Periodic Reporting for period 3 - GridRepresentations (Neural mechanisms, functional roles and pathophysiological relevance of human grid cell-like representations)
Reporting period: 2023-09-01 to 2025-02-28
Spatial navigation in the real world relies on a number of different strategies including allocentric
navigation (i.e. navigation relying on cognitive maps), egocentric landmark-based navigation and
path integration. One overarching hypothesis of the ERC project “GridRepresentations” is that these
strategies can be mapped onto a limited number of relatively distinct brain systems that contain
different types of spatially specific cells. Specifically, I propose that allocentric navigation depends
place cells in the hippocampus, landmark-based navigation on specific cell types in retroslenial cortex
and basal ganglia, and path integration on grid cells in the entorhinal cortex.
I further hypothesize that the employment of these cell types, the respective brain regions, and the
corresponding strategies can be variable and depends on the one hand on the availability of spatial
cues (e.g. landmark-based navigation is only possible when landmarks are available), on the other
hand on the integrity of the respective brain regions. Neurological diseases which impair the function
of these areas may be compensated to a certain degree by enhanced recruitment of other, non-
affected brain regions, leading to relative hyperactivity in these compensatory areas and changes in
navigational strategies.
The main goals of the ERC project “GridRepresentations” are thus (1) to understand the
neurophysiological basis of grid cell-like representations and their interaction with other spatially
specific cells and representations in the human brain; (2) to investigate the cognitive function of
these representations during different processes of spatial navigation and beyond; (3) to measure
the relationship of impaired grid cell-like representations in early AD with AD biomarkers; and
(4) to explore the causal relevance of hippocampal hyperactivity for compensation of entorhinal
dysfunctions. Each of these objectives is addressed in one of the project’s work packages.
These objectives are highly relevant for both basic research and clinical application.
navigation (i.e. navigation relying on cognitive maps), egocentric landmark-based navigation and
path integration. One overarching hypothesis of the ERC project “GridRepresentations” is that these
strategies can be mapped onto a limited number of relatively distinct brain systems that contain
different types of spatially specific cells. Specifically, I propose that allocentric navigation depends
place cells in the hippocampus, landmark-based navigation on specific cell types in retroslenial cortex
and basal ganglia, and path integration on grid cells in the entorhinal cortex.
I further hypothesize that the employment of these cell types, the respective brain regions, and the
corresponding strategies can be variable and depends on the one hand on the availability of spatial
cues (e.g. landmark-based navigation is only possible when landmarks are available), on the other
hand on the integrity of the respective brain regions. Neurological diseases which impair the function
of these areas may be compensated to a certain degree by enhanced recruitment of other, non-
affected brain regions, leading to relative hyperactivity in these compensatory areas and changes in
navigational strategies.
The main goals of the ERC project “GridRepresentations” are thus (1) to understand the
neurophysiological basis of grid cell-like representations and their interaction with other spatially
specific cells and representations in the human brain; (2) to investigate the cognitive function of
these representations during different processes of spatial navigation and beyond; (3) to measure
the relationship of impaired grid cell-like representations in early AD with AD biomarkers; and
(4) to explore the causal relevance of hippocampal hyperactivity for compensation of entorhinal
dysfunctions. Each of these objectives is addressed in one of the project’s work packages.
These objectives are highly relevant for both basic research and clinical application.
In WP1, we re-analyzed data from a large intracranial EEG dataset on spatial learning (for previous
publications on this dataset, see Chen et al., Current Biology 2018; Kunz et al., Science Advances
2018; Chen et al., Science Advances 2020) and from an fMRI dataset of the same paradigm (Kunz
et al., Science 2015). Since these two datasets employed an identical task, they are particularly
well suited to address objective 1, i.e. the relationship of activities across different levels of brain
organization. These data also allow addressing objective 2, because they contribute to a better
understanding of the specific cognitive functions (here: navigational strategies) that are supported by
neural activity in the core areas supporting the distinct spatial navigation strategies. We also started
with the analysis of human single unit data that were recorded concurrently with the intracranial EEG
data in a subset of patients (n=10 patients with both microelectrodes and macroelectrodes in entorhinal
cortex and hippocampus).
In WP2, and in line with our objective #2, which was to unravel the cognitive function of grid
cell-like representations and complementary spatially specific representations in other brain regions,
we developed novel experimental paradigms of “conceptual navigation” and of visual exploration
of the “spaces” of natural scenes. These paradigms capitalize on the employment of deep neural
networks, which we recently described as promising models of different “representational formats”
in the brain (Heinen et al., Brain Struct Funct 2023). First, we developed a paradigm that requires
participants to focus on either perceptual or conceptual dimensions of a stimulus, and to employ the
“cognitive map” defined by these dimensions for similarity judgments. We tested whether memory
traces of individual stimuli were embedded into these maps, i.e. whether these maps influenced the
memorability of the stimuli. This can be considered a prerequisite for a cognitive relevance of these
maps. Finally, we conducted a 7T fMRI study in order to investigate the laminar distribution of grid
cell-like representations in entorhinal cortex and their interaction with hippocampal subregions and
layers. Data acquisition is completed, and the data are currently preprocessed for further analysis.
publications on this dataset, see Chen et al., Current Biology 2018; Kunz et al., Science Advances
2018; Chen et al., Science Advances 2020) and from an fMRI dataset of the same paradigm (Kunz
et al., Science 2015). Since these two datasets employed an identical task, they are particularly
well suited to address objective 1, i.e. the relationship of activities across different levels of brain
organization. These data also allow addressing objective 2, because they contribute to a better
understanding of the specific cognitive functions (here: navigational strategies) that are supported by
neural activity in the core areas supporting the distinct spatial navigation strategies. We also started
with the analysis of human single unit data that were recorded concurrently with the intracranial EEG
data in a subset of patients (n=10 patients with both microelectrodes and macroelectrodes in entorhinal
cortex and hippocampus).
