Low-frequency parietal repetitive transcranial magnetic stimulation reduces fear and anxiety

Nicholas L Balderston, Emily M Beydler, Madeline Goodwin, Zhi-De Deng, Thomas Radman, Bruce Luber, Sarah H Lisanby, Monique Ernst, Christian Grillon, Nicholas L Balderston, Emily M Beydler, Madeline Goodwin, Zhi-De Deng, Thomas Radman, Bruce Luber, Sarah H Lisanby, Monique Ernst, Christian Grillon

Abstract

Anxiety disorders are the most prevalent mental disorders, with few effective neuropharmacological treatments, making treatments development critical. While noninvasive neuromodulation can successfully treat depression, few treatment targets have been identified specifically for anxiety disorders. Previously, we showed that shock threat increases excitability and connectivity of the intraparietal sulcus (IPS). Here we tested the hypothesis that inhibitory repetitive transcranial magnetic stimulation (rTMS) targeting this region would reduce induced anxiety. Subjects were exposed to neutral, predictable, and unpredictable shock threat, while receiving double-blinded, 1 Hz active or sham IPS rTMS. We used global brain connectivity and electric-field modelling to define the single-subject targets. We assessed subjective anxiety with online ratings and physiological arousal with the startle reflex. Startle stimuli (103 dB white noise) probed fear and anxiety during the predictable (fear-potentiated startle, FPS) and unpredictable (anxiety-potentiated startle, APS) conditions. Active rTMS reduced both FPS and APS relative to both the sham and no stimulation conditions. However, the online anxiety ratings showed no difference between the stimulation conditions. These results were not dependent on the laterality of the stimulation, or the subjects' perception of the stimulation (i.e. active vs. sham). Results suggest that reducing IPS excitability during shock threat is sufficient to reduce physiological arousal related to both fear and anxiety, and are consistent with our previous research showing hyperexcitability in this region during threat. By extension, these results suggest that 1 Hz parietal stimulation may be an effective treatment for clinical anxiety, warranting future work in anxiety patients.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1. Design Schematic and overall results.
Fig. 1. Design Schematic and overall results.
a Schematic of the neutral predictable unpredictable (NPU) threat task with online 1 Hz repetitive transcranial magnetic stimulation (rTMS). Subjects were exposed to neutral (N), predictable (P), and unpredictable (U) conditions. During the entire run subjects receive 1 Hz active rTMS, sham rTMS, or no TMS (tones). Startle probes and shocks were embedded in this 1 Hz train at random intervals during the cue (shape) period or inter trial interval (ITI). b Startle responses during the cue and ITI periods of the NPU task as a function of rTMS type. c Concurrent anxiety ratings collected during the NPU task and sampled during the cue and ITI periods as a function of rTMS type. TMS coil icons represent TMS pulses. Green noise traces represent white noise presentations. Lightning bolts represent shocks. Bars represent mean ± standard error.
Fig. 2. Schematic of targeting and electric-…
Fig. 2. Schematic of targeting and electric- (e) field modelling methods.
a 10 mm spheres drawn around peak global brain connectivity coordinates from Balderston et al. ,, overlaid on MNI template Red circles represent search region for individual targets, which were defined at the individual subject level as the voxel within the mask with the highest global brain connectivity. b Representation of e-field modelling approach used in the current analysis. Multiple e-field models corresponding to equally spaced coil orientations were conducted. The coil orientation that yielded the e-field model with the maximum value at the target was used during the TMS session.
Fig. 3. Fear and anxiety-potentiated startle results.
Fig. 3. Fear and anxiety-potentiated startle results.
a Fear and anxiety-potentiated startle (FPS and APS, respectively) as a function of repetitive transcranial magnetic stimulation (rTMS) type. b Potentiated startle (average of FPS and APS) as a function of rTMS type. Active 1 Hz rTMS to the parietal cortex significantly reduces potentiated startle compared to both sham and no TMS conditions. Bars represent mean ± standard error. *p > 0.05.

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