Developmental Topographical Disorientation and Decreased Hippocampal Functional Connectivity Giuseppe Iaria, 1,2 * Aiden E.G.F. Arnold, 1 Ford Burles, 1 Irene Liu, 1 Edward Slone, 1 Sarah Barclay, 3 Torben N. Bech-Hansen, 2,3 and Richard M. Levy 4 ABSTRACT: Developmental topographical disorientation (DTD) is a newly discovered cognitive disorder in which individuals experience a lifelong history of getting lost in both novel and familiar surroundings. Recent studies have shown that such a selective orientation defect relies primarily on the inability of the individuals to form cognitive maps, i.e., mental representations of the surrounding that allow individuals to get anywhere from any location in the environment, although other orienta- tion skills are additionally affected. To date, the neural correlates of this developmental condition are unknown. Here, we tested the hypothesis that DTD may be related to ineffective functional connectivity between the hippocampus (HC; known to be critical for cognitive maps) and other brain regions critical for spatial orientation. A group of individuals with DTD and a group of control subjects underwent a resting-state functional magnetic resonance imaging (rsfMRI) scan. In addition, we performed voxel-based morphometry to investigate potential structural differences between individuals with DTD and controls. The results of the rsfMRI study revealed a decreased functional connectivity between the right HC and the prefrontal cortex (PFC) in individuals with DTD. No structural differences were detected between groups. These findings provide evidence that ineffective functional connectivity between HC and PFC may affect the monitoring and processing of spatial informa- tion while moving within an environment, resulting in the lifelong selec- tive inability of individuals with DTD to form cognitive maps that are critical for orienting in both familiar and unfamiliar surroundings. V C 2014 Wiley Periodicals, Inc. KEY WORDS: navigation; orientation; prefrontal cortex; resting state; spatial memory INTRODUCTION Beyond the well-known occurrence of topographical disorientation as a consequence of acquired brain damage (Aguirre and D’Esposito, 1999), recent stud- ies have shown that topographical disorientation may also originate in childhood in the absence of any brain injuries or neurological conditions (Iaria et al., 2009; Bianchini et al., 2010; Iaria and Barton, 2010; Bianchini et al., 2013; Palermo et al., 2013). This newly discovered cognitive disorder is known as devel- opmental topographical disorientation (DTD), a condi- tion that seems to constitute a discrete disorder rather than representing the extreme case on a continuum of topographical orientation skills in humans. Individuals with DTD are unable to find their way in both novel and familiar surroundings, such as the neighborhoods that they have lived in for many years, or, in some extreme cases, even their own homes; they report suffering from these orientation problems on a daily basis since childhood, and have no other cogni- tive complaints affecting their daily activities. As recently described in a comprehensive investiga- tion of orientation skills in a sample of 120 individu- als affected by DTD (Iaria and Barton, 2010), these individuals have difficulties performing a variety of spatial orientation tasks and, importantly, are unable to orient by means of cognitive maps, as confirmed by testing in both ecological (Iaria et al., 2009; Bian- chini et al., 2010) and virtual (Iaria and Barton, 2010; Bianchini et al., 2013) environments. Although these findings point toward a deficit in cognitive map formation as the behavioral mechanism underlying the lifelong history of topographical disorientation in individuals with DTD, to date, the neural correlates of this developmental condition remain unknown. The inability to orient by means of cognitive maps suggests that the neural mechanisms related to the presence of DTD may have their source within the hippocampus (HC), a region in the medial temporal lobe (MTL) that is well known to be critical for cog- nitive maps in both human and non-human animals (O’Keefe and Nadel, 1978; Iaria et al., 2007). Recent research has elaborated on the role of the HC in encoding and navigating environments by showing that interactions between the HC and other regions 1 Department of Psychology and Hotchkiss Brain Institute, NeuroLab University of Calgary 2500 University Drive NW, Calgary, Alberta, Can- ada, T2N 1N4; 2 Alberta Children’s Hospital Research Institute, Univer- sity of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada, T2N 1N4; 3 Department of Medical Genetics, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada, T2N 1N4; 4 Fac- ulty of Environmental Design, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada, T2N 1N4 TBH is the inaugural Roy and Joan Allen Professor in Sight Research. Grant sponsor: Natural Sciences and Engineering Research Council of Canada (NSERC, to GI), Social Sciences and Humanities Research Coun- cil of Canada (SSHRC, to GI), Alberta Health Services and the Ministry of Human Services as a part of the Collaborative Research Grant Initia- tive: Mental Wellness in Seniors and Persons with Disabilities and an NSERC PGS D (to AA), and graduate student stipend from ACHRI CIHR Genetics Training Program (to SB).; Grant sponsor: Natural Sciences and Engineering Research Council of Canada (NSERC) and Social Sciences and Humanities Research Council of Canada (SSHRC). *Correspondence to: Giuseppe Iaria, Department of Psychology – A218, 2500 University Drive, NW, Calgary, Alberta, Canada T2N 1N4. E-mail: giaria@ucalgary.ca Accepted for publication 19 June 2014. DOI 10.1002/hipo.22317 Published online 28 June 2014 in Wiley Online Library (wileyonlinelibrary.com). V C 2014 WILEY PERIODICALS, INC. HIPPOCAMPUS 24:1364–1374 (2014)