Heterogeneity in Human Retrosplenial Cortex: a Review of Function and Connectivity

Behavioral Neuroscience

Heterogeneity in Human Retrosplenial Cortex: A Review of Function and Connectivity

Elizabeth R. Chrastil University of California, Santa Barbara

Retrosplenial cortex (RSC) is an important information hub in the brain and several mental disorders demonstrate RSC dysfunction, but its role is still largely unclear. Although researchers in many cognitive domains have recognized the importance of RSC, a broader synthesis of RSC function across cognitive domains is lacking. This review examines human RSC function across several cognitive domains, considering both specific cognitive functions and the RSC subregions in which that function occurs. Overall, this review found evidence for a functional gradient across the anterior-posterior axis of RSC involving several cognitive domains. Within the cognitive realm of navigation, RSC is important for path integration (including head direction), landmark processing, and the transformation between viewpoints. The related cognitive domain of scene processing encompasses information about place recognition and spatial context. Both navigation and scene processing are localized to more posterior subregions of RSC. Episodic memory (particularly episodic recall), mental imagery, and self-referential processing tend to be supported by anterior portions of RSC. The heterogeneity of RSC function is consistent with RSC anatomy and connectivity found in animal models. Finally, this review examines several common themes that emerged, including mental imagery and self-referential processing. Both the functional heterogeneity and the common themes of RSC function could provide new avenues for research and insight into the numerous mental disorders characterized by RSC dysfunction.

Keywords: episodic memory, mental imagery, navigation, scene perception, self-referential processing

Retrosplenial cortex (RSC) has been associated with many This review has two primary goals. First, this review aims to diverse functions. In animal models, studies of RSC function are highlight functional differences across subregions of RSC derived largely focused on spatial navigation as well as spatial and con- from human neuroimaging studies, arguing for a functional gradi- textual memory. In humans, RSC is known to be involved in a ent across the anterior-posterior axis of RSC. Similar gradients in wide variety of cognitive functions, including scene perception the hippocampus (Kjelstrup et al., 2008; Poppenk, Evensmoen, (Epstein & Higgins, 2007; Park, Intraub, Yi, Widders, & Chun, Moscovitch, & Nadel, 2013) and medial entorhinal cortex (Gio- 2007; Summerfield, Hassabis, & Maguire, 2010), spatial naviga- como, Zilli, Fransén, & Hasselmo, 2007) relate to the spatial scale tion (Auger, Mullally, & Maguire, 2012; Chrastil, Sherrill, Has- of processing, while gradients of cognitive function have been selmo, & Stern, 2015; Sherrill et al., 2013; Wolbers & Büchel, observed in parahippocampal cortex (Baldassano, Beck, & Fei-Fei, 2005), episodic and autobiographical memory (Steinvorth, Corkin, 2013; Baldassano, Esteva, Fei-Fei, & Beck, 2016) and precuneus & Halgren, 2006; Summerfield, Hassabis, & Maguire, 2009; Vin- (Peer, Salomon, Goldberg, Blanke, & Arzy, 2015). Thus, wherever cent et al., 2006), head direction (Baumann & Mattingley, 2010; possible, anterior/posterior and medial/lateral distinctions will be Marchette, Vass, Ryan, & Epstein, 2014; Shine, Valdés-Herrera, made throughout the review (see Figure 1). Second, this review Hegarty, & Wolbers, 2016), pain and emotional processing (Kucyi aims to reach across cognitive domains to examine the functional et al., 2014; Luo et al., 2014), and mental imagery (Boccia et al., commonalities throughout the entire RSC region. Part of this This document is copyrighted by the American Psychological Association or one of its allied2015 publishers. ; Summerfield et al., 2009). Previous research has taken a process will be to examine RSC contributions to all of its disparate This article is intended solely for the personal use ofdomain-specific the individual user and is not to be disseminated broadly. approach to understanding RSC, yielding consid- functions and to consider what aspects they share, with suggestions erable insight into RSC function, but also preventing a synthesis of where future work could test these potential unifying functions. across domains into a broader understanding of the region. The review will propose that the strongest commonalities are found in self-referential processing, imagery, and memory. This review is designed for researchers of both human and This article was published Online First August 30, 2018. animal models of RSC structure and function, with an emphasis on I thank Chantal Stern, Sean Tobyne, Rachel Nauer, and Allen Chang for anatomical and functional variation across the RSC region. The their many insightful conversations about RSC. A portion of these ideas scholarly traditions and history of RSC research in animals and were presented at the UC Irvine International Conference on Learning and humans differ (Knight & Hayman, 2014), and each tradition can Memory, 2018. Correspondence concerning this article should be addressed to Elizabeth offer insight to the other. Researchers of human RSC can gain R. Chrastil, Department of Geography, University of California, Santa insight from anatomical and structural connectivity studies in Barbara, 1832 Ellison Hall, UCSB, Santa Barbara, CA 93106-4060. E- rodents and nonhuman primates, as well as some key lesion and mail: [email protected] electrophysiological recording studies (for detailed analysis of

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Figure 1. Anatomy of the human retrosplenial cortex (RSC) region. Human anterior RSC corresponds to ventral RSC in the rodent, and posterior in the human corresponds to rodent dorsal. Left: sagittal view of brain near the midline. Right: Axial view. Subregions are shown in different colors and described from anterior to posterior. Red (medium dark gray): posterior cingulate isthmus, very often included as part of anterior RSC. Blue (darkest gray): Anterior RSC, the most anatomically defined section of RSC. Orange (lightest gray): Parietal- occipital sulcus, part of posterior RSC and part of the functionally defined retrosplenial complex. Green (medium light gray): Extreme posterior RSC, part of the functionally defined retrosplenial complex. This subregion does not include any anatomical RSC, but does include part of the calcarine sulcus. See the online article for the color version of this figure.

rodent behavior and RSC function, see Clark et al., in press; Smith Histological studies provide a more fine-grained approach to et al., in press; Todd & Bucci, 2015). Those using animal models defining RSC, making distinctions between cell types and layers. can benefit from the wide variety of complex cognitive tasks used Granular cortex is located in Brodmann areas (BA) 29a-c in in human neuroimaging, as well as from observing RSC dysfunc- anterior RSC (corresponding to ventral in the rodent), whereas tion in clinical populations. dysgranular cortex is found in BA30 in the posterior (dorsal) The review begins with an overview of RSC anatomy and region (Kobayashi & Amaral, 2000; Vann et al., 2009). Histology connectivity based on animal models. It then proceeds through also suggests that much of RSC is buried into the sulcus of the several primary functions of RSC as explored through human corpus callosum (Braak, 1979; Kobayashi & Amaral, 2000). Area neuroimaging, including navigation, scene perception, episodic 30v in the depths of the anterior calcarine sulcus and area 23 in the memory, and body/self-related processing. Throughout, differ- nearby posterior cingulate are often included in discussions of ences between anterior and posterior RSC will be highlighted, and greater RSC (Kobayashi & Amaral, 2000; Morris, Petrides, & the evidence supporting an anterior-posterior gradient of function Pandya, 1999), although this has been debated (Vann et al., 2009). will be examined in a separate section. Finally, the review will Unfortunately, cytoarchitecture cannot typically be resolved from examine several potential candidates for unifying RSC function standard-resolution MRI (although see Fischl et al., 2008). Thus, across cognitive domains. most in vivo human MRI imaging includes BA29, BA30, and a large swath of BA23. Anatomy Employing functional definitions of RSC in human fMRI can In humans, RSC is a three-dimensional diagonally oriented circumvent many of these problems, and can be very useful for This document is copyrighted by the American Psychological Association or one of its allied publishers. region (see Figure 1), such that the anterior portion also tends localizing function within individuals for further analysis, such as This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. to be superior and medial, and the posterior portion tends to be for multivoxel pattern analysis (MVPA). However, this approach inferior and lateral. Because of this oblique orientation, these is less useful for generalizing across studies or cognitive domains terms are often used interchangeably—as this review will do. because they restrict interpretation to an a priori function. In The splenium of the corpus callosum and parietal-occipital addition, BOLD registration with functional definitions could be sulcus (POS) provide respective anterior and posterior anatom- reduced compared with anatomical definitions, making it difficult ical boundaries of RSC (Kobayashi & Amaral, 2000; Vann, to identify the underlying anatomical areas. Functional definitions Aggleton, & Maguire, 2009), but there are no clear anatomical are most common for scene perception, which typically recruits boundaries with precuneus, parahippocampal cortex (PHC), or regions posterior to BA29 and 30 and includes POS, lingual gyrus, posterior cingulate cortex (Kobayashi & Amaral, 2000; Pruess- and calcarine sulcus (Epstein & Kanwisher, 1998; Marchette et al., ner et al., 2002). Without clear anatomical markers to distin- 2014; Park & Chun, 2009; Silson, Steel, & Baker, 2016; Vass & guish where, for example, RSC ends and PHC begins, creating Epstein, 2013). Together, these areas are often defined more regions of interest (ROIs) and ascribing function from MRI broadly as retrosplenial complex (Epstein, 2008). Recently, Silson scans to one region or another can be difficult. et al. suggested renaming the region to the medial place area to HETEROGENEITY IN HUMAN RETROSPLENIAL CORTEX 319

