Lateralized and frequency-dependent effects of prefrontal rTMS on regional cerebral blood flow
Introduction
Repetitive transcranial magnetic stimulation (rTMS) is a research tool to study neural connectivity at the system level and is used therapeutically in a number of neuropsychiatric disorders. It has been extensively studied as a treatment for depression, and the majority of clinical trials that applied rTMS to the prefrontal cortex report results superior to placebo (Burt et al., 2002, Martin et al., 2003). However, the neurophysiological effects of rTMS, particularly as a function of the stimulation parameters (e.g., location, frequency and intensity), remain unclear.
The application of rTMS in depression suggests a rather strong laterality effect. High-frequency stimulation (10 Hz to 20 Hz) was found to induce an antidepressive effect when administered over the left prefrontal cortex (George et al., 1995, Pascual-Leone et al., 1996a), but not when applied over the right prefrontal cortex. Later studies reported effects that depended on stimulation frequency. Thus, low-frequency rTMS over the right prefrontal cortex has an antidepressant effect (Klein et al., 1999, Feinsod et al., 1998, Schutter et al., 2001), whereas the same parameters over the left side are ineffective. In healthy subjects, however, changes in mood observed after prefrontal rTMS are the opposite of those in depressed patients. In healthy subjects, high-frequency rTMS increases feelings of sadness when administered to the left prefrontal cortex but increases feelings of happiness if administered to the right prefrontal area (George et al., 1996, Pascual-Leone et al., 1996b; but see Jenkins et al., 2002, Mosimann et al., 2000, Padberg et al., 2001).
Thus, both the side of stimulation and the frequency of stimulation seem to be highly relevant to the therapeutic effect achieved and, in healthy subjects, to the direction of the mood changes. The strong association between the affected hemisphere of a frontal lesion and the behavioral manifestation is well known from patient studies on mood disorders and impulse control disorders. As, for example, in the disinhibition syndrome and secondary mania, ample evidence indicates that mainly right-sided lesions are associated with manic-like behavior symptoms (Cummings and Mega, 2003). Interestingly, in patients with mania, high-frequency rTMS over the right prefrontal cortex appears to be associated with antimanic effects, whereas the same stimulation on the left side is ineffective (Grisaru et al., 1998, Erfurth et al., 2000, Michael and Erfurth, 2004). Furthermore, we recently reported evidence that prefrontal rTMS affects cognitive processing in a frequency-dependent manner (Knoch et al., 2005).
In contrast to the rapidly growing literature with regard to the laterality- and frequency-dependent swing in mood or therapeutic antidepressant rTMS effects and effects on cognitive performance, there have been few studies examining the potential neurophysiological mechanisms of TMS. To further analyze the role of the stimulation frequency and laterality, we conducted a combined TMS-PET study in healthy subjects focusing on acute rTMS effects. The majority of neuroimaging studies analyzing the acute effects of prefrontal rTMS in healthy subjects conducted so far stimulated only the left DLPFC (Barrett et al., 2004, George et al., 1999, Kimbrell et al., 2002, Nahas et al., 2001, Speer et al., 2003). Since the prefrontal cortex is asymmetric in both structure and function, it is feasible to hypothesize that left and right rTMS over the DLPFC would differentially affect CBF changes. In addition, as mounting evidence suggests that rTMS has not only local effects (e.g., Bestmann et al., 2004, Li et al., 2004, Nahas et al., 2001, Paus et al., 2001), we hypothesize that the frequency- and laterality-dependent effects are not limited to the cortical area targeted by rTMS (at stimulated site) but could also occur at remote interconnected areas. Suprathreshold stimulations were chosen because larger and more widespread rCBF changes can be expected (Kähkönen et al., 2005, Nahas et al., 2001).
Knowledge of potential frequency-dependent and/or laterality-dependent prefrontal rTMS effects on cortical excitability and neural connectivity of the stimulated area may contribute to our understanding of rTMS mechanisms of the regulation of mood and impulse.
Section snippets
Subjects
Sixteen right-handed healthy men (mean age 27 years, SD 4 years) participated in the study, having given written informed consent as per approval by the local ethics committee. All subjects were naive to TMS and had no history of psychiatric illness or neurological disorders. Subjects received 300 Swiss Francs for their participation and were randomly assigned to receive either left or right prefrontal rTMS.
Shielding requirements
Whether or not PET scanners should be shielded from the magnetic field induced by TMS
Results
None of the subjects reported any adverse side effects concerning pain on the scalp or headaches after the experiment. There were no significant differences between groups with respect to age (t = 0.66, df = 14, P = 0.52) and motor threshold (t = 0.68, df = 14, P = 0.51).
Discussion
To our knowledge, the present experiment includes the first comparison of left and right DLPFC stimulation in combination with different stimulation frequencies within a single study protocol. The results demonstrate that right prefrontal rTMS induces a different pattern of rCBF changes than left prefrontal rTMS (laterality effect). Moreover, high-frequency and low-frequency rTMS lead to diverse frontal and remote area CBF changes (frequency effect). CBF changes were not restricted to the
Acknowledgments
This work was supported by the Swiss National Science Foundation (grant no. 31.68097) and a donation by UBS AG. The authors would like to express their gratitude to Thomas Berthold and Michael Belohavy for their assistance with the PET acquisition.
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