Multimodal imaging in attentiondeficit/hyperactivity
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1 DISS. ETH NO Multimodal imaging in attentiondeficit/hyperactivity disorder (ADHD) A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZURICH (Dr. sc. ETH Zurich) presented by Steffen Bollmann M. Sc. in Biomedical Engineering, Technical University Ilmenau, Germany born on citizen of Germany accepted on the recommendation of Prof. Dr. Klaas P. Pruessmann, examiner Prof. Dr. Reto Huber, co-examiner PD. Dr. Ruth O Gorman, co-examiner 2014
2 Abstract Attention-Deficit/Hyperactivity Disorder (ADHD) is a common developmental psychiatric disorder affecting about five percent of the population. Although traditionally considered a disorder of childhood, ADHD persists in every second child into adulthood. Many studies have investigated children or adults with ADHD using different imaging modalities and a variety of candidate regions have been identified. However, no study so far combined these different modalities in children and adults in a single study to understand the interaction between findings in different modalities and the developmental trajectories in a complex developmental disorder such as ADHD. We investigated in total 134 participants, (i.e. 20 ADHD children, 6 ADHD adolescents, 22 ADHD adults, 23 control children, 19 control adolescents and 44 control adults). Imaging data was acquired on a 3.0 T GE HD.xt whole-body MRI scanner using an 8-channel head coil. The multimodal imaging protocol consisted of a T1- weighted gradient echo, a pulsed continuous arterial spin labeling sequence, and MEGA-PRESS spectroscopy in Basal Ganglia and Dorsolateral Prefrontal Cortex (DLPFC, only in adults). Finally, simultaneous EEG/fMRI during a working memory task and during resting state was performed. In the working memory task we found that although some working memory loadspecific differences between ADHD and controls change with age, predominantly in prefrontal regions, other ADHD related effects persist into adulthood. Ageindependent alterations were observed in frontostriatal regions and the basal ganglia. Our spectroscopy results add additional insights to this finding since ADHD adults but not ADHD children showed increased GABA levels relative to controls in the basal ganglia. Glutamine levels where increased in children with ADHD, but this 1
3 difference normalized in adults. Further our simultaneous EEG/fMRI approach allowed us to link the often reported EEG theta band deviations in ADHD to the cingulate and the precuneus cortex and alpha band alterations to thalamic regions. These results suggest an involvement of cortico-striato-thalamo-cortical loops in ADHD. Our multimodal results provide further evidence that frontostriatal regions and the basal ganglia represent core deficits, central to the pathophysiology and development of ADHD. 2
4 Zusammenfassung Die Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) ist eine verbreitete psychiatrische Entwicklungsstörung, die ca. fünf Prozent der Bevölkerung betrifft. Obwohl ADHS ursprünglich vor allem als Störung bei Kindern bekannt war, bleibt sie bei jedem zweiten Patienten im Erwachsenenalter bestehen. Viele Studien haben bereits Kinder oder Erwachsene mit ADHS und verschiedenen bildgebenden Verfahren untersucht und für ADHS zentrale Hirn-Regionen identifiziert. Allerdings gab es bisher keine Studie, die verschiedene bildgebende Verfahren in einer einzigen Studie sowohl in Kindern als auch in Erwachsenen angewendet hat um die Interaktion zwischen verschiedenen Modalitäten und der Entwicklung zu untersuchen. Wir haben 134 Probanden untersucht (i.e. 20 ADHS Kinder, 6 ADHS Jugendliche, 22 ADHS Erwachsene, 23 Kontrollkinder, 19 Kontrolljugendliche und 44 Kontrollerwachsene). Die Bildgebung wurde auf einem 3.0 T GE HD.xt Ganzkörper MRT mit einer 8-Kanal Kopfspule durchgeführt. Wir verwendeten ein T1-gewichtetes Gradientenecho, Magnetresonanzperfusionsbildgebung, MEGA-PRESS Spektroskopie in den Basalganglien und dem dorso-lateralen präfrontal Cortex (nur in Erwachsenen). Abschliessend haben wir simultan EEG und fmrt während einer Arbeitsgedächtnisaufgabe und während Ruhe gemessen. Durch die Arbeitsgedächtnisaufgabe fanden wir heraus, dass, obwohl sich aufgabenschwierigkeitsbedingte Unterschiede mit dem Alter zwischen ADHS Patienten und Kontrollen verändern (vor allem in präfrontalen Regionen), trotzdem bestimmte Unterschiede bis ins Erwachsenenalter bestehen bleiben. Diese altersunabhängigen Veränderungen waren vor allem in frontostriatalen Regionen und den Basalganglien zu beobachten. Die Spektroskopie-Ergebnisse bestärken diese Resultate weiter, da nur die ADHS Erwachsenen, aber nicht die Kinder erhöhte GABA Werte 3
5 im Vergleich zu den Kontrollen in den Basalganglien zeigten. Glutamin Werte dagegen waren in Kindern mit ADHS erhöht, aber normal in Erwachsenen. Weiterhin erlaubt unsere simultane EEG/fMRT Messung die oft berichteten EEG-Thetaband- Veränderungen im ADHS mit dem Gyrus cinguli und dem Precuneus und die Alphaband-Veränderungen mit thalamischen Regionen in Verbindung zu bringen. Diese Ergebnisse bestärken die Annahme, dass kortikal-striatale-thalamisch-kortikale Verbindungen eine wichtige Rolle im ADHS spielen. Unsere multimodalen Ergebnisse liefern mehr Belege dafür, dass frontostriatale Regionen und die Basalganglien Kernbereiche des ADHS sind und eine zentrale Rolle in dessen Entwicklung spielen. 4
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