better reflect the anatomy (Silson et al., 2016), but this naming still 2003, 2007; Sugar & Witter, 2016). Primate brains have a large reflects only one function of RSC. number of reciprocal connections between RSC/posterior cingu- These multiple definitions and lack of consensus in anatomy— late and PHC, but few connections with perirhinal cortex especially in the human—makes determining RSC function diffi- (Lavenex, Suzuki, & Amaral, 2002), suggesting that information cult, and mapping the terminology used in human fMRI studies from RSC flows through the “where” pathway rather than the onto the histologically defined areas is complicated. For simplic- object-oriented “what” pathway. ity, this review will refer to the entire region as “RSC,” with the More fine-grained breakdowns of the anatomical connections strong caveat that this region of interest extends well beyond the initiating or terminating in specific subregions of RSC can be boundaries of RSC as defined by animal and histological studies. informative about differing functions across RSC. Granular This review includes studies under all anatomical, histological, and RSC—also referred to as BA29 and located in anterior (ventral) functional definitions of RSC, making clear whenever possible to RSC—shares connections with hippocampus, subiculum, and an- indicate where within the retrosplenial region the observed acti- terior thalamic nuclei (Kobayashi & Amaral, 2003, 2007; van vation occurs. Where appropriate, both anatomical (e.g., parietal- Groen & Wyss, 1990) and rodent RSC contains head direction occipital sulcus) and functional (e.g., posterior RSC) labels were cells (L. L. Chen, Lin, Green, Barnes, & McNaughton, 1994). Area included to facilitate the mapping between anatomical and func- 29 projects within areas of anterior cingulate, visual cortex (only in tional approaches. some parts of 29), frontal area 11, and subiculum in the rat (Vogt & Miller, 1983), as well as anteroventral, anterodorsal, and lat- RSC Connectivity in Animal Models erodorsal thalamic nuclei (Vogt, Pandya, & Rosene, 1987). These connections suggest that granular RSC integrates thalamic and An important part of determining how function differs across limbic information (Miller et al., 2014; van Groen & Wyss, 1990). RSC in humans is a clear understanding of the anatomical con- For example, granular RSC makes up between 10 and 20% of the nections between RSC and other parts of the brain. This section inputs to entorhinal cortex (Insausti et al., 1987). Area 29 also has details rodent and primate studies to provide information on the reciprocal connections with anterior cingulate, orbital areas, and histology and connectivity of RSC. Although examinations of motor areas in the rat, facilitating the processing of spatial move- animal studies can provide great insight into anatomy and function ments (Shibata et al., 2004; Shibata & Naito, 2008). Granular that cannot be tested in humans, caution should be taken when BA29 is the recipient of the vast majority of projections from interpreting these studies, because the correspondence between hippocampus (via subiculum and presubiculum) and entorhinal human and animal may not be complete. There are substantial cortex in the monkey (Aggleton, Wright, Vann, & Saunders, 2012) differences between the rodent, nonhuman primate, and human and rat (van Groen & Wyss, 2003), although both granular and RSC in the lamination of RSC and the organization of nearby dysgranular RSC project to the postsubiculum in the rat (van posterior cingulate (Vann et al., 2009). In addition, rodents and Groen & Wyss, 1992). Thus, granular RSC appears well-situated humans contrast in their relative reliance on visual, proprioceptive, to play a role in memory, but may contribute less to spatial and olfactory information during navigation, which could affect behavior. the circuitry of RSC connections. In contrast, the more posterior (dorsal) dysgranular region of Animal studies indicate that different subregions of RSC show RSC, or BA30, demonstrates connectivity with early visual areas, variability in their connections with other brain areas (Kobayashi parietal cortex, and PHC (Burwell & Amaral, 1998; Kobayashi & & Amaral, 2003, 2007; Morris et al., 1999; Shibata, Kondo, & Amaral, 2003, 2007; van Groen & Wyss, 1992). Dysgranular Naito, 2004; Shibata & Naito, 2008; van Groen & Wyss, 1990, rodent RSC receives connections from the nucleus reuniens of the 1992; Wyass & Van Groen, 1992; see Miller, Vedder, Law, & thalamus (van Groen & Wyss, 1992), which is a key part of a Smith, 2014; Sugar, Witter, van Strien, & Cappaert, 2011 for circuit theorized to be important for goal-directed spatial naviga- review). There is also a large degree of connectivity between the tion in animals (Ito, Zhang, Witter, Moser, & Moser, 2015). Brodmann areas within RSC, including BA23 (Kobayashi & Ama- Dysgranular rodent RSC has head direction cells that are also ral, 2003, 2007; van Groen & Wyss, 2003), suggesting that infor- sensitive to aspects of movement like speed or turns, unlike gran- mation stemming from other areas of the brain is integrated, ular RSC, which is sensitive to head direction only (L. L. Chen et transformed, or relayed via RSC. In general, afferent input into al., 1994). The connections from RSC to PHC are topographically This document is copyrighted by the American Psychological Association or one of its allied publishers. primate RSC comes from frontal regions (especially from BA46 organized from birth, although the full density does not develop This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. and BA9 connecting to all areas), the hippocampus (especially to until rats develop spatially tuned neurons in PHC, indicating that BA29), parietal (primarily to BA23), and some occipital (espe- RSC projections are important for the development of head direc- cially to BA30 and 23) and anterior cingulate (Kobayashi & tion and border cells (Sugar & Witter, 2016). BA30 has reciprocal Amaral, 2003). Major efferent projections from primate RSC connections with BA23, prefrontal cortex BA9 and BA46, poste- (BA29/30) include frontal regions BA46, 9, 10, and 11, as well as rior PHC, presubiculum and entorhinal cortex, as well as several entorhinal cortex, presubiculum and parasubiculum of the hip- thalamic nuclei (Morris et al., 1999). BA23 has similar projections pocampus, and PHC. Cingulate (BA23) projections are similar, except for limited projections to entorhinal cortex, and the tha- although with different densities, and with additional projections to lamic projections it receives are from anterior medial thalamic parietal regions (Kobayashi & Amaral, 2007). General anatomical nuclei only (Morris et al., 1999; Vogt et al., 1987). A high density connections have been found between RSC and the medial tem- of reciprocal connections between dysgranular RSC and medial poral lobe (MTL) as well as prefrontal areas, including PHC, parietal cortex provides anatomical evidence that RSC serves as hippocampus, entorhinal cortex, and mPFC (Burwell & Amaral, the intermediary for information from parietal to medial temporal 1998; Insausti, Amaral, & Cowan, 1987; Kobayashi & Amaral, lobe regions (Wilber et al., 2015). Interestingly, BA30 of RSC 320 CHRASTIL

projects more heavily to posterior parietal cortex than the other typically include the parahippocampal cortex, medial prefrontal way around (Olsen, Ohara, Iijima, & Witter, 2017). In sum, the cortex (mPFC), angular gyrus, posterior cingulate, and temporo- connections of dysgranular RSC make that subregion more suited parietal junction, with precuneus and the hippocampus appearing to visual and spatial tasks compared with granular RSC. in some, but not in all, definitions of DMN (e.g., Power et al., The anatomical connections involving RSC suggest that it is an 2011). epicenter of information from vision, self-motion, and peri- An understanding of the DMN is important to gain insight into personal space, and is ideally situated to synthesize information RSC function for several reasons. First, broader knowledge of how from these sources. Additional connections with hippocampus and the DMN relates to cognitive function can be informative about other MTL areas suggest a strong involvement in memory. Gen- RSC, because it is a node in the network. Second, RSC BOLD erally, granular RSC has stronger ties to limbic areas, whereas activation is frequently highly correlated with activation in other dysgranular RSC has stronger ties to parietal and visual areas, as nodes of the DMN. This high correlation leads to difficulties in well as the nucleus reuniens of the thalamus, indicating its impor- separating out function specifically related to RSC rather than tance to spatial processing. These differences in anatomical con- other nodes in the network (Figure 2b). Nonadditive models of nections are echoed by functional differences across RSC observed brain function suggest that no one unique brain function can be in human neuroimaging, which are addressed in the remainder of consistently attributed to core brain areas within a network (Bas- the review. sett & Gazzaniga, 2011; Ekstrom, Arnold, & Iaria, 2014), and it is possible that RSC and other regions of the DMN form a nonad- RSC in Human Functional Imaging ditive network. The review will indicate where and when RSC demonstrates similarities and differences from other nodes of the Much of our understanding of the cognitive functions of RSC stems from human fMRI imaging. Human neuroimaging has used DMN. Finally, alterations in DMN function in clinical populations numerous behavioral paradigms to relate brain BOLD activation can be informative about how DMN and RSC function plays a role with cognition. For example, as described earlier, functional def- in neurological disorders. However, there is the potential for initions of RSC have emerged by conducting functional localizers differences in motion artifacts between patients and controls dur- of scene-selective cortex. Although fMRI imaging has yielded a ing rest (Power et al., 2014; Power, Schlaggar, & Petersen, 2015), number of insights into localization in the brain, several caveats so many clinical findings must be interpreted with caution. must be taken when interpreting fMRI studies. Voxel size and The remainder of the review will focus on human fMRI imag- resolution, coupled with spatial smoothing used in the analysis, ing, with key rodent studies included when relevant to cognitive can affect the precision with which localizations can be made. As function. with all discussions of previous literature, the conclusions rely on the quality of the studies examined. In addition, reports on the center of peak activation could differ from the diffuse spread of RSC for Spatial Navigation activation across a larger region. The registration of images from Spatial navigation is one of the most widely cited functions of the individual level to a group average is not always as accurate as RSC (Auger et al., 2012; Baumann & Mattingley, 2010; Chrastil et it should be (Yassa & Stark, 2009). Finally, the posterior midline al., 2015; Marchette et al., 2014; Sherrill et al., 2013; Wolbers & area is a “hot spot” for false positive reports in fMRI (Eklund, Büchel, 2005). Human RSC is involved in planning route to a goal Nichols, & Knutsson, 2016), suggesting that some RSC findings (Spiers & Maguire, 2006), and posterior RSC is involved in both could be spurious. Although these considerations are limitations of the formation and use of a cognitive map (Iaria, Chen, Guariglia, fMRI broadly speaking, with the exception of higher false posi- Ptito, & Petrides, 2007). Navigation on a computer through a tives along the posterior midline, the there is little reason to suspect folder system also elicits activity in RSC, similar to spatial navi- that they impact research on RSC more than any other brain gation (Benn et al., 2015). Older adults have lower activation in region. anterior RSC than younger adults during navigation, and RSC Human neuroimaging has also provided a key concept that will activity is correlated with accuracy across all ages (Moffat, Elkins, play a significant role in this review: intrinsic functional connec- & Resnick, 2006). Intrinsic functional connectivity between RSC tivity networks—areas that spontaneously fluctuate in synchrony This document is copyrighted by the American Psychological Association or one of its allied publishers. and hippocampus is greater for self-reported good navigators than during rest (Fox & Raichle, 2007). Intrinsic networks within the This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. brain reflect past inputs and communication (Damoiseaux et al., for poor navigators during rest (Sulpizio, Boccia, Guariglia, & 2006; Fox & Raichle, 2007; Papo, 2013) as well as structural Galati, 2016). In rodents, temporary inaction of RSC during spatial architecture (van den Heuvel, Mandl, Kahn, & Hulshoff Pol, memory retrieval in a water maze impairs performance, whereas 2009). These networks reflect intrinsic connectivity rather than overexpression of transcription factors in RSC leads to enhance- dynamic connectivity shifts during cognitive tasks, but they do ment of spatial memory (Czajkowski et al., 2014). Similarly, RSC have a strong relationship with task-based networks (Cole, Bassett, lesions in humans are associated with difficulty in spatial orienta- Power, Braver, & Petersen, 2014; Laird et al., 2011). In particular, tion (Aguirre & D’Esposito, 1999; Hashimoto, Tanaka, & Nakano, RSC is a major node of the Default Mode Network (DMN, Figure 2010; Takahashi, Kawamura, Shiota, Kasahata, & Hirayama, 2a). Although this network was initially associated with task- 1997). These findings provide general support for a role for RSC negative states and rest, it has since been linked to episodic in spatial memory and navigation (Ekstrom, Huffman, & Starrett, memory and representations of oneself (Andrews-Hanna, 2012; 2017). Although RSC makes broad contributions to navigation, it Buckner, Andrews-Hanna, & Schacter, 2008; Buckner & Carroll, also makes specific contributions to path integration, landmark 2007; Fox et al., 2005; Laird et al., 2011). Other nodes in the DMN recognition, and transformations between viewpoint perspectives. HETEROGENEITY IN HUMAN RETROSPLENIAL CORTEX 321