In WP2, and in line with our objective #2, which was to unravel the cognitive function of grid
cell-like representations and complementary spatially specific representations in other brain regions,
we developed novel experimental paradigms of “conceptual navigation” and of visual exploration
of the “spaces” of natural scenes. These paradigms capitalize on the employment of deep neural
networks, which we recently described as promising models of different “representational formats”
in the brain (Heinen et al., Brain Struct Funct 2023). First, we developed a paradigm that requires
participants to focus on either perceptual or conceptual dimensions of a stimulus, and to employ the
“cognitive map” defined by these dimensions for similarity judgments. We tested whether memory
traces of individual stimuli were embedded into these maps, i.e. whether these maps influenced the
memorability of the stimuli. This can be considered a prerequisite for a cognitive relevance of these
maps. Finally, we conducted a 7T fMRI study in order to investigate the laminar distribution of grid
cell-like representations in entorhinal cortex and their interaction with hippocampal subregions and
layers. Data acquisition is completed, and the data are currently preprocessed for further analysis.
We investigated the factors that contributed to theta oscillations and to fMRI BOLD activity in
the hippocampus, i.e. the region showing putatively compensatory hyperactivity in the presence
of entorhinal dysfunction. By leveraging the power of the rich multimodal datasets we already
had collected (multiple recording techniques: iEEG and fMRI; multiple populations: healthy young
adults, epilepsy patients, individuals with specific APOE genetic phenotypes), with novel analyses
approaches, we were able to address the following outstanding questions in the field:
1. What is the relationship between neural activity recorded at the mesoscopic level (local field
potentials as recorded by iEEG) and at the macroscopic level (BOLD activity using fMRI);
specifically, what is the relationship between theta oscillations and regional changes in neural activity
in the human hippocampus, during spatial navigation performance? [methodological investigation]
2. How do navigation strategies spontaneously arise over the course of exposure to an environment
in which spatial memory is tested? Do participants employ one single strategy throughout the task,
or does this differ depending on the relationship between goal locations and available cues in
the environment, neural activity, and individual differences? How does strategy relate to overall
performance? [psychological investigation]
3. How does performance, and strategy (as defined above), during navigation change as a function of
genetic risk factors and disease? [cognitive health investigation]
The results of these analyses are described in section 1.1 below. We also obtained important results in a novel paradigm of conceptual navigation, which are also
described in section 1.1. Results from experiments in three complementary studies provide a
promising basis for future investigations of grid cell-like representations in this paradigm, since they
demonstrate that task-dependent cognitive maps are embedded into stimulus-specific memory traces
and are thus functionally relevant. In order to test this, we conducted a follow-up fMRI study of
this paradigm (n=46 participants). Similar to our behavioral studies, we found that task-relevant (but
not irrelevant) distances during similarity judgments at encoding predicted subsequent recognition
memory. We further showed that these distances were reflected by BOLD activity in several visual and
prefrontal regions. These preliminary results were presented as a poster at the Cognitive Neuroscience
Society Meeting in San Francisco 2023 and are currently further analyzed for publication. A similar
paradigm has been established for recordings in epilepsy patients with intracranial EEG electrodes
and with microelectrodes.
the hippocampus, i.e. the region showing putatively compensatory hyperactivity in the presence
of entorhinal dysfunction. By leveraging the power of the rich multimodal datasets we already
had collected (multiple recording techniques: iEEG and fMRI; multiple populations: healthy young
adults, epilepsy patients, individuals with specific APOE genetic phenotypes), with novel analyses
approaches, we were able to address the following outstanding questions in the field:
1. What is the relationship between neural activity recorded at the mesoscopic level (local field
potentials as recorded by iEEG) and at the macroscopic level (BOLD activity using fMRI);
specifically, what is the relationship between theta oscillations and regional changes in neural activity
in the human hippocampus, during spatial navigation performance? [methodological investigation]
2. How do navigation strategies spontaneously arise over the course of exposure to an environment
in which spatial memory is tested? Do participants employ one single strategy throughout the task,
or does this differ depending on the relationship between goal locations and available cues in
the environment, neural activity, and individual differences? How does strategy relate to overall
performance? [psychological investigation]
3. How does performance, and strategy (as defined above), during navigation change as a function of
genetic risk factors and disease? [cognitive health investigation]
The results of these analyses are described in section 1.1 below. We also obtained important results in a novel paradigm of conceptual navigation, which are also
described in section 1.1. Results from experiments in three complementary studies provide a
promising basis for future investigations of grid cell-like representations in this paradigm, since they
demonstrate that task-dependent cognitive maps are embedded into stimulus-specific memory traces
and are thus functionally relevant. In order to test this, we conducted a follow-up fMRI study of
this paradigm (n=46 participants). Similar to our behavioral studies, we found that task-relevant (but
not irrelevant) distances during similarity judgments at encoding predicted subsequent recognition
memory. We further showed that these distances were reflected by BOLD activity in several visual and
prefrontal regions. These preliminary results were presented as a poster at the Cognitive Neuroscience
Society Meeting in San Francisco 2023 and are currently further analyzed for publication. A similar
paradigm has been established for recordings in epilepsy patients with intracranial EEG electrodes
and with microelectrodes.