Recordings of brain activity in moving rats have found neurons that fire when the rat is at specific locations. These neurons are known as grid cells because their activity produces a grid-like pattern. A separate group of neurons, called head direction cells, represents the rat’s facing direction. Functional magnetic resonance imaging (fMRI) studies that have tracked brain activity in humans as they navigate virtual environments have found similar grid-like and direction-related responses. A recent study showed grid-like responses even if the people being studied just imagined moving around an arena while lying still. Theoretical work suggests that spatially tuned cells might generally be important for our ability to imagine and simulate future events. However, it is not clear whether these location- and direction-responsive cells are active when people do not visualize themselves moving.

Bellmund et al. used fMRI to track brain activity in volunteers as they imagined different views in a virtual reality city. Before the fMRI experiment, the volunteers completed extensive training where they learned the layout of the city and the names of its buildings. Then, during the fMRI experiment, the volunteers had to imagine themselves standing in front of certain buildings and facing different directions. Crucially, they did not imagine themselves moving between these buildings.

By using representational similarity analysis, which compares patterns of brain activity, Bellmund et al. could distinguish between the directions the volunteers were imagining. Activity patterns in the parahippocampal gyrus (a brain region known to be important for navigation) were more similar when participants were imagining similar directions.

The fMRI results also show grid-like responses in a brain area called entorhinal cortex, which is known to contain grid cells. While participants were imagining, this region exhibited activity patterns with a six-fold symmetry, as Bellmund et al. predicted from the characteristic firing patterns of grid cells.

The findings presented by Bellmund et al. provide evidence that suggests that grid cells are involved in planning how to navigate, and so support previous theoretical assumptions. The computations of these cells might contribute to other kinds of thinking too, such as remembering the past or imagining future events.

Anticipation of the future is a central adaptive function of the brain and enables adequate decision-making and planning. Simulating or imagining future events and scenarios relies on a network of brain regions known to be involved in episodic memory, navigation and prediction (Buckner, 2010; Byrne et al., 2007; Hassabis and Maguire, 2007; Hasselmo, 2009; Schacter et al., 2012). For instance, before leaving your favorite cafe, you may picture the scenery in front of the cafe in your mind’s eye to determine whether to take a left or a right turn to get home. To accomplish this you have to recall both the location of the cafe as well as the direction you are facing when leaving the building.

Electrophysiological recordings in freely moving rodents have demonstrated that positional information during navigation is represented by place cells in the hippocampus (O’Keefe and Dostrovsky, 1971) and grid cells in entorhinal cortex (Hafting et al., 2005). Place cells typically exhibit one firing field (O’Keefe and Dostrovsky, 1971), while grid cells are characterized by multiple firing fields arranged in a regular hexagonal pattern tessellating the entire environment (Hafting et al., 2005). Complementarily, directional information is carried by head direction cells, which increase their firing rate as a function of the animal’s directional heading irrespective of its location (Taube et al., 1990; Taube, 2007). Intracranial recordings in patients exploring virtual-reality (VR) environments demonstrated the existence of place and grid cells in the human hippocampus and entorhinal cortex, respectively (Ekstrom et al., 2003; Jacobs et al., 2010, 2013). A 60° directional periodicity of BOLD-signal modulations in the entorhinal cortex during virtual navigation indicates that grid-like entorhinal signals can also be detected with fMRI (Doeller et al., 2010; Kunz et al., 2015; Horner et al., 2016).