Figure 2. Images of the default mode network (DMN), a network of brain areas that typically activate together during rest. Nodes of the DMN include RSC, hippocampus, medial prefrontal cortex (mPFC), parahippocampal cortex (PHC), precuneus, posterior cingulate, angular gyrus, and temporoparietal junction, among others. (A) The brain regions identified in DMN using multiple imaging modalities (Adapted from “The brain’s default network,” by R. L. Buckner, J. R. Andrews-Hanna, and D. L. Schacter, 2008, Annals of the New York Academy of Sciences, 1124, pp. 1–38. Copyright 2008 by Wiley Publishing. Adapted with permission). Left: medial sagittal view. Right: lateral sagittal view. (B) Brain areas outside of RSC identified by entering the term “retrosplenial” into the automated meta-analysis program Neurosynth (Yarkoni, Poldrack, Nichols, Van Essen, & Wager, 2011). In addition to regions throughout the RSC region, the term “retrosplenial” returns areas of the hippocampus (left), PHC (middle), and mPFC (right). This finding highlights the difficulty in separating RSC function from the function of other nodes in the DMN. See the online article for the color version of this figure.

Path Integration person navigation in a landmark-free environment that requires updating of position (Sherrill et al., 2013). These findings suggest RSC plays a critical role in the navigational process of path that RSC is important for tracking position and orientation and is integration, the updating of position, and orientation during move- sensitive to distance and orientation magnitudes. ment in the environment. Although human path integration can be One way that RSC might contribute to path integration is by quite coarse (Loomis et al., 1993; Souman, Frissen, Sreenivasa, & supporting head direction information (Baumann & Mattingley, Ernst, 2009), evidence suggests that both human and animal brains 2010; Diekmann, Jürgens, & Becker, 2009; Marchette et al., 2014; process information that could be used to support path integration. Shine et al., 2016). Head direction cells have been found in rodent During path integration, RSC activation varies in response to RSC, with subsets of these cells sensitive to motion information Euclidean distance from a location (Figure 3a; Chrastil et al., 2015) and the magnitude of simple translations and rotations (Chen et al., 1994; Cho & Sharp, 2001), however head direction (Chrastil, Sherrill, Hasselmo, & Stern, 2016). Similar evidence for cells have not yet found in human RSC. Both anatomically defined distance encoding has been found in rodents, with RSC sensitive to RSC and areas extending into the POS region are sensitive to This document is copyrighted by the American Psychological Association or one of its allied publishers. encoding distances within sections of a route and distances be- changes in heading direction in humans (Baumann & Mattingley, This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. tween all route locations (Figure 3b; Alexander & Nitz, 2017). 2010; Shine et al., 2016). In contrast, Vass & Epstein found only During distance estimation and reproduction in humans, RSC weak support for RSC involvement in direction coding, instead activity is associated with the degree to which the current trial’s finding a stronger relationship in RSC with location coding (Vass distance aligns with the mean of previous trials (Wiener, Michae- & Epstein, 2013). During path integration, RSC is more active for lis, & Thompson, 2016). This finding indicates that RSC not only encoding rotations than for encoding translations and RSC activa- tracks distance on a given trial, but that it tracks multiple path tion correlates with individual performance in tracking visual distances during the course of a path integration session. RSC has self-rotations, indicating a particular role in heading orientation been shown to be sensitive to egocentric (navigator centered) (Chrastil et al., 2016). Although the path integration studies re- distance in nonpath integration tasks as well (Gauthier & van viewed earlier suggest that heading cannot be the exclusive func- Wassenhove, 2016; Persichetti & Dilks, 2016). In addition, larger tion of RSC (e.g., RSC is active when tracking translation without gray matter volume in RSC is associated with increased human any rotation), head direction is a major function of RSC. path integration ability (Chrastil, Sherrill, Aselcioglu, Hasselmo, The reference frame of head direction signals in RSC has been & Stern, 2017). Finally, RSC is active during successful first- the focus of considerable research. Head direction cell signals in 322 CHRASTIL

Figure 3. Retrosplenial cortex (RSC) is sensitive to distance during travel in circular trajectories. (A) In humans, RSC showed increasing fMRI BOLD activity with increasing distance from the home location. This finding is consistent with a Homing Vector Model, whereby signal shows periodic increases and decreases with distance from home (Adapted from “There and back again: Hippocampus and retrosplenial cortex track homing distance during human path integration,” by E. R. Chrastil, K. R. Sherrill, M. E. Hasselmo, and C. E. Stern, 2015, Journal of Neuroscience, 35, pp. 15442–15452. Copyright 2015 by Society for Neuroscience. Adapted with permission). (B) Similar findings have been observed in rodent RSC, with firing frequency demonstrating periodic patterns related to distance from different locations in a plus-shaped track (Adapted from “Spatially periodic activation patterns in retrosplenial cortex encode route sub-spaces and distance traveled,” by A. S. Alexander and D. A. Nitz, 2017, Current Biology, 27, 1551–1560. Copyright 2017 by Elsevier Publishing. Adapted with permission). See the online article for the color version of this figure.

rodent RSC have been considered to be allocentric (world-centered 2014). In contrast, when incorporating body-based cues during and independent of the navigator) because they are independent of learning and instructing participants to attend and orient to the the animal’s location and behavior and tend to be influenced by global reference frame, Shine et al. found RSC signals relating to external landmarks (Taube, 2007). However, head direction cell global heading, not just local cues (Shine et al., 2016). In rodents, firing is also related to the animal’s head position, which involves some head direction cells in dysgranular RSC play a role in some egocentric (viewer-centered and dependent on the navigator) associating local landmark cues with heading direction (Jacob et processing within the allocentric coordinate frame. In humans, al., 2017), indicating that local cues dominate global signals for encoding a spatial layout from a first-person perspective with these cells. Thus, the interaction between head direction, local rotation from a fixed location shows selective posterior RSC features, and body-based information is still not totally clear. activation compared with encoding from a top-down view. These effects are not seen in humans for a first-person viewpoint coupled Landmarks and Location with translation, suggesting that RSC could be more important for changes in egocentric head direction than for allocentric location Another theory about how RSC contributes to navigation is that This document is copyrighted by the American Psychological Association or one of its allied publishers. processing (Gomez, Cerles, Rousset, Rémy, & Baciu, 2014). it codes for landmarks. For example, human RSC is more sensitive This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. These findings highlight the difficulty is separating egocentric and to landmark-centered navigation than for viewer- or object- allocentric processing. The relationship of egocentric and allocen- centered navigation (Committeri et al., 2004). Auger and col- tric reference frames as dichotomous and modular entities has leagues found that RSC codes for landmark permanence—but not come under scrutiny recently (Ekstrom et al., 2017; Wang, 2017), necessarily size (Auger et al., 2012)—and for the specific number with implications for head direction. For example, updating head of permanent landmarks in an environment (Auger & Maguire, direction requires vestibular and proprioceptive information about 2013). In addition, RSC appears to be sensitive to information the magnitude of one’s own movements but also knowledge of the about stability and permanency, even in nonspatial situations (Au- external environment, indicating degrees of both egocentric and ger & Maguire, 2018). In contrast to PHC, which also coded the allocentric processing. number of permanent landmarks but showed no difference be- The scale—whether local or global—of heading cues is another tween good and poor navigators, RSC activation was greater for consideration of interest. When considering the source of heading good navigators, suggesting that RSC selectively facilities spatial cues, Marchette et al. found that posterior RSC is sensitive to local learning (Auger & Maguire, 2013). RSC is also involved in un- heading features, not the global reference frame (Marchette et al., derstanding a landmark as a “place” from both external and inter- HETEROGENEITY IN HUMAN RETROSPLENIAL CORTEX 323

