Brain activation related to retrosaccades in saccade experiments Mathijs Raemaekers, CA Matthijs Vink, Martijn P. van den Heuvel, Rene¤ S. Kahn and Nick F. Ramsey Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, the Netherlands CA Corresponding Author: M.A.H.Raemaekers@azu.nl Received19 April 2005; accepted 26 April 2005 In saccade experiments, each trial (e.g. prosaccade/antisaccade) is by de¢nition followed by a saccade, which returns the gaze back to the center (retrosaccade). This event can complicate brain-imaging results when using a simple block-design. We used an event-related functional magnetic resonance imaging design involving prosac- cades and antisaccades (testsaccades) to examine brain activation associated with retrosaccades. Testsaccades activated visual and oculomotor-related brain areas. During retrosaccades, these areas were less active than during testsaccades. In the supplementary eye ¢elds, the insula, and striatum, the retrosaccades gave rise to negative blood oxygenation level-dependent responses. In the striatum, these negative responses were equal in size to the positive responses of the testsaccades. This could mask brain activity of testsaccades when not taken into account. NeuroReport 16:1043^1047  c 2005 Lippincott Williams & Wilkins. Key words: Antisaccades; Event-related; Functional magnetic resonance imaging; Negative blood oxygenation level-dependent responses; Prosaccades INTRODUCTION The antisaccade paradigm is a well established task in clinical and experimental brain research [1]. The antisaccade task measures a study participant’s ability to suppress an eye movement towards a new peripheral stimulus and instead make a voluntary saccade in the opposite direction. The reference task typically involves prosaccades, in which participants must make the saccade towards the peripheral stimulus. Many functional magnetic resonance imaging (fMRI) studies have examined the neural network involved in antisaccades and prosaccades [2–9]. Although generation of antisaccades is a conceptually simple act, the number of neuronal processes involved is considerable. Not only does the task induce activation directly related to the prosaccade or antisaccade, but recent experiments also demonstrate activation related to the preparatory set before the saccadic event [5,6]. In addition, the prosaccade and antisaccade trials are always followed by a saccade back to center, in preparation for the next trial. The contributions of retrosaccade activity have not been studied with fMRI, so it is not known whether they are significant. In spite of this, ignoring retrosaccades in the analyses of imaging data may have given rise to some unexpected results. We obtained unexpected results when we attempted to improve our fMRI design for antisaccades and prosaccades. In a previous experiment, when using a sparse event-related fMRI study, during antisaccades, compared with prosac- cades, we found increased activation in the striatum, the frontal eye fields (FEF), and the supplementary eye fields (SEF) [10]. With the objective of shortening scan time and increasing sensitivity, we piloted a block-design with shortened intertrial intervals. This design yielded the expected activity in the FEF and the SEF. However, it failed to replicate striatal activity during antisaccades, and for the contrast between antisaccades and prosaccades. These differences in results could only originate from differences in design properties. Most importantly, the event-related design can separately model the antisaccades and prosac- cades (testsaccades), and the saccades which return the view to central gaze (retrosaccades), whereas the block-design cannot dissociate these two responses. In a block-design, the response associated with the retrosaccade could therefore effectively mask or confound the event of interest (e.g. the prosaccade or antisaccade). This experiment addresses prosaccades and antisaccades within a sparse, event-related fMRI design. The use of event-related fMRI allows us to separately establish brain activation related to prosaccades and antisaccades on the one hand, and activation related to retrosaccades on the other. An opposite or negative response related to retro- saccades in the striatum and other regions could potentially mask other neural events within a trial when the inter- stimulus interval is short, and could thereby explain the findings of our block-design. The event-related design on the other hand would adequately detect all neural events within the striatum during the task paradigm. MATERIALS AND METHODS Study participants: Thirty-eight participants took part in the experiment. All were right-handed according to the Edinburgh Handedness inventory [11] (mean, 0.84; SD, 0.18). All participants gave informed consent for participa- tion (approved by the Human Ethics Committee of the University Medical Center, Utrecht). BRAIN IMAGING NEUROREPORT 0959-4965  c Lippincott Williams & Wilkins Vol 16 No 10 13 July 2005 1043 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.