Notably, place cell activity can also represent locations other than the one currently occupied by the animal as illustrated by activation sequences corresponding to upcoming trajectories during rest periods (Dragoi and Tonegawa, 2011). Intriguingly, these ‘preplay’ sequences preferentially represent paths leading up to motivationally relevant locations (Ólafsdóttir et al., 2015). These observations support the notion that prospective coding of hippocampal place cells relates to the well-established role of the human hippocampus in mental simulation and imagination (Buckner, 2010; Byrne et al., 2007; Hassabis and Maguire, 2007; Hasselmo, 2009; Schacter et al., 2012). Akin to firing rate increases of neurons in the human medial temporal lobe specific to the content of imagination (Kreiman et al., 2000), firing patterns of spatially tuned cells might be reinstated to imagine the view from a certain location during mental simulation (Bird et al., 2012; Byrne et al., 2007; Hasselmo, 2009). Prospective coding properties of grid cells (De Almeida et al., 2012; Kropff et al., 2015) and recent evidence for spatial coherence of grid with place cell activity during replay (Ólafsdóttir et al., 2016) further suggest a similar involvement of the entorhinal grid system in future anticipation and prediction. This is in line with the observation of grid-like representations during imagined movement through an environment (Horner et al., 2016). However, hitherto it remains unknown if grid-like representations support mental simulation independent of imagined movement, which could suggest a more general role of grid cell computations in navigational planning, future anticipation and cognition.

We combined fMRI with multi-voxel pattern analysis and VR to investigate whether the entorhinal grid system contributes to the imagination of directions from stationary viewpoints (Figure 1a,b). After extensive navigation training (see Materials and methods and Figure 1—figure supplement 1), participants were asked to imagine directions between pairs of buildings in ‘Donderstown’, a large-scale realistic VR city (http://www.doellerlab.com/donderstown/). In a carefully counterbalanced design, we probed the fine-grained representations of twelve equally spaced directions (see Materials and methods and Figure 1—figure supplement 2). Imagined directions had to be indicated (Figure 1b) and participants successfully performed this task (mean error 33.68° ± 19.09° SD; Figure 1c). Behavioral performance in the direction-imagination task was highly correlated with navigation success (r = 0.85, p<0.001) and the accuracy of direction estimates (r = 0.94, p<0.001) during training and performance in a post-scan map test (r = 0.95, p<0.001), indicating successful translation of the acquired representation of Donderstown to the imagination task (Figure 1—figure supplement 3).

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Average absolute angular errors.

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The contribution of spatial representations to imagination was assessed using representational similarity analysis (Kriegeskorte and Kievit, 2013), which compares activation patterns across voxels to estimate neural similarity. In line with the suggested role for grid cell computations in vector navigation (Bush et al., 2015), we expected the grid-cell system to be involved in determining the vector comprising the direction and distance from the start to the target building in our task. Our approach focused on the direction to the target to track putative grid-cell representations during imagination by systematically comparing neural similarity of imagined directions with varying angular differences (see Materials and methods). We predicted that an involvement of the grid system in mental simulation should be reflected in a 60° periodic pattern-similarity structure in the entorhinal cortex, consistent with the hexagonal firing properties of grid cells (Hafting et al., 2005) and the hexadirectional fMRI signal in entorhinal cortex observed during virtual navigation (Doeller et al., 2010; Horner et al., 2016; Kunz et al., 2015). It is important to note that we did not rely on the building layout as an absolute reference frame in our analyses, but rather assessed pattern similarity based on the relative angle between the directions sampled in a trial pair, see below.

In a first step, we ascertained that absolute directional representations are detectable with our novel imagination task. We expected increased neural similarity during imagination of similar directions, consistent with previous findings of absolute directional coding during navigation in parahippocampal cortex (Doeller et al., 2010) and two recent studies reporting directional representations during imagination in a local reference frame in the retrosplenial complex (Marchette et al., 2014) and coarse representations of directions to a goal in the entorhinal/subicular region (Chadwick et al., 2015). However, it remains unclear whether global spatial representations are involved in human imagination in the absence of visual input.

Here, we compared pattern similarity during imagination of directions in pairs of trials sampling similar directions (angular difference ≤ 30°) to pairs of trials sampling dissimilar directions (Figure 2a) in brain regions representing facing direction (Baumann and Mattingley, 2010; Chadwick et al., 2015; Marchette et al., 2014; Vass and Epstein, 2016, 2013). We observed the predicted one-fold symmetric pattern-similarity structure in a cluster of voxels in the left posterior parahippocampal gyrus (T₂₃ = 4.82, p = 0.024, FWE-corrected for multiple comparisons using small volume correction; Figure 2b,c; see Materials and methods). Increased pattern similarity for similar directions was not due to trial comparisons with identical building combinations (Figure 2—figure supplement 1). Further, this effect was not driven by the specific locations used to sample directions or the distances between these locations in Donderstown (Figure 2—figure supplement 2, see Materials and methods).