nal viewpoints, but requires free access to memory to perform this ronment, suggesting the importance of RSC is creating allocentric function, suggesting that it retrieves spatial and conceptual infor- maps based on self-motion (Aguirre & D’Esposito, 1999; Cooper mation associated with the landmark. In contrast to the parahip- & Mizumori, 2001; Hashimoto et al., 2010; Maguire, 2001b; pocampal place area, another place-selective area, RSC did not Takahashi et al., 1997). Lesions in rodent BA29/30 impairs learn- require familiarity with the landmarks to relate different views. ing opposing first-person perspective views within the same room, (Marchette, Vass, Ryan, & Epstein, 2015). A recent computational but not for discrimination between digging media (Hindley et al., model provides clues as to how visual parallax of local landmarks 2014b), indicating the importance of RSC to learning first-person could potentially combine place and head direction information in viewpoints. RSC (Bicanski & Burgess, 2016), indicating the possible ways that Consistent with this model, human RSC activity remained landmark information can be used in navigation. steady over the course of learning in a pure route-learning task In rodents, dysgranular RSC plays a role in associating local (Wolbers, Weiller, & Büchel, 2004). But when encoding informa- landmark cues with heading direction (Jacob et al., 2017), and tion about locations relative to the current location, RSC showed lesions to BA29/30 cause impairments in location learning using increases in activity corresponding to the total amount of spatial distal cues, independently of heading direction (Hindley, Nelson, information participants knew about the layout (Auger et al., 2015; Aggleton, & Vann, 2014b). Granular RSC is important for rodent Wolbers & Büchel, 2005). Likewise, RSC is active when convert- navigation in both the light and dark, suggestive of internal and ing learned route knowledge into judgments about the allocentric external navigational cues, whereas dysgranular RSC is selective environment (Zhang, Copara, & Ekstrom, 2012) and when making for distal cues in the light, suggestive of visually driven cues decisions about a spatial layout from imagined viewpoints (Pothuizen, Davies, Albasser, Aggleton, & Vann, 2009). Granular (Dhindsa et al., 2014). In addition, medial RSC demonstrates RSC neurons fire in response to a light cue indicating a reward functional connectivity with visual optic flow areas when navigat- location, demonstrating the importance for goal-directed naviga- ing from a first-person—but not an overhead—perspective, indi- tion (Vedder, Miller, Harrison, & Smith, 2017). Together, these cating its importance in incorporating self-motion information into rodent studies indicate the importance of RSC to relating land- updating position (Sherrill et al., 2015). Furthermore, individuals marks, goals, and orientation while also demonstrating a distinc- who used an allocentric reference frame during a first-person tion between anterior (granular) and posterior (dysgranular) RSC. spatial updating task showed patterns of alpha band power which However, a landmark-based explanation of RSC function con- suggest that RSC is active during the processing of spatial infor- flicts with RSC’s involvement in navigation in landmark-free mation from an allocentric framework (Lin, Chiu, & Gramann, environments observed in humans (Chrastil et al., 2015; Sherrill et 2015), although caution must be taken in interpreting localizations al., 2013; Wiener et al., 2016). One possibility is that path inte- from scalp EEG. Rodent RSC is sensitive to both local and global gration in landmark-free environments still elicits some form of spaces, with cells active for the conjunction of progress in the location signal that can act as a landmark, such as when tracking route, location within the larger environment, and specific left or the home location. Another possibility is that landmark processing right turns (Alexander & Nitz, 2015). Rodent RSC also responses and self-motion tracking are supported by different subregions of to subroutes of the broader environment with periodic activations RSC, tapping subtly differing functions. From the images and at multiple spatial scales that cannot be attributed to turns alone coordinates provided, the activation related to permanent land- (Alexander & Nitz, 2017), suggesting that RSC is involved in marks tended to be more anterior/medial sections of RSC (Auger processing both local and global cues for orientation. Together, & Maguire, 2013, 2018; Auger et al., 2012; Auger, Zeidman, & these findings suggest that RSC is crucial to first-person naviga- Maguire, 2015), suggesting that it could be related to mnemonic tion that leads to learning allocentric information. rather than purely spatial function. In contrast, the activation Could this transformation between egocentric and allocentric related to landmark generalization as a place was localized to more reference frames also relate to other types of egocentric transfor- lateral RSC (Marchette et al., 2015), suggesting a more spatial mations? In particular, RSC could be important for perspective function. However, it is difficult to draw conclusions from a few taking—the changing of one’s viewpoint to a different viewpoint studies that were not designed to test this question; future work within the environment. Perspective taking differs from reference should examine these differences more directly. frame transformation—which converts from a top-down/survey/ bird’s eye perspective to a first-person perspective—in that per- This document is copyrighted by the American Psychological Association or one of its allied publishers. spective taking involves a change from one first-person perspec- This article is intended solely for the personal use ofTransformations the individual user and is not to be disseminated broadly. Between Perspectives tive to a different first-person perspective within the same Still within the spatial domain, one influential model has pro- environment. Using a tabletop spatial layout, participants viewed posed that RSC is important for transforming information between the table layout along with an indicator of the upcoming viewpoint egocentric (viewer-centered) and allocentric (world-centered) per- perspective shift. During this preparation, RSC/POS showed ac- spectives (Byrne, Becker, & Burgess, 2007). For a navigator to tivity that increased in relationship to increasing magnitude of the successfully reach their goals, the navigator must transform what upcoming perspective shift. Yet during the shift itself, RSC/POS they know about the larger environment into body-based actions. showed decreased activity compared with trials in which the shift For example, knowing the location of city hall relative to the was not marked ahead of time, suggesting that RSC is sensitive to current location requires a transformation into a series of left and perspective changes, whether in preparation of a change or during right turns to actually travel there. Motivation for this model stems a perspective change itself (Sulpizio, Committeri, Lambrey, from lesion studies in humans and animals showing that damage to Berthoz, & Galati, 2016). This pattern held true for movements to RSC impairs navigation when learning from direct experience, different perspectives within the room, but not when changes including the ability to change viewpoints and orient in an envi- occurred because of the rotation of a central table (Sulpizio, 324 CHRASTIL

