In this study, 30 patients with PTSD were randomly assigned to receive treatment with 10 daily sessions of either 20 Hz rTMS of right DLPFC (“right rTMS”), 20 Hz rTMS of left DLPFC (“left rTMS”), or sham stimulation. Our results demonstrate that active stimulation of the right and left DLPFC were both effective in the relief of core PTSD symptoms (hyperarousal, vigilance, intrusive thoughts, emotional numbness, withdrawal, etc) at days 5 and 10 as determined by scores on the PTSD Checklist and Treatment Outcome PTSD Scale. Interestingly, right rTMS was associated with a greater improvement in core PTSD symptoms (ie, larger reduction in PTSD Checklist and Treatment Outcome PTSD Scale scores) when compared to left rTMS. On the other hand, left rTMS resulted in a significant improvement with respect to symptoms of depression (ie, significant reduction in Hamilton Depression Rating Scale scores) at days 5 and 10 whereas changes in symptoms of depression were not significant for right rTMS. Interestingly, right rTMS generated a significant improvement in the measure of anxiety (Hamilton Anxiety Rating Scale) at days 5 and 10 while left rTMS did not. Finally, with respect to the measures of cognitive performance (Stroop Test, Digit Span Test, Wisconsin Card Sorting Test, and Raven Colored Progressive Matrices), right and left rTMS were both associated with improvements in neuropsychological performance, although these results were not statistically significant (see ). Unexpectedly, there was a significant improvement in verbal fluency—as indexed by Controlled Oral Word Association Test (phonemic category—letters F, A, S)—following right rTMS.
Our findings here support the results of Cohen et al,8
which show that 10 Hz rTMS applied to the right DLPFC results in improvements to both core PTSD symptoms and anxiety. Indeed, our study shows that 20 Hz rTMS of right DLPFC has similar effects as previously described for 10 Hz right TMS, namely improvements in core PTSD and anxiety symptoms; because of our longer follow-up period, we were also able to show that these beneficial effects persist for at least 3 months. Furthermore, here we also tested the efficacy of left DLPFC stimulation in PTSD and showed that, indeed, 20 Hz left rTMS improves symptoms of depression as well as core PTSD symptoms but not symptoms of anxiety. However, because the effect of left rTMS on core PTSD symptoms was significantly smaller in magnitude in comparison to the effects of right rTMS, the improvement seen with 20 Hz rTMS of left DLPF may be secondary to the antidepressant effects of this mode of stimulation.
As demonstrated above, right rTMS has a significant effect in relieving the anxiety dimension of PTSD; this feature may be the primary factor underlying the beneficial effects observed. Longitudinal studies show that anxiety sensitivity and trait anxiety are important components of PTSD onset and vulnerability,39,40
and targeting central nervous system networks involved in the perpetuation of anxiety may be a highly effective approach. In addition, antidepressant SSRIs used in the treatment of PTSD have a common effect in reducing anxiety across the spectrum of anxiety disorders.39
Hence, we propose that high-frequency stimulation of right DLPFC may be an effective approach in the neuromodulatory treatment of PTSD and that it may function by decreasing the anxiety component of this disorder.
A functional magnetic resonance imaging (fMRI) study by Whalley et al41
provides additional evidence for the understanding of a potential mechanism that may explain the demonstrated anxiety-relieving capacity of right rTMS in patients with PTSD. In this imaging study of patients with either PTSD or depression as well as trauma-exposed controls, fMRI results for the contrast between old and new items during an episodic memory retrieval task revealed activation in a predominantly left-sided network of cortical regions, including the left middle temporal, bilateral posterior cingulate, and left prefrontal cortices for all groups. Furthermore, relative to the control and depressed groups, the PTSD group exhibited greater sensitivity to correctly recognized stimuli in the left amygdala/ventral striatum and right occipital cortex, and more specific sensitivity to items encoded in emotional contexts in the right precuneus, left superior frontal gyrus, and bilateral insula. These results are interesting as they demonstrate that, first of all, retrieval of episodic memory is a predominantly left-sided task; thus, it may be speculated that because high-frequency rTMS of right DLPFC is known to inhibit left-sided structures via transcollosal inhibition, excitatory neuromodulation of the right DLPFC with 20 Hz rTMS may, in fact, manifest its PTSD-alleviating effects via inhibition of left-sided memory retrieval networks. In this line, 1 Hz inhibitory rTMS of the left prefrontal cortex might also be an effective approach for the treatment of PTSD. Secondly, the study shows that patients with PTSD may have specific foci of hyperactivity/sensitivity in subcortical nuclei; therefore, prefrontal modulation might inhibit subcortical nuclei that are highly active in PTSD. An alternative suggestion for the mechanism of right rTMS may be based on work by Shin et al,42
which shows hypoactivation of the medial prefrontal cortex in patients with PTSD. In this case, enhancement of activity in right or left prefrontal areas with high-frequency rTMS could be compensating for deficient prefrontal regulation of memory retrieval. These hypotheses are in accordance with proposed neurobiological models for PTSD,43
which hold that the symptoms of flashbacks and intrusive thoughts, among other core PTSD symptoms, may be the result of either hyperactive transmission of fear-relevant information to the amygdala, which is independent of thalamic and hippocampal nuclei, but which relies strongly on visual areas of the inferior temporal cortex, and/or the result of hypoactivation of prefrontal cortex. Indeed, Koenigs et al44
show that ventral medial prefrontal cortex and amygdala are critically involved in the pathogenesis of PTSD.
An important limitation when using a device, especially rTMS, in clinical trials is the sham method. Although we tried to improve the sham method with the electrical stimulator attached to the sham coil and divided the sham group in right and left DLPFC stimulation, it is still possible that our blinding method was not effective, and this is an inherent limitation to rTMS studies.
Therefore, in summary, 10 daily sessions of high-frequency 20 Hz rTMS of right and left DLPFC resulted in improvements in core PTSD symptoms (right > left). Right rTMS also improves anxiety, while left rTMS improves depression. Our results show a long-lasting effect of rTMS—consistent with other applications of rTMS as in neuropathic pain45
and major depression46
—and indicate that both right and left rTMS are safe as they are not associated with cognitive worsening and show only mild adverse effects in patients with PTSD. This study supports the continuation of clinical investigation of brain stimulation for the treatment of PTSD: our results confirm that high-frequency rTMS over the right DLPFC may be the best approach in most patients, yet we suggest that patients with high levels of depression may show greater benefit from high-frequency rTMS applied over left DLPFC.