Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity
Highlights
► There is significant individual variability in the connectivity of the left DLPFC. ► Individual differences in DLPFC connectivity are reproducible across days. ► Individualized TMS targets appear superior to population-based targets. ► Seed maps improve signal/noise compared to small seed regions. ► Individualized targeting is likely of greater benefit with more focal stimulation.
Introduction
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is showing utility in the treatment of a variety of neurological and psychiatric disorders (Burt et al., 2002, Fregni and Pascual-Leone, 2007, Hallett, 2007). Its most common use involves high-frequency stimulation to the left dorsal lateral prefrontal cortex (DLPFC) for the treatment of depression (George et al., 1995, O'Reardon et al., 2007, Padberg and George, 2009, Pascual-Leone et al., 1996). In the US, the Neuronetics® device and Neurostar protocol are approved by the Food and Drug Administration for some patients with medication-resistant depression. However, the clinical utility of rTMS remains limited by large heterogeneity in clinical response.
One factor known to contribute to this response heterogeneity is differences in the site of stimulation in the left DLPFC (Ahdab et al., 2010, Fitzgerald et al., 2009, Herbsman et al., 2009, Herwig et al., 2001, Padberg and George, 2009). The targeting technique routinely employed in clinical practice, and followed by the FDA approved protocol, is to center the TMS coil at a point 5 cm anterior to the motor cortex measured along the curvature of the scalp. This approach identifies different stimulation sites in different subjects (Ahdab et al., 2010, Herwig et al., 2001) and some sites appear to be more effective than others at producing an antidepressant response (Fitzgerald et al., 2009, Herbsman et al., 2009, Padberg and George, 2009, Paillère Martinot et al., 2010). In an effort to understand why some sites are more effective, we recently used intrinsic (resting state) fMRI to identify differences in functional connectivity between effective and less effective DLPFC stimulation sites at the population level (Fox et al., 2012a). Significant differences in connectivity were seen in a variety of cortical and limbic regions including the subgenual cingulate, a region repeatedly implicated in antidepressant response to a variety of treatment modalities (Drevets et al., 2008, Mayberg, 2009, Mayberg et al., 2005). Specifically, left DLPFC sites which when targeted with TMS leads to greater antidepressant effects, showed a stronger negative correlation (anticorrelation) with the subgenual. Based on these findings, we proposed a connectivity-based targeting strategy for TMS and used this technique to identify theoretically optimal TMS target coordinates in the left DLPFC at the population level (Fox et al., 2012a).
An important advantage of this connectivity-based targeting strategy is that it might be scaled from the population level down to the level of single subjects to tailor treatment to individual patients. The DLPFC varies greatly between individuals on a histological basis (Rajkowska and Goldman-Rakic, 1995) thus the population-average TMS coordinates might be suboptimal for many patients. However individualized targeting will be associated with an inherent worsening of signal to noise that could overwhelm any benefit of accounting for individual differences. For example, targeting a population-average focus of hypometabolism in the left DLPFC with TMS appears superior to the standard 5 cm technique (Fitzgerald et al., 2009), however three separate studies aiming to target individualized foci of hypometabolism failed to provide clinical benefit (Garcia-Toro et al., 2006, Herwig et al., 2003a, Paillère Martinot et al., 2010). In fMRI, the subgenual is a region with poor signal to noise ratio (Ojemann et al., 1997) and intrinsic anticorrelations may be less reproducible than positive correlations (Shehzad et al., 2009). It therefore remains unclear if connectivity-based targeting can identify individualized TMS sites in the DLPFC that are sufficiently robust and reproducible to potentially be used in the treatment of depression.
In the current article we show that individual differences in DLPFC connectivity are large, reproducible across scanning sessions, and can be translated into individualized TMS targets on the cortical surface. Further, we identify factors likely to improve individualized targeting such as the use of seed maps and the focality of stimulation.
Section snippets
Subjects and data collection
This study utilized three independent datasets, each of which was used for a particular set of analyses (Fig. 1). Datasets 1 and 2 have been used in prior published articles (Fox et al., 2012a, Van Dijk et al., 2012, Yeo et al., 2011) and were not collected specifically for the present paper. However these prior articles investigated different experimental questions than those investigated in the current article and no part of the present report overlaps with prior published findings. Dataset 3
Results
Functional connectivity was computed with three seed regions/seed maps to identify candidate TMS targets in the left DLPFC (Fig. 2). Regardless of whether one used the small subgenual seed region (Fig. 2A), the full subgenual-based seed map (Fig. 2B), or the efficacy-based seed map (Fig. 2C), a clear anticorrelated area was identified at the group level (black circles). Peak MNI coordinates for these anticorrelations for the three group maps are (− 42, 38, 34), (− 42, 44, 26), and (− 38, 44, 26)
Discussion
There are several novel results in the present paper important for successful individualized targeting of TMS to the DLPFC based on functional connectivity. First, individual differences in DLPFC connectivity are large and reproducible across sessions. Second, TMS targets can be selected based on these individual differences and have the potential to be clinically superior to targets selected on the basis of a group map. Finally, individualized targeting might be improved through the use of a
Conclusions
There is significant individual variability in the connectivity of the left DLPFC. This variability is stable across scanning sessions and can be used to generate individualized and reproducible TMS targets. Seed maps demonstrate more stability than a small subgenual seed region and may be an effective technique for improving signal to noise in single subject functional connectivity analyses. Finally, the more focal the stimulation field, the greater the benefit likely to come from
Acknowledgments
We thank the Brain Genomics Superstruct Project for contributing data and David Alsop for assistance with MRI acquisition and sequence optimization for the depression patients. MDF was supported by NIH grant R25NS065743 and HL by NIH grant K25NS069805. APL serves on the scientific advisory boards for Nexstim, Neuronix, Starlab Neuroscience, Neuroelectrics, Neosync, and Novavision, and is listed as inventor in issued patents and patent applications on the real-time integration of transcranial
References (64)
- et al.
Comparison of “standard” and “navigated” procedures of TMS coil positioning over motor, premotor and prefrontal targets in patients with chronic pain and depression
Neurophysiol. Clin.
(2010) - et al.
Test-retest reliability of resting-state connectivity network characteristics using fMRI and graph theoretical measures
Neuroimage
(2012) - et al.
Defining functional areas in individual human brains using resting functional connectivity MRI
Neuroimage
(2008) - et al.
Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism
Eur. Neuropsychopharmacol.
(2002) - et al.
Efficacy of Transcranial Magnetic Stimulation Targets for Depression Is Related to Intrinsic Functional Connectivity with the Subgenual Cingulate
Biol. Psychiatry
(2012) - et al.
Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS)
Neuroimage
(2012) - et al.
High (20-Hz) and low (1-Hz) frequency transcranial magnetic stimulation as adjuvant treatment in medication-resistant depression
Psychiatry Res.
(2006) Transcranial magnetic stimulation: a primer
Neuron
(2007)- et al.
More lateral and anterior prefrontal coil location is associated with better repetitive transcranial magnetic stimulation antidepressant response
Biol. Psychiatry
(2009) - et al.
Transcranial magnetic stimulation in therapy studies: examination of the reliability of “standard” coil positioning by neuronavigation
Biol. Psychiatry
(2001)