Committeri, Lambrey, Berthoz, & Galati, 2013). Similarly, Lam- text are an important consideration for scene perception that goes brey et al. found that RSC/POS activation was related to viewpoint far beyond the concerns of navigation. Scene processing is a key rotation rather than the rotation of a table (Lambrey, Doeller, component of episodic memory, mental imagery, and mental pro- Berthoz, & Burgess, 2012). What is less clear is whether this jection. Studies of scene perception and spatial context typically perspective taking role for RSC applies to nonspatial—such as encompass posterior RSC, including parietal-occipital sulcus social—as well as spatial perspectives. (POS), in the functionally defined retrosplenial complex. On the other hand, the bidirectionality of this relationship is in question. Interestingly, dysgranular rodent BA30 projects more Place Recognition heavily to posterior parietal cortex than the other way around (Olsen et al., 2017), suggesting potential asymmetries in this Human RSC is important for mental imagery generally, but it is translation that should be explored in future research, including the more active when imagining local environmental cues used for potential for larger amounts of information to travel from RSC to navigation, compared with imagining geographical maps or spatial posterior parietal cortex. In addition, rodent posterior parietal relations in a familiar object, particularly in posterior RSC (Boccia cortex and visual areas project to a more restricted area of RSC et al., 2015). In a study of rodent place learning, when rats were than they receive input from (Wilber et al., 2015), indicating that not allowed to swim while learning a novel environment and less egocentric information is flowing into RSC compared with its instead were simply placed on the platform, those with RSC output. These findings may indicate that the transformation is lesions were unable to navigate to the platform later on. However, largely allocentric-to-egocentric, rather than the other way around the lesioned animals were able to find the platform when allowed or a bidirectional flow. Furthermore, there are very few connec- to actively swim to the platform during learning (Nelson, Hindley, tions between posterior parietal cortex and granular BA29 in the Pearce, Vann, & Aggleton, 2015). This finding suggests that RSC rodent, suggesting that any transformation function takes place in is important for incidental learning of spatial geometric features posterior RSC (Olsen et al., 2017). However, dysgranular RSC within a scene and environment through visual means and then serves as the indirect pathway between parietal cortex and hip- integrating that visual information into navigationally relevant pocampus, providing anatomical evidence that RSC serves as the behavior, but RSC may not be as important when learning includes intermediary for information from parietal to medial temporal lobe body-based cues. Human patients with RSC damage were able to regions (Wilber et al., 2015). These somewhat conflicting reports remember the locations of shapes using prominent landmarks regarding the connections between posterior parietal cortex and when they could remain stationary, but when rotated before test, RSC require further investigation to help substantiate or refute the patients were unable to remember the locations. (Hashimoto et al., viewpoint transformation hypothesis. 2010). This finding supports the idea that RSC is important for A further complication, as described earlier, is that egocentric integrating visual cues into navigationally relevant behavior, al- and allocentric reference frames might not be neatly separated into though RSC does not appear necessary to simply use landmark discrete processes but could form more of a continuum (Ekstrom cues without having to navigate. et al., 2017; Wang, 2017). Many of the behaviors described in this As discussed in the Navigation section, RSC is important for section rely on aspects of both egocentric and allocentric reference survey learning and putting scenes into context during movement frames and might not involve a direct transformation per se. One in humans (Epstein, 2008; Galati, Pelle, Berthoz, & Committeri, possibility is that RSC is involved across the continuum, such that 2010; Wolbers & Büchel, 2005). It is also sensitive to mirror- BOLD activity that appears to be related to perspective transfor- reversals in scenes, possibly as a means to encode egocentric mations could be as readily explained by general support of directions (Dilks, Julian, Kubilius, Spelke, & Kanwisher, 2011). navigation or other spatial functions. However, posterior RSC is not particularly responsive to the To sum up, navigation clearly makes up a considerable portion navigational affordances of a scene (Bonner & Epstein, 2017). of RSC’s cognitive functions. RSC tracks locations and movement Although a null result can be difficult to interpret, this result without landmarks, yet also is highly sensitive to landmark infor- potentially contradicts RSC’s role in transforming between ego- mation (Auger et al., 2015; Byrne et al., 2007; Ekstrom et al., centric and allocentric perspectives, but because the images were 2017). Tracking movement during path integration, especially all taken from a first-person perspective it is possible that this task converting that movement into a representation of the path trajec- tapped only egocentric navigation. Another possibility is that the This document is copyrighted by the American Psychological Association or one of its allied publishers. tory, might be related to the transformations between viewpoints. lesion studies described above involved remembering locations for This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. Stable landmarks provide information about location, which is later use, and in this study the navigational affordances were important for navigation as well as for understanding scenes and directly perceived. spatial context. What are the cues that RSC uses to support scene processing? Posterior human RSC is sensitive to environmental layout, global RSC for Scene Perception and Spatial Context scene properties, and size information, even without the presence of objects in the scene (Harel, Kravitz, & Baker, 2013; Kamps, Related to navigation, scene perception concerns how the visual Julian, Kubilius, Kanwisher, & Dilks, 2016; Park, Konkle, & system processes spatial information regarding places. Navigation Oliva, 2015). Posterior RSC even responds to just a bare line relies on places and views, and so is closely tied to scene percep- drawing of the scene (Walther, Chai, Caddigan, Beck, & Fei-Fei, tion; however, navigation also includes a variety of other mental 2011), suggesting that RSC is important for processing spatial mapping processes and the dynamic integration of visual informa- information, without necessarily associating any object contextual tion over time. On the other hand, the relevant features of scenes— details. Further, decoding of RSC signals suffers when using including scene statistics—that make up a “place” or spatial con- inverted images, suggesting that low-level visual information is HETEROGENEITY IN HUMAN RETROSPLENIAL CORTEX 325

not responsible for its response to scenes but instead that visual beyond simple place recognition, and indicates that contextual context or relating scenes to memory is more relevant to its cues are important for navigation and memory. processing (Walther, Caddigan, Fei-Fei, & Beck, 2009). In con- Spatial context cues have been shown to be important for trast, Troiani et al. found that RSC is responsive to scenes that learning. In rodents, granular RSC (BA29; anterior) responds to scored higher on several object-based dimensions, including place- contextually dependent rewards, indicating that both a reward and related, spatially defined, strongly associated with context, fixed in its location are important for RSC firing. In that study, RSC also a stable location, larger real-world size, and further in distance, developed place fields during the course of learning, although they which together form a “landmark suitability” factor. RSC is sen- were not context-specific, highlighting the importance of learning sitive to objects with this landmark suitability without a scene to RSC function (Smith, Barredo, & Mizumori, 2012). Further- background present, but the response was stronger when a back- more, granular rodent RSC neurons also show sensitivity to spatial ground was present (Troiani, Stigliani, Smith, & Epstein, 2014). conjunctions with a light indicating the location of reward, even RSC is also sensitive to egocentric distance information in scene though any particular spatial location was not predictive of reward. processing (Persichetti & Dilks, 2016), indicating that the observer This finding suggests that RSC plays a broader role of encoding plays a role in RSC processing. Because the scene-selective prop- the “conjunction of important cues and events and the contexts in erties that RSC is most responsive to is still not fully determined, which they occur” (Vedder et al., 2017). it is possible that multiple models of perceptual properties could RSC is involved in representations of nonspatial context, as well underlie RSC scene function (Lescroart, Stansbury, & Gallant, as spatial context. Lesions in dysgranular RSC (BA30; posterior) 2015). in rodents selectively impaired cross-modal (light to dark or vice RSC is functionally connected to other portions of the scene versa) object recognition between learning and recognition test, perception network, especially anterior parahippocampal place but there was no impairment when learning and test were both in area (PPA) and inferior parietal lobule (Baldassano et al., 2013, the light or dark (Hindley, Nelson, Aggleton, & Vann, 2014a). 2016), and is intrinsically connected during rest to frontal associ- This finding indicates that dysgranular RSC mediates learning ation areas (Nasr, Devaney, & Tootell, 2013). This network is across cue contexts, not just in spatial domains. In humans, Bar functionally connected to anterior parahippocampal cortex, fusi- and Aminoff found that RSC was sensitive to objects that had a form face area, and hippocampus more so than to visual areas, strong contextual relationship in both spatial and nonspatial do- suggesting that the scene-sensitive subnetwork that includes RSC mains, indicating a more domain-general role of building contex- is related to mnemonic function (Baldassano et al., 2016; Silson et tual associations in RSC (Bar & Aminoff, 2003). Of the scene- al., 2016). Supporting this finding, RSC is more responsive to selective regions, RSC is the most predictive of learning contextual familiar than to unfamiliar scenes (Epstein, Parker, & Feiler, associations, suggesting that it may be important for long-term 2007). One recent case study of a person with developmental encoding of contextual associations (see Figure 4; Aminoff & Tarr, topographic disorientation—the lifelong ability to orient in famil- 2015). Nonspatial contextual information processing in RSC could be part of a task-dependent associative learning system. For ex- iar surroundings (Iaria & Burles, 2016)—indicates that this patient ample, Ranganath and Ritchey proposed that RSC—as part of a has intact scene-responsivity in RSC and other scene-selective posterior medial memory system—is important for creating situ- areas as well as intact structural connectivity, but that the selective ation models that specify the gist of the spatial, temporal, and tuning properties of RSC and its functional connectivity with causal relationships that apply within a particular context. In their PPA differ from healthy controls (Kim, Aminoff, Kastner, & proposed system, RSC integrates external cues with internal in- Behrmann, 2015). These findings underscore the relationship be- formation by updating visual movement with body-based informa- tween scene perception, place recognition, and navigation. tion (Ranganath & Ritchey, 2012). This interpretation suggests a more direct line to episodic memory, which we turn to next. Spatial Context In sum, RSC is decidedly an important component of scene perception, along with the parahippocampal place area (PPA) and Related to its potential mnemonic functions, RSC is important occipital place area (OPA; also called transverse occipital sulcus for creating spatial context. RSC has preferential activation for a [TOS]). Scene perception is typically supported by posterior RSC, scene in a larger context, such as a labeled location (Epstein & in the parietal-occipital sulcus (POS, also called the retrosplenial This document is copyrighted by the American Psychological Association or one of its allied publishers. Higgins, 2007) and is sensitive to boundary extension illusions, in complex). Of the scene-sensitive regions, RSC is most closely This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. which people recall seeing a surrounding region of the scene that associated with memory functions, indicating that scene process- was not actually studied (Park et al., 2007). These findings suggest ing in RSC could be related to the development of spatial context that RSC extrapolates location information beyond the visual for memory. However, a strong place-recognition element, possi- perceptual input. RSC is sensitive to recalling the room context in bly related to landmark processing, is also a key component of which an item was learned, rather than the location on the com- scene processing in RSC, which could be more directly tied to its puter screen on which it was learned, suggesting that the spatial role in navigation. context is more specific to places rather than 2D spatial memory (Suzuki, Tsukiura, Matsue, Yamadori, & Fujii, 2005). RSC treats Episodic/Autobiographical Memory and Mental different views of a scene as being the same when viewed from Imagery continuous movement (Park & Chun, 2009; Park, Chun, & John- son, 2010), and is important for uniting multiple scenes together RSC is part of a network of regions that are important for into a single panorama space (Robertson, Hermann, Mynick, Krav- episodic and autobiographical memory—memory relating to one’s itz, & Kanwisher, 2016). Spatial context moves the discussion personal experience—in a variety of contexts (Addis, Moscovitch, 326 CHRASTIL

Figure 4. Human retrosplenial cortex (RSC) demonstrates BOLD activity that is sensitive to identity associations, spatial associations, and the conjunction of spatial and identity associations compared with no associations. This finding indicates that RSC might support making general contextual associations (Adapted from “Associative processing is inherent in scene perception,” by E. M. Aminoff and M. J. Tarr, 2015, PLoS ONE, 10, e0128840. Copyright 2015 by Public Library of Science. Adapted with permission). See the online article for the color version of this figure.

