Transcranial magnetic stimulation (TMS) is a method of inducing firing of cortical neurons. Studies examining prefrontal repetitive TMS (rTMS) show effects on cerebral oxygen perfusion in both local and distant brain regions (Bestmann, Baudewig, Siebner, Rothwell, & Frahm, 2005; Chouinard, Van Der Werf, Leonard, & Paus, 2003; Ohnishi et al., 2004; Paus, Castro-Alamancos, & Petrides, 2001). Speer et al. (2000) have suggested that low- and high-frequency rTMS have opposite effects on cerebral perfusion. Specifically, high-frequency (20 Hz) rTMS increases cerebral perfusion, and low-frequency (1 Hz) rTMS decreases it (Speer et al., 2000). Other studies have verified that low-frequency rTMS reduces cortical excitability (Hoffman & Cavus, 2002; Huang, Edwards, Bhatia, & Rothwell, 2004). In addition, one study in mice demonstrated that rTMS normalized the hypothalamic–pituitary–adrenal (HPA) axis following stress (Czeh et al., 2002).
Repetitive TMS is emerging as a potentially effective treatment for mood symptoms including depression (Berman et al., 2000, George et al., 2000 and Klein et al., 1999). One research group has conducted a placebo-controlled trial of high-frequency (10 Hz) rTMS in humans for post-traumatic stress disorder (PTSD) with some success (Cohen et al., 2004; Grisaru, Amir, Cohen, & Kaplan, 1998), but this has yet to be replicated by other investigators. Open case series of TMS in PTSD have also been encouraging (McCann et al., 1998 and Rosenberg et al., 2002).
Early functional neuroimaging research on PTSD reported increased oxygen perfusion in the right prefrontal cortex as subjects were reminded of their traumatic experiences (Rauch et al., 1996). This was replicated in some but not all subsequent studies, and led to the general interpretation that right-sided activity in PTSD was related to the role of the right hemisphere in anxiety and other adverse emotional experiences (Rauch et al., 1996; Simmons, Matthews, Stein, & Paulus, 2004). If low-frequency rTMS could decrease activity in right hemispheric cortical areas, it might prove to be helpful for improving functional brain abnormalities associated with PTSD.
Anxiety disorders can be treated by systematically exposing patients to the objects and events that induce anxiety or distress, or to reminders of them (Echeburua, de Corral, Zubizarreta, & Sarasua, 1997; Pitman et al., 1996). Imaginal exposure is used to treat PTSD by exposing patients to memories of the traumatic event(s) in a controlled setting, thereby desensitizing them to the event(s) and teaching them that they are no longer in danger (Cahil & Foa, 2005). Evidence from animal research suggests that paradoxically, rather than relaxation and autonomic deactivation, autonomic excitation improves the results of extinction training (Cain, Blouin, & Barad, 2004), the theoretical basis of exposure therapy. The same has been found for human anxiety disorder treatment, as well summarized by Craske and Mystkowski (2006). Because of emerging models of PTSD as a failure of fear extinction it is likely to be especially important to bring the neural circuits and the autonomic arousal involved in the conditioned fear “on-line” when attempting to extinguish the fear response.
Because of this previous research on fear extinction, application of rTMS to actively engaged, rather than passive, brain circuits may be a more effective method of modifying brain circuits. The use of rTMS as an enhancement to fear extinction in PTSD has been suggested by Milad, Rauch, Pitman, and Quirk (2006). To date, there have been no studies investigating the effects of low frequency rTMS for decreasing cortical excitability during recollection of unpleasant traumatic memories. In this study we combined low frequency rTMS and exposure for the treatment of long-standing, treatment-refractory PTSD.
