilant/agitated symptoms, and hyperactivation in right prefrontal cortex (PFC). These left and right PFC locations can be directly targeted in an individualized manner for TMS. Additionally, this individually targeted rTMS can be integrated with cognitive interventions designed to activate the neural circuitry associated with promotion vs. prevention, thus allowing the neuroplasticity induced by the rTMS to benefit the systems likely to be involved in remediating depression. Targeted engagement of cortical systems involved in emotion regulation using individualized fMRI guidance may help increase the efficacy of rTMS in depression.

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Objectives: Despite the growing use of repetitive transcranial magnetic stimulation (rTMS) as a treatment for unipolar depression, its typical effect sizes have been modest and methodological and conceptual challenges remain regarding how to optimize its efficacy. Linking rTMS to a model of the neurocircuitry underlying depression and applying such a model to personalize the site of stimulation may improve the efficacy of rTMS. Recent developments in the psychology and neurobiology of self-regulation offer a conceptual framework for identifying mechanisms of action in rTMS for depression, as well as for developing guidelines for individualized rTMS treatment. We applied this framework to develop a multi-modal treatment for depression by pairing self-system therapy (SST) with simultaneously administered rTMS delivered to an individually targeted region of dorsolateral prefrontal cortex identified via fMRI. Methods: In this proof-of-concept study we examined the acceptability, feasibility, and preliminary efficacy of combining individually fMRI-targeted rTMS with SST. Using the format of a cognitive paired associative stimulation (C-PAS) paradigm, the treatment was administered to five adults with unipolar depression in an open-label trial. Results: The rTMS/SST combination was well-tolerated, feasible, and acceptable. Preliminary evidence of efficacy also was promising. We hypothesized that both treatment modalities were targeting the same neural circuitry through C-PAS, and observed changes in task-based fMRI were consistent with our model. These neural changes were directly related to improvements in depression severity. Conclusions: The new combination treatment represents a promising exemplar for theory-based, individually targeted, multimodal intervention in mood disorders.