Modulation antizipierbarer experimentell induzierter Schmerzen durch neuronavigierte rTMS des rechten inferioren frontalen Kortex

Transcranial magnetic stimulation (rTMS) allows for the modulation of neuronal structures. By generating an electrical field membrane potentials may be altered which concludes in activation or inhibition of neurons. Even not directly stimulated regions may be influenced by conduction of action potentials. This non-invasive method has already been employed in neurological therapy and research for a few decades. So far rTMS was successfully used in therapyresistent types of depression, epilepsy or schizophrenia. The effect of rTMS – in particular of the primary motor cortex - on acute and chronic pain conditions has been shown in several studies. Examinations with patients suffering from chronic pain syndromes yielded a reduction of pain following rTMS of the primary motor cortex following high-frequency rTMS (Khedr et al. 2005; Hirayama et al. 2006). Studies of Lefaucheur et al. showed reduced pain perception of experimentally induced pain after high-frequency rTMS in patients with chronic neuropathic pain (Lefaucheur et al. 2006; Lefaucheurt et al. 2008; Lefaucheur et al. 2010). But also in healthy subjects pain perception of experimentally induced pain may be influenced by rTMS. In different rTMS studies an increase of A delta-fibre mediated pain and a reduction of C-fibre mediated pain was found after stimulation of the primary motor cortex and the right dorsolateral prefrontal cortex irrespectively of the stimulation technique (Graff-Guerrero et al. 2005; Mylius et al. 2006; Borckardt et al. 2007; Mylius et al. 2007). Announced painful stimuli are usually perceived as less painful than unannounced painful stimuli (Willer et al. 1979; Rhudy and Meagher 2000; Terkelsen et al. 2004). In a functional MRI study of Ploghaus et al. it was shown that brain regions that are activated by anticipation of a painful heat stimulus differ from those that are activated by pain itself. These “anticipatory regions” are located in the vicinity of the “pain regions”. The anticipatory regions lie within the anterior medial frontal cortex, the right inferior frontal cortex (IFC) and within the posterior cerebellar cortex (Ploghaus et al. 1999). The aim of our study was to find out whether rTMS of one of these anticipatory regions – we have chosen the right IFC – allows for the modulation of the perception of painful stimuli. To control anticipation we decided to use announced and therefore anticipatory painful stimuli und unannounced painful stimuli. Prior to the main experiments we performed preliminary tests to demonstrate that the perception of announced painful stimuli is less than the perception of unannounced ones. Significant results were found both for pain intensity and pain unpleasantness. To carry out neuronavigated rTMS of the IFC a cranial MRI of the subjects was produced. With the Brainvoyager software including the neuronavigation module a Talairach transformation was performed to mark the cortical target. The subjects were randomized in groups and received in a single-blind, Shamcontrolled study design 1-Hz, 10-Hz or Sham rTMS on three different days. Electrical pain thresholds and the VAS intensity and unpleasantness scores for supra threshold announced (1.3 X pain threshold) and unannounced (1.6 X pain threshold) electrical stimulation were determined before, directly after and 30 minutes after rTMS. Our hypothesis that rTMS allows for the modulation of anticipation of pain of announced electrical painful stimuli could not be confirmed. Pain threshold was reduced after all three stimulation techniques. Neither stimulation technique showed a significant modulaton of the perception of pain intensity or pain unpleasantness. Concerning the decreased pain thresholds over time, we suggest that subsequent determination of the pain thresholds sensitizes the afferent fibres towards experimental stimulation. Potential objections of our study include that different intensities for the painful stimuli were chosen, that we did not perform painful stimuli in a control group without rTMS and that we applied A delta-fibre mediated electrical pain although it is been shown previously that rTMS rather modulates the medial pain pathway where e.g. painful thermal stimuli are processed. The procession of electrically induced pain is attributed to the lateral pain pathway (Ploner et al. 2002), while we stimulated a cortical target within the IFG which belongs to the medial pain pathway. We suggest employing C-fibre mediated pain of higher intensities in future studies and including patients with chronic pain conditions. In addition to that further cortical targets may be stimulated. We believe that rTMS is and will be a useful method to treat pain conditions and especially chronic pain. The exact stimulation intensities as well as the cortical targets remain to be determined.