Influence of prefrontal target region on the efficacy of repetitive transcranial magnetic stimulation in patients with medication-resistant depression: a [18F]-fluorodeoxyglucose PET and MRI study

Abstract

It is currently unknown whether the antidepressant effect of repetitive transcranial magnetic stimulation (rTMS) depends on specific characteristics of the stimulated frontal area, such as metabolic changes. We investigated the effect of high-frequency rTMS, administered over the most hypometabolic prefrontal area in depressed patients in a two-site, double-blind, randomized placebo-controlled add-on study. Forty-eight patients with medication-resistant major depression underwent magnetic resonance imaging and [(18)F]-fluorodeoxyglucose positron emission tomography (PET) in order to determine a target area for rTMS. After randomization to PET-guided (n = 16), standard (n = 18), or sham rTMS (n = 14) conditions, the patients received 10 sessions of 10-Hz rTMS (1600 pulses/session) at 90% motor threshold. Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) scores did not differ between PET-guided, standard and sham groups at 2-wk end-point. Exploratory comparison of left PET-guided (n = 9), right PET-guided, standard, and sham rTMS revealed significant effects. The highest improvement in MADRS scores was observed with left PET-guided (60 + or - 31%), significantly superior to sham (30 + or - 37%, p = 0.01) and right-guided (31 + or - 33%, p = 0.02) stimulation. Comparison between left PET-guided and standard rTMS (49 + or - 28%) was not significant (p = 0.12). Comparison between stimulation over dorsolateral prefrontal cortex (BA 9-46), stimulation of other areas, and sham rTMS was statistically significant. Stimulation over BA 9-46 region (n = 15) was superior to sham rTMS (p = 0.02). The results do not support the general hypothesis of increased antidepressant effects of high-frequency rTMS with prefrontal hypometabolism-related PET guidance. Nonetheless, whether metabolism and anatomy characteristics of left frontal area underneath the coil might account for an increase or speeding up of rTMS effects needs further investigation.

Efficacy of Transcranial Magnetic Stimulation Targets for Depression Is Related to Intrinsic Functional Connectivity with the Subgenual Cingulate

“…2) Correlation between functional connectivity and clinical efficacy as predicted by a previously reported equation (36): HDRS drop = −.84 + (X * −0.022) + (Y * 0.012). 3) Correlation between functional connectivity and clinical efficacy as previously reported in individual patients (42). Motivated by the results of the above analyses, coordinates were identified in the left DLPFC that could potentially serve as optimized TMS targets by computing seed-based functional connectivity with our a priori ROI in the subgenual and our effective-ineffective map.…”

“…To test this, we utilized a published table of left DLPFC stimulation coordinates and changes in the Montgomery & Asberg Depression Rating Scale for 27 individual patients receiving therapeutic TMS for depression (42). For each patient, we plotted their antidepressant response versus the resting state correlation between their specific stimulation site and the subgenual cingulate (Fig S3B in the Supplement).…”

“…Alternative approaches to DLPFC target identification have been examined including standardized EEG electrode positions (40), a variety of anatomical MR coordinates focused around Brodmann areas 9 and 46 (35, 36, 41), and individualized hypometabolic foci (42–44) (Table 1B). These alternative targeting strategies have not led to substantial clinical improvements beyond the 5 cm approach, however data from these studies suggests that some DLPFC stimulation sites are more effective than others (12, 35, 36, 42). Unfortunately, it remains unclear why some sites are more effective, making it difficult to capitalize on this information to optimize target selection or clinical effect.…”

Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS)

“…DTI, a noninvasive measure of anatomical connectivity, has been shown to relate well to both functional connectivity measured with resting state fcMRI (Koch, Norris et al 2002; De Luca, Beckmann et al 2006; Lowe, Beall et al 2008; Skudlarski, Jagannathan et al 2008; van den Heuvel, Mandl et al 2008; Greicius, Supekar et al 2009; Honey, Sporns et al 2009; van den Heuvel, Mandl et al 2009; Zhang, Snyder et al 2010) and connectivity as assessed with TMS (Wahl, Lauterbach-Soon et al 2007; Voineskos, Farzan et al 2010). Some of the strongest evidence comes from studies relating individual differences in transcallosal connectivity measured with DTI to that measured with resting state fcMRI (Lowe, Beall et al 2008), paired pulse TMS (Wahl, Lauterbach-Soon et al 2007; Wahl, Hubers et al 2011), and TMS-EEG (Voineskos, Farzan et al 2010).…”

Anatomically based targeting of prefrontal cortex for rTMS

“…using the International 10–20 EEG system(2)(3). This may lead to suboptimal clinical responses when compared to individualized targeting techniques based on structural brain scanning(4–6). Research studies investigating the mechanism of action of TMS and those utilizing it as a tool usually require the type of precision not offered by probabilistic targeting methods.…”