Crawley, & McAndrews, 2004; Maguire, 2001a; Piefke, Weiss, Grady, Hevenor, & Moscovitch, 2004; Piefke, Weiss, Zilles, Markowitsch, & Fink, 2005; Vilberg & Rugg, 2012; Wagner, Markowitsch, & Fink, 2003; Steinvorth et al., 2006). Medial RSC Shannon, Kahn, & Buckner, 2005). In addition, a substantial demonstrates functional connectivity with the hippocampus during portion of episodic memory research also relates to mentally successful episodic memory formation (Ranganath, Heller, Cohen, projecting oneself backward or forward in time, also called Brozinsky, & Rissman, 2005) and is part of a subnetwork of DMN prospection. Finally, to successfully project oneself into memories along with the hippocampus that is active during memory search or into the future, mental imagery is a key component of episodic (Kragel & Polyn, 2015). These empirical findings suggest a strong function. RSC plays a critical role in these processes, but is also link with hippocampal activation during episodic retrieval, high- highly correlated with activity in the hippocampus and other lighting the difficulty of separating mnemonic function in RSC regions of the default mode network (DMN). Thus, RSC’s specific from that of the hippocampus. It is possible that a nonadditive

This document is copyrighted by the American Psychological Association or one of its alliedrole publishers. in episodic memory may be difficult to untangle from other model of an episodic memory network is more appropriate to

This article is intended solely for the personal use ofregions the individual user and is not to be disseminated broadly. in DMN. describe the relationship between RSC and medial temporal lobe (MTL) structures such as the hippocampus and parahippocampal Episodic Remembering cortex (Ekstrom et al., 2014). In such a model, no one brain Most evidence related to RSC’s contributions to human episodic structure contributes a specific, separable component of memory, memory stems from memory retrieval, although it is also involved but rather memory occurs as an emergent property from the in encoding context-dependent episodic information (Huijbers et interactions between regions. al., 2012). Medial/anterior RSC shows increased activity as a On the other hand, damage to RSC in humans—without addi- function of retrieval delay when remembering words, similar to the tional damage to the hippocampus—can lead to profound amnesia hippocampus (Huijbers, Pennartz, & Daselaar, 2010), indicating a on its own (Valenstein et al., 1987). Furthermore, ECoG record- strong role in episodic memory retrieval. Both recent and remote ings demonstrate RSC selectivity to autobiographical stimuli in the autobiographical memories activate anterior RSC, along with hip- gamma range (30–180 Hz), which differed from other posterome- pocampus and other MTL structures, although it is more active for dial areas of the DMN (Dastjerdi et al., 2011). Thus, some evi- recent memories than for distant memories (Gilboa, Winocur, dence has emerged to differentiate RSC’s contributions to episodic HETEROGENEITY IN HUMAN RETROSPLENIAL CORTEX 327

memory from those of MTL or DMN regions. Considering mem- processing, imagery, or self-projection. Thus, RSC plays a key role ory more broadly, RSC has been posited to serve as an associative in personal and familiar memories and situations, but the separa- cortex for visual, sensory, as well as temporal associations (Jiang tion between spatial and nonspatial episodic information has not et al., in press; Todd & Bucci, 2015; Todd et al., 2018), or as a been fully tested. comparator between reference frames and relationships (Nelson et Finally, the association between RSC and memory is also evi- al., in press). When rodent RSC neurons were silenced in a denced through memory disorders. For instance, the earliest de- preconditioning phase during which nonreinforced associations creases in metabolic activity and cell loss associated with Alzhei- between a tone and a light were made, later associative learning mer’s disease (AD) are found in RSC and posterior cingulate behavior was impaired. This finding suggests that RSC is neces- (Aggleton, 2014; Nestor, Fryer, Ikeda, & Hodges, 2003). RSC, sary to make the initial associations between stimuli, well before along with other regions of the DMN, shows significant amyloid hippocampal processing occurs (Robinson et al., 2014). The sim- deposition and atrophy in people with AD (Buckner et al., 2005), ilarities and differences between RSC memory deficits and those including significantly reduced cortical volume and thickness in stemming from hippocampal damage have yet to be tested; more AD and multiple-domain mild cognitive impairment (MCI) pa- experimentation could determine the degree to which RSC mem- tients (Fennema-Notestine et al., 2009; Frisoni, Prestia, Rasser, ory functions are unique or part of a distributed network. Bonetti, & Thompson, 2009), but not in other types of dementia One proposed model of episodic memory describes how inter- (Tan, Wong, Hodges, Halliday, & Hornberger, 2013). In healthy actions between RSC and hippocampus could underlie normal young APOE ε4-carriers (a risk factor for AD), higher resting state memory processing, particularly spatial memory (Miller et al., coactivation has been observed throughout the DMN—including 2014). Basing their model on anatomical and functional connec- posterior RSC—compared with controls. This finding might indi- tions, lesion studies, and computational models of spatial memory, cate that APOE ε4-carriers have neural mechanisms to compensate Miller and colleagues argue that RSC interacts with the hippocam- for reduced plasticity and altered long-term potentiation (Filippini pus during the consolidation of information from the initial acqui- et al., 2009), although given the potential differences in motion sition into long-term memory. They proposed that RSC provides artifact between patients and controls during rest (Power et al., input to hippocampus with cues to navigation and context; RSC 2014, 2015), these findings must be interpreted with caution. then receives output from the hippocampus to facilitate memory Together, these findings suggest that RSC plays a critical role in consolidation. Information during encoding is fed forward into understanding memory loss. hippocampus, with memory consolidation occurring via interactions between RSC and hippocampus. Once fully learned, novel Mentalizing, Simulation, and Mental Imagery input activates the consolidated memory in RSC, which in turn activates the memory representation in the hippocampus. Memory In addition to episodic retrieval, RSC has been implicated in updating occurs via novelty detection mechanisms in the hip- other “episodic-related” or “episodic-like” functions. One such pocampus initiating rapid consolidation of the new information related function is mental imagery—vivid imagination of places, (Miller et al., 2014). Temporally coordinated spiking activity and people, or situations without visual input—which can be referred local field potentials between RSC and the hippocampus could to as mental simulation. For example, training in the method of support this integration (Alexander et al., in press). This approach loci—a spatial association strategy that relies on mental imagery— emphasizing interactions between brain regions can greatly infor memory enhancement results in increased activation in RSC crease our systems-level understanding of memory function. during memory recall in humans (Kondo et al., 2005). Many of the Although episodic and autobiographical memories have strong studies discussed in the episodic retrieval section relied on mental overlap, autobiographical memories that stir up a personal event, imagery to conjure up the memories rather than direct perception rather than simply remembering the act of learning an item, are of a stimulus (e.g., Addis et al., 2004; Piefke et al., 2003; Shirer et more related to default mode network activation, and thus also al., 2012; Steinvorth et al., 2006). For instance, RSC activity RSC activity (Chen, Gilmore, Nelson, & McDermott, 2017). RSC occurred during self-initiated episodic retrieval without any exter- is more responsive to items that are personally known, rather than nal visual cues (Kragel & Polyn, 2015). RSC has been proposed to recently studied items (Elman, Cohn-Sheehy, & Shimamura, play a role in episodic simulation more broadly by representing 2013), although the items in question were locations, potentially information important to temporal and other causal relationships This document is copyrighted by the American Psychological Association or one of its allied publishers. confusing the spatial and nonspatial aspects of memory. Similarly, within a context (Ranganath & Ritchey, 2012). This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. anterior RSC including posterior cingulate has been shown to be Another episodic-like function is mental projection, such as more responsive to familiar places as well as objects compared putting oneself in another place or time, but which could also be with unfamiliar places and objects (Sugiura, Shah, Zilles, & Fink, related to projecting oneself into the perspective of another person. 2005), and RSC is important for navigation in familiar, compared This projection into another person’s perspective, or mentalizing, with unfamiliar, environments (Boccia, Nemmi, & Guariglia, is an important part of the social and cognitive skills supporting 2014). RSC is recruited both when remembering episodic details theory of mind (ToM), which has been shown to activate anterior about a location and when making both coarse and fine-grained RSC and posterior cingulate (Calarge, Andreasen, & O’Leary, allocentric decisions about those locations (Hirshhorn, Grady, 2003). For example, overlap between ToM and episodic retrieval Rosenbaum, Winocur, & Moscovitch, 2012). RSC–MTL network was observed in the left anterior RSC, and anterior RSC into interactions increase during free episodic recall of the day’s events posterior cingulate had strong resting state connectivity to both compared with rest (Shirer, Ryali, Rykhlevskaia, Menon, & Gre- ToM and episodic networks (see Figure 5). In contrast, posterior icius, 2012). Together, these results suggest that both spatial and RSC has greater resting state functional connectivity with episodic information is processed in RSC, possibly via relational memory-defined seed regions than with mentalizing (ToM) seed 328 CHRASTIL

Figure 5. Conjunction analysis from a meta-analysis of episodic retrieval, autobiographical tasks, and mentalizing. Default Mode Network (DMN) regions are outlined in black. Anterior retrosplenial cortex (RSC) shows overlaps between these three constructs, which differs somewhat by hemisphere. Posterior RSC in the parietal- occipital sulcus has limited episodic activity (Adapted from “Contributions of episodic retrieval and mentalizing to autobiographical thought: Evidence from functional neuroimaging, resting-state connectivity, and fMRI meta-analysis,” by J. R. Andrews-Hanna, R. Saxe, and T. Yarkoni, 2014, NeuroImage, 91, pp. 324–335. Copyright 2014 by Elsevier Publishing. Adapted with permission). See the online article for the color version of this figure.

