Noninvasive brain stimulation with high-frequency and low-intensity repetitive transcranial magnetic stimulation treatment for posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is an incapacitating anxiety disorder characterized by intrusive thoughts, hyperarousal, flashbacks, nightmares, sleep disturbances, emotional numbing, and withdrawal, among other clinical symptoms (as classified by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]).1 Posttraumatic stress disorder has a lifetime prevalence of about 6.8% and may develop in susceptible individuals after exposure to a terrifying ordeal that involved physical harm or the threat of physical harm.2 This severe anxiety disorder affects about 7.7 million people each year and remains challenging to treat, with persistent symptoms leading to considerable social, occupational, and interpersonal dysfunction.3 Although selective serotonin reuptake inhibitors (SSRIs)—among other antidepressants—have resulted in various degrees of improvement in patients with PTSD, there is no definitive pharmacotherapy available to date for the treatment of this debilitating disorder. A review of 37 clinical trials of pharmacotherapies4 found inadequate evidence to determine the value of antidepressants, benzodiazepines, anticonvulsants, α-blockers, and second-generation antipsychotics for the treatment of PTSD. Even so, according to an American Psychiatric Association guideline,5 SSRIs remain the first line of treatment for PTSD. In addition, due to the complex nature of this disorder, individuals with PTSD also seem to benefit from 10 to 12 sessions of cognitive-behavioral therapy, prolonged-exposure therapy, or cognitive-processing therapy. Nevertheless, many individuals respond inadequately to currently available therapies, and research for more effective treatment paradigms is ongoing. Most recently, repetitive transcranial magnetic stimulation (rTMS)—a method of noninvasive neuromodulation—has been emerging as a potentially effective technique in the treatment of PTSD. Indeed, rTMS has already been shown to be highly effective in the treatment of medically refractory depression6 and is now a clinically available form of treatment in certain settings. Similarly, there is evidence that rTMS can also be effective for the treatment of PTSD. In a prior open-label study,7 a single session of low-frequency (0.3 Hz) transcranial magnetic stimulation (TMS) applied to the left and right motor cortex was found to be transiently effective in lowering the core PTSD symptom of avoidance as well as somatization and symptoms of anxiety and depression. Stimulation with 10 Hz rTMS to the right DLPFC was then shown to generate even greater effects with an especially marked improvement in symptoms of re-experiencing and avoidance; these effects lasted for at least 2 weeks after the end of stimulation.8 Furthermore, 2 case studies suggest that stimulation of the right DLPFC with 1 Hz rTMS can, in fact, normalize the right frontal and paralimbic metabolic hyperactivity that is associated with PTSD as measured with positron emission tomography studies.9 In sum, these previous studies suggest that modulation of prefrontal activity, perhaps particularly on the right frontal cortex, with rTMS holds promise as a form of therapy in the treatment of PTSD. Therefore, in this study, we aimed to investigate the clinical efficacy of high-frequency rTMS in the relief of core PTSD symptoms (such as hyperarousal, flashbacks, vigilance, intrusive thoughts, emotional numbness, and withdrawal) as well as PTSD-associated symptoms of anxiety and depression. In contrast to previous studies, here we investigate treatment with 20 Hz rTMS (higher frequency than previous studies), as there is evidence that higher-frequency stimulation may result in more substantial effects. In addition, we compare the effects of treatment of either right or left DLPFC (“left rTMS” and “right rTMS”), since rTMS is known to have side-specific effects. For example, in patients with major depression, rTMS can induce antidepressant effects either by enhancing left DLPFC excitability via high-frequency stimulation or by decreasing right DLPFC excitability via low-frequency stimulation.10 Finally, our study here also offers a longer follow-up period of 3 months’ duration and an inclusion of an extensive battery of neuropsychological assessments. The main goal of this study was to evaluate the effects of high-frequency rTMS of right and left DLPFC, as compared to sham stimulation, on the clinical symptoms of PTSD. As secondary aims, we explored whether the clinical effects of stimulation were long lasting and associated with any cognitive changes as indexed by a battery of neuropsychological tests.