Elsevier Editorial System(tm) for NeuroImage Manuscript Draft Manuscript Number: Title: Right-lateralized brain oscillations in human spatial navigation Article Type: Regular Article Section/Category: Cognitive Neuroscience Keywords: Corresponding Author: Mr. Joshua Jacobs, Corresponding Author's Institution: University of Pennsylvania First Author: Joshua Jacobs Order of Authors: Joshua Jacobs; Igor O Korolev; Jeremy B Caplan; Arne D Ekstrom; Brian Litt; Gordon Baltuch; Itzhak Fried; Andreas Schulze-Bonhage; Joseph R Madsen; Michael J Kahana Manuscript Region of Origin: Abstract: During spatial navigation, lesion and functional-imaging studies suggest that the right hemisphere has a unique functional role. However, studies of direct human brain recordings have not reported interhemisphere differences in navigation-related oscillatory activity. We investigated this apparant discrepancy using intracranial electroencephalographic recordings from twenty-four neurosurgical patients playing a virtual taxi-driver game. When patients were virtually moving in the game, brain oscillations at various frequencies increased in amplitude, compared with periods of virtual stillness. We analyzed the region and frequency specificity of this pattern and found that neocortical movement-related gamma oscillations (34-54 Hz) were significantly lateralized to the right hemisphere, especially in posterior neocortex. We also observed a similar right lateralization of gamma oscillations related to searching for objects at unknown virtual locations. Thus, our results indicate that gamma oscillations in the right neocortex play a special role in human spatial navigation. 1. Cover Letter Joshua Jacobs 3401 Walnut Street Room 303C Philadelphia, PA 19104 215-746-3500 [email protected] Dear NeuroImage editor: Attached please find our manuscript entitled Right-lateralized brain oscillations in human spatial navigation for your consideration for publication in NeuroImage. In this manuscript, we describe our analysis of intracranial brain recordings from twenty-four neurosurgical patients while they play a taxi-driver video game. Our main finding is that, during the task, (virtual) movement-related brain oscillations in the gamma band were significantly lateralized to the right neocortex, as opposed to the left. We also observed a similar right lateralization of brain oscillations related to searching for randomly positioned objects. These findings supports recent theories of spatial cognition that suggest the right hemisphere plays a unique functional role. Thank you for your consideration. Sincerely, Joshua Jacobs * 2. Reviewer Suggestions Suggested reviewers: Brian Cornwell [email protected] Hugo Spiers [email protected] Suzanna Becker [email protected] Albert Postma [email protected] * 3. Manuscript Click here to view linked References Right-lateralized brain oscillations in human spatial navigation 1 2 3 4 5 Joshua Jacobs, ∗ Igor O. Korolev, ∗ Jeremy B. Caplan, Arne D. Ekstrom, Brian Litt, Gordon Baltuch,6 Itzhak Fried,7,8 Andreas Schulze-Bonhage,9 Joseph R. Madsen,10 & Michael J. Kahana2 1 Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA 2 Department of Psychology, University of Pennsylvania, Philadelphia, PA 19104, USA 3 Department of Psychology, University of Alberta, Edmonton, Alberta T6G-2E9, Canada 4 Center for Cognitive Neurosciences, Semel Institute, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA 5 Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA 6 Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA 7 Department of Neurosurgery and Neuropsychiatric Institute, University of California, Los Angeles, CA 90095, USA 8 Functional Neurosurgery Unit, Tel-Aviv Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel 9 Neurozentrum, Universitat Freiburg, 79106 Freiburg, Germany 10 Department of Neurosurgery, Children’s Hospital Boston, MA 02115, USA ‘ ’ denotes that these authors contributed equally to this manuscript and are listed alphabetically. ∗ Direct correspondence to: Michael J. Kahana Department of Psychology University of Pennsylvania 3401 Walnut Street Room 303C Philadelphia, PA 19104 Phone: 215-746-3500 Fax: 215-746-6848 Email: [email protected] Acknowledgements: This work was supported by National Institutes of Health research grants MH61975, MH062196, NS50067, F31AG031100, and F32NS50067, NSF grant SBE0354378, and the Deutsche Forschungsgemeinschaft (SFB 780, Synaptic Mechanisms, TPC3). Abstract During spatial navigation, lesion and functional-imaging studies suggest that the right hemisphere has a unique functional role. However, studies of direct human brain recordings have not reported interhemisphere differences in