regions (Andrews-Hanna, Saxe, & Yarkoni, 2014). This result have a simpler, more direct relationship: the concept of self. RSC suggests a broad contribution to memory throughout RSC, with makes contributions to self-referential processing in a number of ToM restricted to anterior sections. Summerfield and colleagues ways, including the physical body, pain, emotional pain, and found that RSC was sensitive to self-referential processing, com- self-image. pared with nonself-referential processing. Furthermore, recalling As just discussed, RSC makes contributions to self-projection events that really happened to the participant compared with for episodic thinking, but we also see RSC contributions to self- imagined events also lead to anterior RSC activation (Summerfield referential processing independent of episodic memory functions. et al., 2009). These findings suggest that the mental projection vital For example, Johnson and colleagues found that human RSC and to episodic memory could also be related to self-referential pro- posterior cingulate activation is more related to judgments about cessing in other contexts. Finally, people with autism spectrum oneself and to self-reference than to other types of judgments, such disorder—characterized by difficulties with ToM—have a com- as subjective preference (Johnson et al., 2002, 2005). Self- plex array of intrinsic functional connectivity throughout RSC, referential evaluations of personal characteristics activates RSC posterior cingulate, and precuneus. Connectivity in these regions (Schmitz, Rowley, Kawahara, & Johnson, 2006), but so do eval- ranges from hypo-connected to hyper-connected, depending on the uations of other’s personality characteristics, suggesting a possible particular subregion and the developmental stage (Lynch et al., metacognitive evaluation, an encroachment of semantic informa- 2013; Monk et al., 2009; Weng et al., 2010), while acknowledging tion, or a mixing of self and other since the others in this case were that there could be motion artifacts in resting state (Power et al., close to the person (Schmitz, Kawahara-Baccus, & Johnson, 2014, 2015). We will discuss further studies relating RSC function 2004). Lower resting state functional connectivity, with the cave-

This document is copyrighted by the American Psychological Association or one of its alliedto publishers. the concept of self in the next section. ats regarding motion artifacts (Power et al., 2014, 2015), between

This article is intended solely for the personal use of the individual userOn and is not to bebalance, disseminated broadly. the evidence strongly indicates that RSC is impor- RSC and other regions of DMN has been observed in patients with tant to many memory processes, including both spatial and non- schizophrenia, which is characterized by alterations in self- spatial episodic memories. Its large contributions to episodic mem- oriented processing. Furthermore, negative correlations were seen ory retrieval in particular point to a significant amount of mental between RSC and anterior cingulate and mPFC in these patients— imagery involved in recalling events, whereas encoding may not opposite the normal connectivity patterns of DMN (Bluhm et al., require the same degree of imagery. Imagery is key to self- 2009). projection both for episodic future thinking and for understanding other’s mental states, and so could be a vital part of RSC contri- In addition to the concept of one’s self or personality, RSC also butions to memory and other functions. appears to be involved in processing of the physical body. For example, patients with chronic itch (atopic dermatitis) have ele- vated cerebral blood flow in RSC during a histamine-induced itch Self, Body, and Pain compared with baseline (Ishiuji et al., 2009). In an out-of-body The cognitive processes that are important for self-projection teleportation illusion, RSC activity reflected self-location, while during episodic memory, future thinking, and mentalizing, perhaps nearby posterior cingulate mediated both self-location and sense of HETEROGENEITY IN HUMAN RETROSPLENIAL CORTEX 329

body ownership. RSC showed increased functional connectivity to occipital sulcus (POS) area, with little scene processing occurring posterior cingulate corresponding to the illusory self-location de- anterior to POS. In contrast, the other cognitive functions of RSC coding accuracy, suggesting that first-perspective ownership of a are somewhat more diffusely spread. stranger’s body is associated with increased connectivity between In addition to the evidence presented here looking across stud- these regions (Guterstam, Björnsdotter, Gentile, & Ehrsson, 2015). ies, several studies have shown direct functional differences be- When judging which of a pair of places, events, or people was tween anterior and posterior RSC. For example, in a navigation closer to themselves, activation for spatial judgments was clustered task, Burles and colleagues found a dissociation between superior/ in posterior RSC/POS, whereas person tended to be more superior/ medial RSC and inferior/lateral RSC in spatial updating. They anterior in RSC (Peer et al., 2015), consistent with other self- found superior/medial RSC more related to “orienting,” that is, localization studies. Motor learning could also tap into represen- recalling locations, whereas inferior/lateral RSC was more sensi- tations of self and body. A novel motor learning task showed tive to “updating,” integration of locations into memory during changes in cerebral blood flow in posterior RSC (Fernández-Seara, movement (Burles, Slone, & Iaria, 2017). This finding is consis- Aznárez-Sanado, Mengual, Loayza, & Pastor, 2009), going against tent with the anterior/memory and posterior/spatial division in the findings for body representations in more anterior RSC. How- RSC. In rodents, granular/anterior RSC is important for rodent ever, that task was highly spatial, so these contrary findings could navigation in both the light and dark, suggestive of internal and also be explained by body-related processing in space. external navigational cues, whereas dysgranular/posterior RSC is Being liked and one’s self-image also has implications for RSC. selective for distal cues in the light, suggesting a more direct link Anterior RSC is responsive to being liked by others (Davey, Allen, to visual processes (Pothuizen et al., 2009). Harrison, Dwyer, & Yücel, 2010) and is responsive to admiration With regards to scene processing, lateral human RSC is more for virtue and compassion for social pain—rather than admiration sensitive to visual scene processing and medial RSC is sensitive to for skill and compassion for physical pain—although most of the general contextual memory retrieval, regardless of whether or not cluster is more superior to RSC (Immordino-Yang, McColl, the context is a scene (Baumann & Mattingley, 2016). This dis- Damasio, & Damasio, 2009). These findings suggest that emo- sociation indicates that medial/anterior RSC is related more to tional valence and social processing also play a role (although RSC memory. Furthermore, Silson and colleagues recently found a is particularly active for items with low emotional content; Benelli functional distinction within scene-selective areas of medial pari- et al., 2012). The salience of emotions relating to self-image may etal cortex, demonstrating that more posterior areas in the calcarine be particularly important for the body image disorders anorexia sulcus are intrinsically connected to visual areas, whereas POS is nervosa and bulimia nervosa (Celone, Thompson-Brenner, Ross, more strongly connected to memory regions (Silson et al., 2016). Pratt, & Stern, 2011; Lee et al., 2014), both of which show Using cluster analysis to classify how RSC responds to scenes disordered RSC function. Finally, pain and rumination about pain during movie clips, a recent study found that RSC could be is another related area in which RSC shows abnormal activity in separated into two broad domains: an anterior-medial domain patients (Kucyi et al., 2014). For example, patients with borderline broadly related to locomotion and vehicles, and a posterior-lateral personality disorder have less integration of left posterior RSC into domain that was generally responsive to inanimate man-made the DMN than controls, and their symptom severity is associated artifacts (Çukur, Huth, Nishimoto, & Gallant, 2016). Although the with signal decrease across DMN in response to pain (Kluetsch et categories involved in this discrimination between subregions do al., 2012). One of the characteristics of BPD is a distorted sense of not fit most of the classic scene literature, finding a functional self and unstable self-image. subdivision does fit more broadly into the scope of functional Overall, self-referential processing is a broad concept that can heterogeneity in RSC. encompass a diverse array of topics. Despite this breadth, we can Looking across cognitive domains, spatial judgments tend to be see that RSC contributes to processing of the body and self-image, found in posterior RSC, compared with time or person judgments, and could be important for pain and emotional processing related which tend to be anterior (Gauthier & van Wassenhove, 2016; Peer to the self. A number of mental disorders that demonstrate RSC et al., 2015). Posterior RSC has greater intrinsic functional con- dysfunction have connections to processing of self; a greater nectivity with memory-defined seed regions than with mentalizing understanding of RSC function could help in developing treat- (ToM) seed regions, although more anterior RSC and into poste- ments for these disorders. rior cingulate has strong connectivity to both (Andrews-Hanna et This document is copyrighted by the American Psychological Association or one of its allied publishers. al., 2014). These findings suggest that there is heterogeneity in This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. Functional Differences Across RSC RSC, with subnetworks supporting different processes of autobiographical thought, and a large contribution to memory through- Throughout this review, we have seen functional heterogeneity out. A meta-analysis of many of the functions related to the DMN, in RSC, not only terms of what the functions are, but of where including autobiographical memory, navigation, theory of mind, within RSC these functions are localized. In particular, there is prospection, and default mode, found RSC activity for all four evidence for a functional gradient or subregions along the anterior- domains. However, more anterior and superior regions (including poster axis of RSC. This functional gradient largely maps onto precuneus and cingulate) showed activations for autobiography memory and self-related functions in anterior of human RSC (e.g., and theory of mind (Spreng, Mar, & Kim, 2009), again demon- Calarge et al., 2003; Guterstam et al., 2015; Huijbers et al., 2010; strating both commonalities and heterogeneity across RSC. In- Ranganath et al., 2005), with navigational and scene processing in deed, both the similarity in function between superior RSC and posterior RSC (e.g., Baumann & Mattingley, 2010; Kamps et al., inferior precuneus and the lack of a clear anatomical boundary 2016; Lambrey et al., 2012; Marchette et al., 2014). Scene pro- between those two areas suggests that this functional gradient cessing in particular appears to be restricted to the parietal- could extend well into medial parietal lobe. 330 CHRASTIL

