With TMS it is possible to influence the activity of cortical structures and to investigate the effects on behaviour. In the present thesis the impact of TMS over the prefrontal cortex, particularly the DLPFC, on the inhibition of initiated responses, an important part of cognitive control functions, and on the sympathetic and parasympathetic branches of the autonomic nervous system was investigated. The prefrontal cortex is involved in these functions but the exact role of the left and right DLPFC is still unclear.
An important aim of Study 1 was the investigation of the role of the DLPFC for the inhibition of initiated responses. Single-pulse TMS was applied over the left, right or bilateral DLPFC at different time points following the stop signal in a stop signal inhibition task to elucidate the functional role of the DLPFC during response abortion and to understand the time course of its involvement. An acceleration of inhibition of initiated responses was observed in all TMS conditions compared to the control condition without TMS. The effect was significantly more pronounced during stimulation over the right DLPFC 50 ms and 100 ms after the stop signal. Right DLPFC seems to be involved in inhibition of initiated responses.
The aim of the second study was the investigation of the influence of low-frequency (1 Hz) rTMS over the DLPFC on the control and regulation of ANS activity, particularly cardiovascular activity. MRI guided rTMS was applied to the left and right DLPFC, and a control site (vertex), respectively. ECG was recorded during and after rTMS stimulation.
Spectral parameters of HRV were extracted as indicators of the sympathetic and parasympathetic activity of the ANS. Thus it was possible to study the impact of prefrontal rTMS on the cortical control of the sympathetic and parasympathetic branches of the ANS separately. The main finding of the experiment was a differential neuromodulatory effect of low-frequency rTMS applied to the left and right DLPFC on HRV as an indicator of ANS activity. Left-sided stimulation increased parasympathetic activity and attenuated the
prefrontal cortex enhanced sympathetic activity and decreased parasympathetic activity.
Thus a double dissociation of sympathovagal balance was observed. It was possible to manipulate sympathetic and parasympathetic ANS activity separately by TMS.
There are several suggestions for further investigations. In the present thesis two aspects of DLPFC function and its manipulability were investigated separately in two experimental studies. But the effect of TMS over the left and right DLPFC on inhibition and on the ANS activity could be part of a combined study. Before, during and after TMS stimulation both a stop signal task could be performed and HRV could be measured. The relationship between both dependent variables could be studied to further analyse the interconnection of inhibition, cognitive as well as emotional prefrontal functions, and its integration with ANS mediated body processes (see Thayer and Brosschot 2005).
The results of the thesis could be validated by a replication with transcranial direct current stimulation (tDCS) instead of TMS. tDCS enables the modulation of cortical activity by a small current (about 1 mA) applied over the scalp. The basic underlying mechanism is a shift in the resting membrane potential towards either hyper- or depolarisation, depending on stimulation polarity. Anodic stimulation increases cortical excitability, while cathodic stimulation decreases it. These changes persist after the end of stimulation up to one hour if the stimulation lasts at least several minutes. tDCS allows a reversible, pain-free, and non-invasive induction of changes in cortical excitability with fewer side effects than TMS and with the possibility of a sham stimulation not distinguishable from verum stimulation (Nitsche et al. 2002). This could solve methodological problems affecting the studies of the present thesis (see chapter 2.4 and 3.5). In addition, tDCS is easier to apply and cheaper than TMS and thus well suitable for clinical use.
Whether the findings of this thesis are of therapeutic or diagnostic use needs also to be investigated. In several diseases accompanied by disorders of inhibition of ongoing responses, e.g. attention deficit hyperactivity disorder (ADHD) (e.g. Konrad et al. 2000;
Lampe et al. 2007), Parkinson’s disease (e.g. Gauggel et al. 2004), schizophrenia (e.g.
Badcock et al. 2002) or frontal brain damage (e.g. Aron et al. 2003; Rieger et al. 2003), other therapeutic interventions could be supported by TMS over the right DLPFC.
Further studies in healthy subjects as well as in patients with neuropsychiatric diseases are also needed to investigate if the modulatory effects of rTMS can be used therapeutically to correct, for instance, a pathological imbalance of sympathovagal regulation related to psychosomatic and psychopathological states, e.g. cardiac infarction or depression. Also tDCS should play a role in clinical studies because it provides a safer, cheaper and easier way to modulate cortical excitability than TMS.
Thus the results of the present experimental thesis could help to develop clinical interventions to support the cure of several somatic, psychosomatic and mental diseases.