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Searchlight results for absolute directional coding analysis.

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Having verified that we can detect directional representations in our novel imagination paradigm, we tested, in a next step, whether activation patterns during imagination follow a six-fold rotational symmetry, akin to the six-fold symmetric firing pattern of grid cells (Hafting et al., 2005) and the six-fold modulation of entorhinal fMRI signals during virtual (Doeller et al., 2010; Kunz et al., 2015) and imagined (Horner et al., 2016) navigation in humans. The rationale underlying our analysis is that activation patterns during directional imagination should exhibit the highest neural similarity for directions that are (multiples of) 60° apart from each other (see Figure 3a–d and Figure 3—figure supplement 1 for details of analysis logic). Because grid cells are most abundant in the medial entorhinal cortex in rodents (Hafting et al., 2005), we predicted the effect to be present in posterior medial entorhinal cortex (pmEC), the likely homologue region of the rodent medial entorhinal cortex in the human brain (Navarro Schröder et al., 2015) (Figure 3e).

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Pattern similarity difference between 0° modulo 60° and 30° modulo 60° condition in left and right posterior medial entorhinal cortex.

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We observed pattern similarity increases with a 60° periodicity in the left pmEC (T₂₃ = 2.37, p = 0.027; one-tailed test, Bonferroni corrected for test in both hemispheres; Cohen’s d = 0.48; Figure 3f and Figure 3—figure supplement 2c). The effect was further confirmed using permutation-based significance testing (pseudo T₂₃= 2.89, p = 0.008; see Materials and methods). A control analysis showed that the effect was not present in the anterior lateral entorhinal cortex (p>0.9; Figure 3—figure supplement 2; see Figure 3—figure supplement 3 for information on signal quality in the entorhinal cortex), the human homologue of lateral EC, which does not contain grid cells (Hafting et al., 2005). The 60° periodicity in left pmEC was consistent across all angular differences (Figure 3—figure supplement 4 and Figure 3—figure supplement 5) and the effect was not driven by the specifics of our design and the VR town used. Specifically, the effect remained significant after excluding combinations of trial pairs (Figure 3—figure supplement 6) with the same start (T₂₃ = 2.39, p = 0.025) or target location (T₂₃ = 2.57, p = 0.017), the same combination of start and target location (T₂₃ = 2.45, p = 0.022) and comparisons from the same task block (T₂₃ = 2.08, p = 0.049). Further control analyses demonstrated that the effect was independent of the mean distance between start and target locations in a trial pair (T₂₃ = 2.37, p = 0.027; Figure 3—figure supplement 7), the difference of this distance within a pair (T₂₃ = 4.32, p<0.001) and the mean distance between all four buildings in a given trial pair (T₂₃ = 2.37, p = 0.027). Behavioral performance did not differ between the conditions (T₂₃ = 1.24, p = 0.227, Figure 3—figure supplement 8).

Furthermore, the effect was specific to a 60° modulation of pattern similarity values and there was no evidence for coding of cardinal directions in the entorhinal cortex (Figure 3—figure supplement 9; see also Materials and methods). Results of a whole-brain searchlight analysis confirmed the 60° periodicity of pattern similarity increases in pmEC observed in the ROI analysis (T₂₃ = 4.04, p = 0.046, FWE-corrected for multiple comparisons using small volume correction; Figure 3—figure supplement 10). A similar pattern similarity structure was observed in regions in parietal and visual cortices (Figure 3—figure supplement 10), which might reflect reactivation of egocentric and visual representations associated with imagined directions, possibly modulated by entorhinal representations in line with a model of mental imagery (Bird et al., 2012; Byrne et al., 2007). Future research will need to investigate these putative interactions in more detail.