To examine this potential for a functional gradient across RSC, connectivity, experimental paradigms, and meta-analysis. Within we recently conducted several meta-analyses of human fMRI cognitive domains such as navigation, the more mnemonic aspects publications (Chrastil, Tobyne, Nauer, Chang, & Stern, 2018). We tend to elicit activity in anterior RSC, whereas more perceptual and found that, across studies, anterior RSC was related to the cogni- spatial processes are found more posteriorly. Furthermore, this tive domains of memory, imagery, and self, whereas posterior RSC division is also observed when looking across cognitive domains. was related to navigation and scene processing (see Figure 6). This functional distinction squares nicely with the animal anatomy Furthermore, we conducted resting state functional connectivity and connectivity discussed in this review. Physical connections analysis, finding three primary clusters across RSC: one in far differ between anterior/granular RSC and posterior/dysgranular posterior RSC including some occipital areas that connected to RSC in rodents, suggesting an anatomical basis for this heteroge- vision networks, one in POS that connected to the mPFC and neity. lateral temporal lobe subnetwork of the DMN, and a third anterior cluster that connected to parahippocampal cortex and posterior Commonalities of RSC Function intraparietal lobule (angular gyrus) subnetwork of the DMN. The two posterior clusters broadly overlap with those of Silson et al. Throughout, this review has examined where and how RSC (Silson et al., 2016), whereas the connectivity of the third, anterior, function differs, yet a number of common threads have also RSC area distinguishes between DMN subnetworks (Andrews- emerged. One such thread is that of memory, particularly episodic Hanna, Reidler, Sepulcre, Poulin, & Buckner, 2010) and illumi- memory. Beyond the narrow interpretation of recalling personal nates subnetwork level connectivity within RSC. Differences events, memory processes involving human RSC can also include among human posterior cingulate regions and RSC in their corre- memory for places and scenes (Baldassano et al., 2016; Marchette lations of resting glucose metabolism with other brain regions have et al., 2015), memory of one’s self-motion (Chrastil et al., 2016; been observed, (Vogt, Vogt, & Laureys, 2006), whereas a func- Sherrill et al., 2013), and memory of how to navigate from place tional gradient across RSC and parietal cortex as also been pro- to place (Auger et al., 2015; Gomez et al., 2014; Wolbers & posed (Clark et al., in press), further supporting the idea of differ- Büchel, 2005). In addition, both spatial and nonspatial contextual ential connectivity and function across this region. information is an important part of RSC function (Aminoff & Tarr, Despite this evidence from these meta-analyses and the exam- 2015; Hindley et al., 2014a; Ranganath & Ritchey, 2012; Vedder ination of previous literature laid out in this review, it is possible et al., 2017), which can help in distinguishing between similar that the appearance of a gradient or subregions within RSC does memories. RSC tends to be more heavily involved in recall than in not reflect true underlying differences. Such an occurrence could encoding (Addis et al., 2004; Gilboa et al., 2004; Huijbers et al., be attributable to artifacts from imaging techniques or to a greater 2010; Steinvorth et al., 2006; Vilberg & Rugg, 2012), and is distribution of function across the RSC region than has previously sensitive to familiarity (Boccia et al., 2014; Elman et al., 2013), been reported. A definitive experimental test of RSC subregions suggesting that personal experience plays a key part of the various has not yet been conducted, and until that time the null remains a memory processes occurring in RSC. possibility. Related to memory, calling up mental images of people, places, Overall, a number of factors point to functional heterogeneity or events is a major aspect of RSC function across cognitive across the anterior-posterior axis of RSC, including resting state domains. Although the posterior areas of RSC into POS are more This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.

Figure 6. Meta-analyses of retrosplenial cortex (RSC) function. (A) Meta-analysis of publications involving RSC, showing posterior RSC relating to navigation and scenes and anterior related to memory and imagery. Only the posterior half of the brains are displayed in these sagittal views. (B and C) Meta-analyses by location, showing common groupings of cognitive domains in RSC. Memory ϩ scenes ϩ navigation are shown in B; memory ϩ self ϩ theory of mind (TOM) are shown in C (Chrastil et al., 2018). See the online article for the color version of this figure. HETEROGENEITY IN HUMAN RETROSPLENIAL CORTEX 331

sensitive to directly perceived stimuli, much of the navigation, time (Fennema-Notestine et al., 2009; Tan et al., 2013). These place recognition, and memory functions of RSC have a strong diverse disorders together suggest how dysfunction in RSC could component of mental imagery or imagination. The viewpoint be destructive to self-referential abilities. As we have seen with transformation functions of RSC for navigation (Byrne et al., other cognitive domains, self-reference demonstrates high overlap 2007) could be considered a part of mental imagery, to be able to with multiple other regions of the DMN. The ways in which RSC picture how a scene would look like from a different reference differs from other members of the DMN could provide insight into frame. Similarly, the RSC functions related to self-processing tend the particular characteristics of a given mental disorder. For ex- to be more about self-image or self-judgments (Davey et al., 2010; ample, anorexia nervosa and bulimia nervosa differ in how RSC Johnson et al., 2002; Schmitz et al., 2006)—which might require interacts with their respective resting-state connectivity profiles imagery—and less about the direct perception of oneself. Mental (Lee et al., 2014), and so future work could examine the specific projection into the future or into other people’s perspectives ways in which RSC function contributes to these disorders in a (Buckner et al., 2008; Buckner & Carroll, 2007) also requires a more systematic fashion. heavy dose of mental imagery as well. It is quite possible that the Taking a synthetic approach to these commonalities has facili- imagery component plays an even larger role than memory per se, tated a broader understanding of RSC function. Although a strong since episodic memories could be considered mental imagery of a case exists for a functional gradient along the anterior-posterior particular place and time. The proposed common thread of mental axis of RSC, it is possible that a common function or functions imagery and visualization remains to be tested as a primary func- underlies all the diverse cognitive processes. This synthesis leads tion of RSC. to the enticing idea that a common neural substrate could underlie Mental imagery provides a potential modality for RSC func- self-referential processing in multiple cognitive domains, however, tion, but the primary content of those images has not yet been this theory has not yet been tested empirically. Moreover, the determined. One likely possibility is self-referential processing. neural mechanisms that engender a common substrate have not yet Self-referential processing could explain why self-related mem- been established. Mixed selectivity, in which neurons can be tuned ories, transformations between navigational perspectives, the- to multiple task-related features, is one mechanism that could ory of mind, and spatial context all generate activation in RSC. possibly support multiple aspects of cognitive processing in RSC For example, previous research has found a link between social (Fusi, Miller, & Rigotti, 2016; Rigotti et al., 2013). Such mixed skills and spatial perspective-taking (Brunyé et al., 2012; selectivity could allow RSC to support multiple aspects of self- Clements-Stephens, Vasiljevic, Murray, & Shelton, 2013; Shel- referential processing, such as tracking distance traveled or recall- ton, Clements-Stephens, Lam, Pak, & Murray, 2012), suggesting a memorable event from childhood. Recent computational ing that these two types of perspective-taking could be related. work suggests that RSC could have such mixed selectivity capa- Self-referential processing is a broad umbrella, but the anterior- bilities related to different navigational features (Rounds, Alexan- posterior gradient across RSC could provide more granularity. der, Nitz, & Krichmar, 2018), demonstrating the potential for Anterior RSC could facilitate imagery and mental projection in future studies in this area. In sum, the commonalities of RSC time (episodic memory) and into the perspectives of other function leave many open questions and avenues for future direc- people (ToM), whereas posterior RSC could be more strongly tions. tuned to self-reference in space (navigation and scene processing). Thus, self-processing could be related to RSC’s contribu- Conclusions and Future Directions tions to episodic memory as well as to mental imagery of scenes and locations. This review has examined the contributions of the retrosplenial Self-referential processing has the possibility to amend and cortex to numerous cognitive domains, including navigation, scene broaden previous models of RSC function. For example, the ad- processing, episodic memory, and self-referential processing. The dition of self-referential processing could transform the viewpoint/ unique mix of cognitive processes that RSC supports separates it reference frame translation model of RSC function (Byrne et al., from other scene-selective cortices, such as the PPA, and from 2007) from a purely spatial projection to include temporal and more directly mnemonic cortices, such as the hippocampus. The social processing. As a key part of the DMN, RSC has previously review found evidence for a functional gradient across the been associated with self-projection (Buckner & Carroll, 2007); anterior-posterior axis of RSC. Both navigation and scene process- This document is copyrighted by the American Psychological Association or one of its allied publishers. however, this review demonstrates how self-projection processes ing are localized to more posterior subregions of RSC, whereas This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. differ across RSC and expands self-projection into POS regions episodic memory and self-referential processing tend to be sup- that are not typically considered part of the DMN. Mental imagery ported by anterior RSC. The heterogeneity of RSC function is of self-reference is consistent with both of these models, but consistent with RSC anatomy and connectivity found in animal further investigation into self-referential processing in RSC is models. Finally, several common themes emerged in the course of needed to fully expand the relationship with current models or to the review, including mental imagery and self-referential process- develop a new model of RSC function. ing, which could potentially unite RSC function. Self-referential processing could also provide a common root Although this review has explored a vast amount of research and for many mental disorders associated with RSC, ranging from the insights into RSC function, many challenges still remain. A con- clearly body-related disorders anorexia nervosa, bulimia nervosa, siderable amount of future research is required to understand how and chronic pain (Celone et al., 2011; Kucyi et al., 2014; Lee et al., RSC can support such diverse array of cognitive domains, and 2014), to disorders related to putting oneself in another’s perspec- empirical tests of the anterior-posterior gradient are still needed. A tive, such as autism (Lynch et al., 2013; Weng et al., 2010), to deeper understanding of the potential unifying functions of RSC is memory-related disorders that involve recalling oneself through also necessary, including more direct experimental work. In addi- 332 CHRASTIL

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