Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - MEMENTO (MEMory processing in the human ENTOrhinal cortex)

Teaser

MEMENTO stands for “MEMory processing in the human ENTOrhinal cortex”. The entorhinal cortex is a brain region which is highly important for episodic memory: The vivid, detailed memory for events and experiences. In fact, a large part of the information that we encode...

Summary

MEMENTO stands for “MEMory processing in the human ENTOrhinal cortex”. The entorhinal cortex is a brain region which is highly important for episodic memory: The vivid, detailed memory for events and experiences. In fact, a large part of the information that we encode into, or retrieve from, episodic memory is channelled through the entorhinal cortex, linking high-level perceptual and memory-specific brain regions. The entorhinal cortex is also one of the first brain regions affected in Alzheimer’s disease, emphasising its significance for memory. A clear understanding of entorhinal cortex function is therefore invaluable for understanding dementia.

Much of our knowledge of how the healthy human brain works has been discovered using functional magnetic resonance imaging (fMRI). However, due to its small size and location, detecting brain activity in the entorhinal cortex is challenging. Only recent advances in high-resolution and ultra-high field fMRI (at 7 Tesla rather than the common 3 Tesla) have started to illuminate its functional properties. We now know that the entorhinal cortex consists of subregions supporting different aspects of memory. The content of memory matters, with objects and scenes processed in different entorhinal cortex subregions (i.e. anterolateral and posteriormedial). On an even smaller scale, the cortex can be divided into cortical layers that differ with regard to their cellular makeup and connectivity. Ultra-high field fMRI with sub-millimetre resolution has shown that superficial and deep layers of the entorhinal cortex are active during different stages of memory.

Previous research has provided significant puzzle pieces for understanding the function of this brain region. MEMENTO aimed at bringing these together by providing a thorough investigation of memory processing in the entorhinal cortex on four levels - from smallest to largest: 1) The level of cortical layers, 2) the subregion level, 3) the systems level (i.e. interactions with other brain regions), and 4) the behavioural level. We investigated memory for different content (i.e. objects, scenes) and during different memory stages (encoding, retrieval, consolidation), using state-of-the-art ultra-high field fMRI at 7T and advanced data analysis protocols.

Work performed

In cooperation with the University of Cambridge (MRC Cognition and Brain Sciences Unit and the Wolfson Brain Imaging Centre, WBIC), we planned and conducted an elaborate memory study using high-resolution, ultra-high field fMRI at 7 Tesla. Over several piloting sessions, we refined an fMRI sequence that would allow us to scan the entorhinal cortex and surrounding medial temporal lobe (MTL) at sub-millimetre resolution, achieving a voxel size of 0.8mm cubed. At only 1.9% of the volume of “standard” 3mm voxels in typical 3 Tesla experiments, this voxel size allows us to tease apart deep and superficial entorhinal cortex layers. In fMRI, individual brain images are not scanned all at once, but slice by slice. Advanced multiband scanning allowed us to scan 3 slices at once, meaning we could scan the entire MTL while still retaining a comparatively high acquisition speed (<1.8s between consecutive images). The anatomical T1- and T2-weighted scans were optimised, returning incredibly detailed images of the MTL structure at a resolution of down to 0.4mm. We also prepared the preprocessing pipeline, an important step prior to statistical analysis. Here, the data are corrected for differences in acquisition time between slices, head movements throughout the fMRI time-series, and image distortions caused by magnetic field inhomogeneities.

Furthermore, we refined the memory task that participants would solve in the MRI scanner. First, participants learned word-object and word-scene pairs. Then, they engaged in a mathematical task that kept them distracted. This phase was included to investigate off-line reactivation of the just-learned content as a key component of consolidation. Finally, during retrieval, participants saw only the words and, via button presses, they indicated whether they could vividly recall the associated object or scene, or not. Hence, the task allows us to investigate brain activity associated with memory for objects and scenes during three memory stages: Encoding, consolidation, and retrieval.

During preparation of the 7T study, we also worked on an existing (previously unpublished) 3T dataset acquired using a similar behavioural task. Here, we could show not only that major input/output regions of the entorhinal cortex are active during object/scene recall – providing an excellent starting point for our 7T study - we also developed a number of data analysis protocols, which included a novel approach testing for perception-retrieval overlap (PRO), indicating correlations across MTL voxels between object/scene perception and object/scene recall.

After meticulous preparation of the 7T study, we invited 27 healthy volunteers between the ages of 18 and 35. Each completed a 7T MRI session in which they solved the memory task while we scanned their brain activity. Afterwards, they completed a number of additional tasks on the computer which measured different aspects of their long-term memory. Results are highly promising. In line with our hypotheses, we could show that the entorhinal cortex, along with other MTL regions, is active during successful recall, and that anterolateral and posteriormedial entorhinal subregions prefer object and scene recall, respectively. Moreover, despite the known difficulties scanning this brain region, we have yielded good quality signal. This is an excellent base for our ongoing analyses on layer and subregional differences.

These first results of the 7T study have been well-received at two talks presented at the Universities of Birmingham and Cambridge. They will be shared with a wider audience at the Neuroscience 2019 conference in Chicago, USA. During the action, we also developed a novel analysis pipeline (PRO) based on the 3T data that has recently been published in eNeuro.

Final results

MEMENTO has yielded an incredibly rich and versatile dataset tackling a number of timely research questions. In testing memory processing for different content and at different stages, it provides the first comprehensive investigation of the human entorhinal cortex’s role in memory. Ongoing analyses tackle subregional and layer-specific differences, taking into account both the functional embedding of the entorhinal cortex into the MTL system, and its significance for behaviour. Thus, MEMENTO will contribute to a thorough understanding of the neural underpinnings of episodic memory. In future, this may help better understand the neural basis of Alzheimer’s disease, which is a pressing public health issue across the European Union. Progress will be disseminated in conference contributions and scientific articles, and shared on the Fellow’s twitter account (@HeidrunSchultz).

Website & more info

More info: https://www.staresinalab.com/heidrun.