In sum, we report two important findings: Firstly, pattern similarity values in the parahippocampal gyrus exhibited a one-fold symmetry congruent with fine-grained representations of imagined facing direction, reflecting the role of this brain region - which has been implicated in spatial processing in the absence of visual input (Wolbers et al., 2011) - in representing the directional aspect of the imagined views. An alternative explanation of this effect through visual similarity of the imagined views appears unlikely due to the complex nature of the task in which each direction was sampled from multiple locations in our large-scale environment (Figure 1—figure supplement 2) and buildings served as cues for a wider range of sampling directions. Therefore, our finding provides the first evidence for fine-grained coding of absolute direction at an unprecedented angular resolution of 30°, consistent with the characteristics of the head direction system in rodents (Taube et al., 1990; Taube, 2007), and constitutes a three-fold increase in resolution of the directional representations observed in humans compared to previous studies (Marchette et al., 2014; Chadwick et al., 2015; Baumann and Mattingley, 2010; Vass and Epstein, 2013, 2016; Shine et al., 2016). Secondly, the structure of pattern similarity in entorhinal cortex was characterized by a six-fold rotational symmetry akin to the firing properties of grid cells (Hafting et al., 2005). Our findings provide evidence for an involvement of grid-like representations in mental simulation in the absence of imagined movement.

Crucially, participants imagined directions from stationary viewpoints in a realistic, large-scale virtual city and were not re-exposed to the virtual town during the imagination task. Therefore, our findings provide novel evidence, complementary to a recent report (Horner et al., 2016) showing evidence for grid-like entorhinal processing during imagined movement through a simple virtual arena. Furthermore, in contrast, we investigated spatial processing in a large-scale, urban environment (Stokes et al., 2015) and, moreover focused on multi-voxel patterns. In particular, we demonstrate that this novel analysis approach, which does not rely on the estimation of the orientation of the hexadirectional signal in entorhinal cortex in an independent data set (Doeller et al., 2010; Kunz et al., 2015; Horner et al., 2016; Constantinescu et al., 2016), is sensitive to grid-like entorhinal signals by capitalizing on the six-fold symmetry of grid cell firing patterns. Contrary to the previously employed approach relying on the estimation of the orientation of the hexadirectional signal for each participant (Doeller et al., 2010; Kunz et al., 2015; Horner et al., 2016; Constantinescu et al., 2016), the individual grid orientation is not approximated using the multivariate analysis. Yet, the grid orientation might influence the strength of the grid-like entorhinal signal observed in a given participant because the sampled directions might be more or less aligned with this individual’s grid orientation (Figure 3a–c and Figure 3—figure supplement 1 for illustration). This needs to be taken into consideration when aiming to relate grid-like signals to behavior. However, only the multivariate approach enabled us to investigate the six-fold rotational symmetry in our large-scale environment, in which a continuous sampling of directions as required for the estimation of the orientation of the hexadirectional signal would not have been feasible. This parsimonious approach might prove valuable for future studies investigating the role of grid-like signals in human cognition, in particular in studies with children (Bullens et al., 2010) or older participants (Schuck et al., 2015) and in clinical settings (Hartley et al., 2007; Maguire et al., 2001), where time for data acquisition is typically limited and could for instance help to further understand the putative link between the entorhinal grid system and Alzheimer’s disease (Kunz et al., 2015).

On a theoretical level, our findings are consistent with accounts of imagination positing medial-temporal-lobe involvement in the reactivation and recombination of prior experiences (Buckner, 2010; Byrne et al., 2007; Hassabis et al., 2007; Hassabis and Maguire, 2007; Hasselmo, 2009; Schacter et al., 2012). The hippocampal formation and grid cells in particular have been implicated in path integration (Hafting et al., 2005; Wolbers et al., 2007), for which computing a homing vector based on translations from a given starting point is central (Vickerstaff and Cheung, 2010). Notably, the grid system is well-suited to also perform the inverse operation of calculating relative vectors between known positions in the service of navigational planning (Bush et al., 2015). Hence, it is plausible that the grid-cell system contributes to the calculation of vectors between start and target location during imagination (Bird et al., 2012; Bush et al., 2015; Hasselmo, 2009; Horner et al., 2016), while the head direction system (Taube, 2007; Taube et al., 1990) processes the absolute direction between the two locations (Bird et al., 2012; Byrne et al., 2007; Hasselmo, 2009) in our task. Our findings suggest an involvement of the entorhinal grid system in calculating vectors to target locations during navigational planning, in line with a theoretical account of vector navigation (Bush et al., 2015).