navigation-related oscilla- tory activity. We investigated this apparant discrepancy using intracranial electroen- cephalographic recordings from twenty-four neurosurgical patients playing a virtual taxi-driver game. When patients were virtually moving in the game, brain oscilla- tions at various frequencies increased in amplitude, compared with periods of virtual stillness. We analyzed the region and frequency specificity of this pattern and found that neocortical movement-related gamma oscillations (34–54 Hz) were significantly lateralized to the right hemisphere, especially in posterior neocortex. We also observed a similar right lateralization of gamma oscillations related to searching for objects at unknown virtual locations. Thus, our results indicate that gamma oscillations in the right neocortex play a special role in human spatial navigation. 1 1 Introduction Spatial navigation is a basic part of everyday life for both humans and animals. Because navigation is so ubiquitous throughout the animal world, examining the neural basis of spatial processing is especially useful because it is informative about neural mechanisms in various species. Furthermore, research on spatial navigation may also be informative about other related cognitive processes, such as episodic memory (Buzs´aki,2005). Thus, recently increasing numbers of researchers have been examining the neural basis of spatial navigation in both humans and animals. One of the most direct ways to examine neuronal activity underlying spatial processing is to directly record electrical activity from the brain of an animal during navigation. This technique is often used to examine neuronal activity in rodents navigating laboratory mazes. One of the most robust findings of these studies is that hippocampal theta oscillations (3– 12 Hz) increase in amplitude during navigational behavior such as movement and foraging (for review, see Buzs´aki,2002). Navigation-related theta oscillations were first discovered in rodents, but were recently also observed in humans engaged in virtual-navigation tasks, first from intracranial electroencephalographic (iEEG) recordings of neurosurgical patients (Kahana et al., 1999; Caplan et al., 2001, 2003), and subsequently from magnetoencephalo- graphic (MEG) recordings in healthy subjects (de Araujo et al., 2002; Cornwell et al., 2008). Although much human navigation research focuses on theta to parallel rodent studies, many human studies also report navigation-related brain oscillations at a broad range of frequen- cies, including the gamma band (Caplan et al., 2001; Ekstrom et al., 2005; Cornwell et al., 2008). Both theta and gamma oscillations have been implicated in a wide range of human cognitive processes including perception, attention, learning, and memory (Kahana, 2006). In a largely parallel line of research, a number of researchers have examined the func- tional roles of different brain regions in navigation via patient-lesion and functional-magnetic- resonance-imaging (fMRI) techniques. The results from these studies emphasize the role of the hippocampus and related medial temporal lobe structures, along with regions of parietal 2 and frontal cortices, in tasks that require spatial information processing (see Burgess et al., 2002; Kessels et al., 2001, for a review). In particular, regions of right frontal, temporal, and parietal cortex are specifically activate when participants are engaged in spatial processing (Gramann et al., 2006; Neggers et al., 2006), and impaired spatial memory performance is associated with right-hemisphere lesions (Asselen et al., 2006). Furthermore, studies show that the magnitude of right-hippocampus activation positively correlates with navigation accuracy (Maguire et al., 1998) and that the size of a subject’s right hippocampus is pos- itively correlated with their navigation experience (Maguire et al., 2000). Thus, a critical hypothesis emerging from these studies is that certain types of spatial processing, particu- larly those underlying navigation and knowledge of spatial locations, are lateralized to the right hemisphere (Smith & Milner, 1989; Nunn et al., 1999; Wolbers & Buchel, 2005; Neggers et al., 2006; Diaz-Asper et al., 2006; Gramann et al., 2006; Asselen et al., 2006; Parslow et al., 2005; Spiers, Burgess, et al., 2001; Voermans et al., 2004; Abrahams et al., 1997; Leung et al., 2007; Worsley et al., 2001; Bohbot et al., 2004; Kessels et al., 2002; Weniger & Irle, 2006). In recent years, a number of methodical studies reported close relations between fMRI data and direct recordings of brain oscillations (Logothetis et al., 2001; Mukamel et al., 2005). To the extent that navigation-related