Serotonergic modulation of response inhibition [Elektronische Ressource] : a fMRI study / vorgelegt von Sonja Marta Augustine Schlägel

Sonja Snacken

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• Gesundheit

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• Publié par: rheinisch-westfalischen_technischen_hochschule_-rwth-_aachen
• Publié le: 01 janvier 2010
• Nombre de lectures: 22
• Langue: Deutsch

Extrait

Serotonergic modulation of response inhibition:
a fMRI study



Von der Medizinischen Fakultät
der Rheinisch-Westfälischen Technischen Hochschule Aachen
zur Erlangung des akademischen Grades
einer Doktorin der Medizin
genehmigte Dissertation








vorgelegt von

Sonja Marta Augustine Schlägel

aus Detmold





Berichter: Herr Universitätsprofessor
Dr. phil. Dipl.-Psych. Siegfried Gauggel

Herr Universitätsprofessor
Dr. med. Gerhard Gründer


Tag der mündlichen Prüfung: 27. September 2010


Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfügbar.
























































Meiner Mutter
und
meinen Großeltern


















Contents

Abbreviations ...................................................................................................... I
List of figures ...... II
List of tables ....... III
Abstract ............................................................................................................... 1
Zusammenfassung ............................ 2
Introduction ......... 4
Methods ............................................................................................................... 11
Participants ................................................................................................ 11
Design and procedure .. ............. 11
Escitalopram .............................. 13
Stop change paradigm ............................................................................. 14
fMRI acquisitation ..................... 16
Statistics .................................... 17
Results................................................................................. 19
Behavioral data .......................... 19
fMRI data .................................................................................................. 19
Discussion .......... 28
Limitations .. 34
Conclusions .............................................................................................. 36
References .......................................... 37
Acknowledgments 43
Erklärung zur Datenaufbewahrung ................................... 45







Abbreviations

5-HT Serotonin
ACC Anterior cingulate cortex
ANOVA Analysis of variance
ADHD Attention-deficit / hyperactivity disorder
ATD Acute tryptophan depletion
BA Brodmann area
BOLD Blood Oxygen Level Dependency
BPD Borderline personality disorder
DLPFC Dorsolateral prefrontal cortex
DMStr Dorsomedial Striatum
C Maximal plasma concentration max
fMRI Functional magnetic resonance imaging
fMRT Funktionelle Magnetresonanztomographie
IFC Inferior frontal cortex
mCPP m- chlorophenylpiperazine
NA Noradrenaline
OCD Obsessive-compulsive disorder
OFC Orbito frontal cortex
PET Positron emission tomography
PFC Prefrontal cortex
RT Reaction time
SD Standard deviation
SMA Supplementary motor cortex
SNRI Selective noradrenalin reuptake inhibitor
SOA Stimulus onset asynchrony
SPM 5 Statistical Parametric Mapping Software
SPSS Statistical Package for the Social Sciences
SSRI Selective serotonin reuptake inhibitor
SSRT Stop signal reaction time
STN Subthalamic nucleus


I
List of figures

Figure 1 The horse race model

Figure 2 Schematical illustration of serotonergic projections (according to
Törk, 1990)

Figure 3 The test procedure

Figure 4 Chemical structure of escitalopram (www.kekulepharma.com)

Figure 5 The Stop Change Paradigm

Figure 6 Performance on the stop signal task following escitalopram and
placebo

Figure 7 Brain activations during successful response inhibition for
escitalopram > placebo

Figure 8 Enhanced brain activation in BA 10/11 during response inhibition
with escitalopram

Figure 9 Enhanced brain activations by escitalopram compared to placebo
for the contrast Stopinhibit minus Go

Figure 10 Brain activations during failed response inhibition for escitalopram >
placebo

Figure 11 Brain activations during going for escitalopram > placebo



II
List of tables

Table 1 Brain activations during successful response inhibition

Table 2 Brain activations for the contrast StopInhibit minus Go

Table 3 Brain activations during failed response inhibition

Table 4 Brain activations during going

























III
Abstract

In animal and human studies, the neurotransmitter serotonin (5-HT) has been
implicated in inhibitory control. Using functional magnetic response imaging (fMRI), the
present study investigated the acute effects of pharmacological modulation in the
serotonergic system on brain activations during response inhibition in healthy human
volunteers. In all, 14 male participants received either a single oral dose of selective
serotonin reuptake inhibitor (SSRI) escitalopram (10 mg) or placebo in a randomized
double-blind placebo-controlled cross-over design. At the time of the expected plasma
peak participants performed a stop change task during fMRI. Functional images were
analyzed using Statistical Parametric Mapping software (SPM5). Escitalopram did not
affect behavioral inhibitory performance as the main effect did not reveal significant
differences of stop signal reaction time (SSRT). Likewise no differences were found for
reaction time on go-trials (goRT) as well as for reaction time on trials of unsuccessful
response inhibition (StopRespondRT). However, escitalopram was associated with
alterations in brain activation patterns compared to placebo. Escitalopram enhanced
brain activations in right prefrontal cortex, including right OFC, in right
supplementary/pre motor and bilateral cingulate cortex as well as in subcortical regions
during successful response inhibition. Also, escitalopram modulated a widespread
network of brain regions, including anterior cingulate, right parietal cortex, right OFC,
areas in right temporal cortex and subcortical regions during failed inhibition. During the
go-process escitalopram increased brain activations in numerous regions like right
anterior and posterior cingulate and in right prefrontal, parietal and temporal cortex as
well as in subcortical areas. Our findings implicate an involvement of 5-HT in neural
regulation of response inhibition. Moreover, this study provides evidence that 5-HT
influences not only action restraint but also action cancellation through modulation of
activations of brain areas. In addition, we found modulating effects of serotonin also on
activations during failed inhibition. Especially, the anterior cingulate seems to play a
critical role here. Results of this study support the assumption of an involvement of the
anterior cingulate in error-detection. The results also implicate a fronto-striatal-circuitry
for response inhibition in conjunction with serotonin.


1
Zusammenfassung

Sowohl Tierstudien als auch Studien mit menschlichen Probanden belegen, dass der
Neurotransmitter Serotonin (5-HT) eine entscheidende Rolle in der Handlungskontrolle
spielt. Diese plazebokontrollierte, randomisierte Doppelblindstudie im cross-over Design
beschäftigt sich mit den akuten Effekten einer pharmakologischen Modulation im
serotonergen System in Bezug auf Handlungskontrolle. Dabei wurden Verhaltens- und
Aktivierungsunterschiede im Gehirn während der Bearbeitung einer Stop-Change-
Aufgabe mit Hilfe von funktioneller Magnetresonaztomografie (fMRT) erfasst. 14
männliche, gesunde Probanden erhielten eine orale Dosis von 10 mg Escitalopram oder
Plazebo und absolvierten zum Zeitpunkt des erwarteten Plasmapeaks die Stop-
Change-Aufgabe während der fMRT-Messungen. Die funktionellen MRT-Bilder wurden
mit der Software Statistical Parametric Mapping (SPM5) analysiert. Escitalopram
beeinflusste weder die Reaktionszeit (GoRT) noch die Stopsignalreaktionszeit (SSRT),
was sich darin zeigte, dass es keinen signifikanten Haupteffekt des Faktors Substanz
gab. Auch die Reaktionszeit während des erfolglosen Stoppens wurde nicht beeinflusst.
Im Vergleich zu Plazebo bewirkte Escitalopram jedoc