Functional neuroimaging can measure the firing pattern of specific cell types only indirectly (Logothetis, 2008). However, intracranial recordings in patients exploring virtual-reality environments demonstrated the existence of place (Ekstrom et al., 2003; Jacobs et al., 2010) and grid (Jacobs et al., 2013) cells in the human hippocampus and entorhinal cortex, respectively. Importantly, our results are in line with single-cell recordings in rodents that suggest a possible contribution of spatially tuned cells to future anticipation via place cell preplay of upcoming trajectories (Dragoi and Tonegawa, 2011) and preferential preplay of firing sequences of paths leading to motivationally relevant locations (Ólafsdóttir et al., 2015). Prospective coding properties of grid cells (De Almeida et al., 2012; Kropff et al., 2015) and recent evidence for grid cell replay (Ólafsdóttir et al., 2016) further suggest a similar involvement of the entorhinal grid system in future anticipation and prediction. By translating these ideas to human imagination, during which content-specific firing rate increases of neurons in the human medial temporal lobe have been observed (Kreiman et al., 2000), it is conceivable that spatially tuned cells provide the machinery for the flexible recombination of spatial and mnemonic details necessary for the construction of mental simulations (Bird et al., 2012; Brown et al., 2016; Buckner, 2010; Byrne et al., 2007; Eichenbaum and Cohen, 2014; Hassabis et al., 2007; Hassabis and Maguire, 2007; Hasselmo, 2009; Schacter et al., 2012) and the representation of conceptual knowledge (Constantinescu et al., 2016).

In concert with the recent report of grid-like processing in the entorhinal cortex during imagined navigation (Horner et al., 2016) our findings provide a substantial advancement for the field. Importantly, grid-like entorhinal signals during imagined navigation were observed with a similar orientation as during actual navigation through the VR environment (Horner et al., 2016). This finding strengthens our interpretation of the six-fold symmetric pattern similarity structure in the entorhinal cortex during imagination of directions from stationary viewpoints observed in this study as reflecting computations of the entorhinal grid system operating similarly in our realistic large-scale VR city as during navigation in smaller and simpler environments typically used in electrophysiological recording studies in rodents (Hafting et al., 2005) or fMRI experiments in humans (Doeller et al., 2010; Horner et al., 2016; Kunz et al., 2015). Importantly, the interpretation of our results as a global grid signal coding for space beyond boundaries and obstacles is in line with the report of a global grid pattern emerging with experience in rodents exploring an environment divided into two connected compartments (Carpenter et al., 2015).

In conclusion, we show involvement of both absolute directional parahippocampal and grid-like entorhinal signals in imagination, which provides important evidence for these representations in the absence of sensory input or imagined movement. This might suggest a more fundamental role of spatial computations in the grid-cell system during mental simulation and possibly other forms of prospective coding and future thinking in the service of goal-directed decision-making (Bird et al., 2012; Buckner, 2010; Byrne et al., 2007).

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Author details

1. Jacob LS Bellmund

   1. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
   2. Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Norwegian University of Science and Technology, Trondheim, Norway

   Contribution

   JLSB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   j.bellmund@donders.ru.nl

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-2098-4487

2. Lorena Deuker

   1. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
   2. Department of Neuropsychology, Institute of Cognitive Neuroscience, Ruhr University Bochum, Bochum, Germany

   Contribution

   LD, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-4939-5862

3. Tobias Navarro Schröder

   1. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
   2. Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Norwegian University of Science and Technology, Trondheim, Norway

   Contribution

   TNS, Conception and design, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-6498-1846

4. Christian F Doeller

   1. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
   2. Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Norwegian University of Science and Technology, Trondheim, Norway

   Contribution

   CFD, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   c.doeller@donders.ru.nl

   Competing interests

   The authors declare that no competing interests exist.

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