Modulation of Pain and Working Memory Following Navigated Transcranial Magnetic Stimulation of Segregated Corticostriatal Fiber Tracts in Humans
Principal Investigator: ANTTI PERTOVAARA1,2
Researchers: Satu Jääskeläinen2, Jarmo Hietala2, Harry Scheinin2, Ullamari Pesonen2, Synnöve Carlson1, Risto Ilmoniemi3,4, N.Hagelberg, J.Lähdesmäki, I.K.Martikainen, T.Valmunen, H.Hannula, S.Komssi, T.Neuvonen
1University of Helsinki, 2University of Turku, 3Nexstim Inc., 4Helsinki University of Technology
Repetitive transcranial magnetic stimulation (rTMS) of corticofugal fiber tracts provides a method for modulation of activity in deep brain nuclei in human subjects. Depending on the frequency of rTMS, the modulatory action may vary from long-term depression (<1 Hz) to potentiation (>5 Hz). Recently developed magnetic resonance image-guided stereotactic system allows focusing rTMS into the desired cortical target at the accuracy of a few mm. This, combined with diffusion tensor imaging (DTI) for determination of fiber tract connections between the regions of interest, provides an accurate method for studying the influence of suppression or activation of selected deep brain structures on human behavior. We propose a series of studies in which we apply a combination of rTMS and DTI technology to address the roles of specific corticostriatal fiber tracts in regulation of pain and memory. Particularly we determine the potential segregation of various components of pain and memory functions within the striatum by assessing the influence of stereotactical application of rTMS to cortical regions with DTI-verified connections to selected regions of interest within the striatum. In pain assessments, we test the hypothesis that release of dopamine and the consequent activation of dopamine D2 receptors in the posterior part of the dorsal striatum selectively influence pain due to action on nonsensory factors (the subject's response criterion) with little effect on sensory factors (discriminative capacity). In memory assessments, we test the hypothesis that activation of dopamine receptors in the anterior part of the dorsal striatum has a selective effect on manipulation of information in a working memory task, with little influence on simple maintenance or retrieval of working memory. According to our hypothesis, high- and low-frequency rTMS of corticostriatal tracts will produce opposite effects on these functions. In addition to healthy subjects, the hypotheses will be tested in patients with a verified striatal dysfunction. The contribution of striatal dopamine receptors in rTMS-induced effects will be confirmed by determining striatal dopamine receptor binding potential with positron emission tomography. The role of striatal dopamine receptors is further tested by determining the association of rTMS-induced modulatory effects with polymorphism for some critical genes regulating dopaminergic system (e.g., COMT gene and C957T gene for D2 receptor). The results of this study are expected to extend our understanding of mechanisms underlying memory and pain disorders associated with striatal dysfunction, such as in Parkinson's disease. Additionally, navigated rTMS of corticofugal fiber tracts leading to a deep brain region of interest potentially provides a novel method for regulating selectively memory and pain through activation of long-term depression by low-frequency rTMS or long-term potentiation by high-frequency rTMS. A further implication of our working hypothesis is that DTI for verification of axonal connections between regions of interest takes into account individual neuroanatomical characteristics allowing focusing rTMS to the optimal site. Moreover, assessment of polymorphism for critical underlying neurotransmitter genes will help in predicting the magnitude of rTMS-induced effect in each individual.
Contact: antti.pertovaara(at)helsinki.fi, tel. +358 9 1912 5280