5 Deutschsprachige Zusammenfassung
Mit Hilfe der transkaniellen Magnetstimulation (TMS) ist es möglich, die Aktivität kortikaler Strukturen kurzzeitig zu beeinflussen und daraus resultierende Verhaltenseffekte zu untersuchen. In der vorliegenden Arbeit wurde der Einfluss von TMS auf Funktionen des Präfrontalkortex, insbesondere des dorsolateralen Präfrontalkortex (DLPFC) experimentell überprüft. Kognitive Kontrollfunktionen einerseits und die kortikale Regulation des sympathischen und parasympathischen Zweiges des Autonomen Nervensystems (ANS) andererseits sind wichtige Aufgaben des Präfrontalkortex. Dabei bleibt die genaue Rolle des linken und rechten DLPFC jedoch weiterhin unklar.
In der ersten Studie wurde deshalb die Bedeutung des DLPFC für die Inhibition bereits initiierter motorischer Reaktionen, einem Teilaspekt kognitiver Kontrolle, untersucht. Einzelpuls-TMS wurde über dem linken, rechten oder bilateralen DLPFC während eines Stop-Signal Experimentes appliziert. Die Stimulation erfolgte zu unterschiedlichen Zeitpunkten nach dem Stopsignal, welches den Probanden signalisierte, eine bereits begonnene motorische Reaktion zu unterbrechen. Es wurde eine signifikante Beschleunigung des Inhibitionsprozesses nach TMS beobachtet. Dieser Effekt war am
stärksten ausgeprägt nach rechtseitiger TMS 50 ms und 100 ms nach dem Stopsignal.
Der rechte DLPFC scheint im Vergleich zum linken somit stärker am Inhibitionsprozess beteiligt zu sein. Seine Stimulation verbessert die Inhibitionsleistung.
Das Ziel der zweiten Studie der vorliegenden Dissertation war die Untersuchung der Rolle des DLPFC bei der Kontrolle und Regulation der Aktivität des ANS, insbesondere der kardiovaskulären Aktivität. Repetitive TMS (niedrigfrequent, 1 Hz) wurde über dem rechten oder linken DLPFC, oder dem Vertex als Kontrollregion, angewendet. Die Lokalisation der TMS Spule über dem DLPFC erfolgte dabei neuronavigiert mit Hilfe individueller struktureller Magnetresonanztomografien der Probanden. Während und nach der Stimulation wurde das Elektrokardiogramm aufgezeichnet. Spektrale Parameter der
parasympathischen Anteils an der kardiovaskulären Regulation ermöglichen. TMS über dem linken DLPFC erhöhte die parasympathische Aktivität und verminderte die sympathische. TMS über dem rechten DLPFC zeigte den entgegengesetzten Effekt, erhöhte die Aktivität des Sympathikus und verminderte die parasympathische Aktivität. Es zeigte sich eine Modulierbarkeit der ANS Aktivität durch DLPFC Stimulation.
Beide Studien zeigten, dass es möglich ist, Funktionen des DLPFC mit Hilfe von TMS zu beeinflussen. Zukünftige Studien sollten sich zum Ziel setzen, die experimentellen Ergebnisse zu replizieren und die klinische Anwendbarkeit der Resultate zu prüfen.
Verschiedene psychische Erkrankungen, die mit Störungen der Inhibitionsfähigkeit assoziiert sind (zum Beispiel Schizophrenie oder ADHS) sowie psychosomatische Erkrankungen in Folge von Störungen der autonomen Balance (zum Beispiel Herzerkrankungen) könnten mit Hilfe von TMS zusätzlich behandelt werden.
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7 Acknowledgment
I would like to thank
Prof. Dr. Siegfried Gauggel Prof. Dr. Klaus Willmes – v. Hinckeldey
Dr. Roland Sparing Dr. Ingo G. Meister Dr. Beate M. Herbert Dipl.-Psych. Maren Böcker Christiane Christiansen, M.A.
&
My parents
Christina & Eberhard Städtgen
8 Curriculum Vitae
2005 - 2008 Work on thesis, University Clinic, RWTH Aachen University 1991 - 1997 Study of Psychology, Friedrich Schilller University, Jena
-Degree: Diploma in Psychology
1988 - 1990 EOS (Gymnasium) Arnoldischule, Gotha
-Degree: Abitur (general qualification for university entrance) 1978 -1988 POS Theodor-Neubauer Schule, Gotha
Professional experience
2005 - Research assistant, Department of Neurology and IZKF Biomat, University Clinic, RWTH Aachen University
2003 - 2004 Research assistant, Department of Psychiatry, Charité University Clinic, Berlin
2002 - 2003 Neuropsychologist and research assistant, Department of Epileptology, University Clinic, Bonn
2001 - 2002 Research assistant, Centre for Neuropsychological Research, University of Trier
1998 - 2001 Neuropsychologist and research assistant, Department of Psychiatry III, University of Ulm
1997 - 1998 Research assistant, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig