Conduction velocity along a key white matter tract is associated with autobiographical memory recall ability
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Evaluation Summary:
In this paper, the authors show that autobiographical memory recall is related to a specific biophysical property of the parahippocampal cingulum bundle, the so-called MR g-ratio. This paper will be of interest to neuroscientists studying associations between brain structure and cognitive processes. The data support the main conclusions of the paper. However, it is unclear how reliable the results are and whether the findings would generalize to situations beyond the specific one studied.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
Conduction velocity is the speed at which electrical signals travel along axons and is a crucial determinant of neural communication. Inferences about conduction velocity can now be made in vivo in humans using a measure called the magnetic resonance (MR) g-ratio. This is the ratio of the inner axon diameter relative to that of the axon plus the myelin sheath that encases it. Here, in the first application to cognition, we found that variations in MR g-ratio, and by inference conduction velocity, of the parahippocampal cingulum bundle were associated with autobiographical memory recall ability in 217 healthy adults. This tract connects the hippocampus with a range of other brain areas. We further observed that the association seemed to be with inner axon diameter rather than myelin content. The extent to which neurites were coherently organised within the parahippocampal cingulum bundle was also linked with autobiographical memory recall ability. Moreover, these findings were specific to autobiographical memory recall and were not apparent for laboratory-based memory tests. Our results offer a new perspective on individual differences in autobiographical memory recall ability, highlighting the possible influence of specific white matter microstructure features on conduction velocity when recalling detailed memories of real-life past experiences.
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Author Response
Reviewer #1 (Public Review):
This paper addresses an important question: whether the conduction velocity in white matter tracts is related to individual differences in memory performance. The authors use novel MRI techniques to estimate the "g-ratio" in vivo in humans - the ratio of the inner axon relative to the inner axon plus its outer myelin sheath. They find that autobiographical recall is positively related to the g-ratio in a specific white matter tract (the parahippocampal cingulum bundle) in a population of 217 healthy adults. This main finding is extended by showing that better memory is associated with larger inner axon diameters and lower neurite dispersion, which suggests more coherently organised neurites. The authors also argue that their results show that the magnetic resonance (MR) g-ratio can reveal …
Author Response
Reviewer #1 (Public Review):
This paper addresses an important question: whether the conduction velocity in white matter tracts is related to individual differences in memory performance. The authors use novel MRI techniques to estimate the "g-ratio" in vivo in humans - the ratio of the inner axon relative to the inner axon plus its outer myelin sheath. They find that autobiographical recall is positively related to the g-ratio in a specific white matter tract (the parahippocampal cingulum bundle) in a population of 217 healthy adults. This main finding is extended by showing that better memory is associated with larger inner axon diameters and lower neurite dispersion, which suggests more coherently organised neurites. The authors also argue that their results show that the magnetic resonance (MR) g-ratio can reveal novel insights into individual differences in cognition and how the human brain processes information.
The study is exploratory in nature and the analyses were not pre-registered. The technique has not been used before to associate cognitive performance with MR estimates of conduction velocity in candidate white matter tracts. It is therefore unknown how strong any associations are likely to be and what sort of sample size might be needed to observe them. Nevertheless, if the technique proves to be reliable, then it certainly offers a valuable new tool to understand individual differences in cognitive abilities. However, brain structure to behavior associations are notoriously variable across studies and have been argued to require very large sample sizes to obtain reproducible results.
We respectfully disagree that the study was exploratory. We had distinct aims and hypotheses from the outset. Our prime interest is in autobiographical memory, the hippocampus and its connectivity. This motivated our focus on three specific white matter tracts. We also planned from the time of study design to examine the MR g-ratio, and even contributed to refining the pre-processing pipeline for this approach, as reported in a previous paper (Clark et al., 2021, Frontiers in Neuroscience). Moreover, in the current manuscript we outlined well thought through possible outcomes and declared specific predictions.
Regarding pre-registration, due to the scope of this work, the experiment was planned eight years ago, and data collection commenced seven years ago. At that time, formal pre-registration was not common practice. However, it has been a long-standing feature of our Centre that proposed studies and their analysis plans undergo rigorous internal peer review, including presentation to the whole Centre, before data acquisition can commence. The proposal for the research under consideration here was presented on 26th September, 2014.
As noted in our response to the Editors’ Public Evaluation Summary above, someone has to be the first to report a novel result, and we believe that the depth and transparency of our approach permits confidence in the findings. Not least, and to reprise, because we employed the most widely-used and best-validated method of testing autobiographical memory recall that is currently available – Levine’s Autobiographical Interview. Our primary analyses were performed using the behavioural outcome measure from this test, the results of which were directly compared to those from a closely-matched control measure to test whether significantly larger effects were observed for our variable of interest. The potential for false positives was further reduced by extracting microstructure data from hypothesised tracts of interest (instead of performing whole brain voxel-wise analyses), with statistical correction performed on all structure-behaviour analyses. Moreover, we performed partial correlations with age, gender, scanner and number of voxels in a region of interest (ROI) as covariates. Complementary investigations were also conducted using other commonly-reported measures, providing supporting evidence. We report all analyses (and provide all the source data), including those finding no relationships. The consistent results throughout were associations between autobiographical memory recall ability and the microstructure of the parahippocampal cingulum bundle only. Moreover, thanks to the excellent suggestions of the Reviewers, the revised version reports additional analyses that allow us to further corroborate and interpret our findings.
Our sample of 217 participants allowed for sufficient power to identify medium effect sizes when conducting correlation analyses at alpha levels of 0.01 and when comparing correlations at alpha levels of 0.05 (Cohen, 1992, Psychological Bulletin). While it has recently been suggested that thousands of participants are required in order to investigate brain structure-behaviour associations (Marek et al., 2022, Nature), other, more sophisticated, analyses suggest that samples of ~200 participants can be sufficient, in line with our estimates (Cecchetti and Handjaras, https://psyarxiv.com/c8xwe; DeYoung et al., https://psyarxiv.com/sfnmk). Given that our study was principled, well-controlled, analysed appropriately and produced very specific and consistent findings, we are confident that the findings are robust.
The authors decided to analyse performance on a single task - the Autobiographical Memory Interview - and identified three candidate white matter tracts that connect the hippocampal region with other brain regions. While it is clear why these three tracts were chosen, it is less obvious why the authors chose to investigate associations with the Autobiographical Memory Interview and not other memory tests that were part of the battery of tests administered to the participants. It is reasonable to assume that something as general as the conduction velocity of a white matter tract would have an effect on memory ability across a range of tasks, so to single out one seems an unnecessarily narrow focus.
Our main interest over many years, and hence the focus of this study, is autobiographical memory recall because it directly relates to how people function in real life. As noted above, autobiographical experiences occur in dynamic, multisensory, multidimensional, non-linear, ever-changing contexts; they involve actively engaging with the environment and other people; they are embodied; they span milliseconds to decades. Many of these features cannot be captured by laboratory-based episodic memory tests. This issue is increasingly being discussed (for example, see recent reviews by Nastase et al., 2020, NeuroImage; Mobbs et al., 2021, Neuron; Miller et al., 2022, Current Biology). It is further laid bare in McDermott et al.’s (2009, Neuropsychologia) meta-analysis of functional MRI studies which showed that laboratory-based and autobiographical memory retrieval tasks differ substantially in terms of their neural substrates. Consequently, we were not surprised to find that when we analysed laboratory-based memory test performance, there were no correlations with the MR g-ratio. Recall of vivid, detailed, multimodal, autobiographical memories may rely on inter-regional connectivity to a greater degree than simpler, more constrained laboratory-based memory tests. Therefore, as well as speaking to conduction velocity, these findings also contribute to wider discussions about real-world compared to laboratory-based memory tests. We thank the Reviewer for making the excellent suggestion to include these additional data, analyses and discussion points.
The results of the study are interesting and highlight a key role of the parahippocampal cingulum bundle in autobiographical memory recall. The results are corrected for multiple comparisons across the three fiber tracts of interest and the recall of "external details" provides a nice control compared to the "internal details" which are the measure of interest. The main findings are extended to show that it is likely to be an increase in axon diameter and an increase in neurite coherency that characterize those individuals with better autobiographical recall. Despite these positives, it remains unclear whether memory recall, in general, is better in people with higher g-ratios in this tract (as implied in the Abstract), or if this effect is specific to scores on the Autobiographical Memory Interview.
Our interest is in autobiographical memory, and so we employed the most widely-used and best-validated method of testing autobiographical memory recall that is currently available – Levine’s Autobiographical Interview. Not only does this test include a control measure, external details (as noted by the Reviewer), but we had independent raters score the autobiographical memory descriptions, and found that the inter-class correlation coefficients were very high (see Materials and Methods). Despite using this current, gold standard approach, at the request of the Reviewer we have now analysed data from eight additional laboratory-based memory tests. These are standard memory tests that are often used in neuropsychological studies: testing recall - the immediate and delayed recall of the Logical Memory subtest of the Wechsler Memory Scale IV, the immediate and delayed recall of the Rey Auditory Verbal Learning Test, the delayed recall of the Rey–Osterrieth Complex Figure; testing recognition memory - the Warrington Recognition Memory Tests for Words and Faces; testing semantic memory - the “Dead or Alive Test”. While these tests can assess some aspects of memory recall, they cannot be regarded simply as proxies for autobiographical memory recall, for the reasons we outlined in our response to the previous point. They do not capture key aspects of autobiographical memories. It is therefore all the more interesting that we found no associations between these laboratory-based memory tasks and the MR g-ratio of the parahippocampal cingulum bundle, in contrast to the relationship identified with autobiographical memory recall ability. Recall of vivid, detailed, multimodal, autobiographical memories may rely on inter-regional connectivity to a greater degree than simpler, more constrained laboratory-based memory tests. Therefore, as well as speaking to conduction velocity, these findings also contribute to wider discussions about real-world compared to laboratory-based memory tests. We thank the Reviewer once again for making the excellent suggestion to include these additional data, analyses and discussion points.
Reviewer #2 (Public Review):
In this study, Clark and colleagues tackle a very intriguing question: how differences in autobiographical recall abilities reflect in the human brain structure and function? To answer this question, they interviewed a large cohort of subjects and proceeded to acquire MRI data, specifically diffusion-weighted imaging and magnetization transfer data, to estimate the g-ratio, a measure of myelination deeply linked to conduction velocity. Looking at three specific white matter pathways of interest, all interconnecting the hippocampus with other brain structures, they studied the relationship between the g-ratio and the autobiographical recall abilities, together with many more measures from MRI. They found a significant positive association between the g-ratio of the parahippocampal cingulum bundle and the number of inner details from the interviews. These results can provide new potential directions to further study the underlying neural features beyond memory.
I think that this is a very interesting article, it is well written, the methods are extensively explained, and the appendix provides further details for more expert readers. The authors put an effort into providing a comprehensive context in the introduction and in the discussion, and as a result, the paper seems overall quite suitable for both general and specialistic readerships.
Thank you.
The main issue I can currently see in the paper is that the mentioned relationship between g-ratio and recall abilities is then used to infer that better recall abilities are associated with higher conduction velocity and larger axons. The authors' line of reasoning is that given the hypothesized association, the increase in the g-ratio implies increases in myelin and axonal diameter. Despite this scenario being indeed possible given the current result, an increased g-ratio may also not indicate higher conduction velocity. In fact, the first potential inference would be that, without having any information on the axon size, the quantify of myelin can indeed be lower and as result, the conduction velocity would decrease. I understand that the authors expected higher conduction velocity associated with better autobiographical memory recall, but it is hard to see any experimental outcome that could have disproved this hypothesis: from the possible scenarios depicted in the introduction, any change in the g-ratio (and even not any change at all) could indicate higher conduction velocity. What would be then needed to corroborate one of these scenarios is some independent or complementary measure, which unfortunately is missing.
The mentioned issue does not mean that the paper loses relevance - I think that it should focus on the very practical result, a change in myelination and microstructure, and discuss what are the potential implications, including the one that currently dominates the discussion section.
Thank you for these comments and the opportunity to provide further clarification.
First, we have now provided additional background information regarding the relationship between the MR g-ratio and conduction velocity. We explicitly note that while finding a significant relationship between the MR g-ratio and autobiographical memory recall suggests the existence of an association between autobiographical memory recall and parahippocampal cingulum bundle conduction velocity, it cannot speak to the direction of this association.
Second, we have further noted that interpretation of the parahippocampal cingulum bundle MR g-ratio in relation to the underlying microstructure requires knowledge, or an assumption, about whether the associated change in conduction velocity is faster or slower. Given that faster conduction velocity is thought to promote better cognition (e.g. Brancucci, 2012; Dicke and Roth, 2016; Miller, 1994; Reed and Jensen, 1992), we interpreted our MR g-ratio findings under the assumption of faster conduction velocity, and now explicitly note in several places in the revised manuscript that this is an assumption.
Third, we thank the Reviewer for the excellent suggestion that a complementary measure could help to further inform the findings. Consequently, we now also include additional analyses examining the relationship between the extent of myelination and autobiographical memory recall ability. This is possible using the magnetisation transfer saturation maps, which are optimised to assess myelination. Given our assumption of faster conduction velocity when interpreting our positive MR g-ratio correlations, then no relationship between parahippocampal cingulum bundle magnetisation transfer saturation and autobiographical memory recall would be expected. On the other hand, if conduction velocity is actually decreasing, then a negative correlation between magnetisation transfer saturation values and autobiographical memory recall ability would be observed. In fact, we found no relationship between parahippocampal cingulum bundle magnetisation transfer saturation and autobiographical memory recall. This suggests that myelin was not associated with autobiographical memory recall ability, supporting our assumption that relationships with the MR g-ratio were indicative of faster rather than slower, conduction velocity.
We have now added these new data, analyses and discussion points to the revised manuscript.
It would also be helpful to include some paragraphs on both interpretation and methodological issues when it comes to MRI-based microstructural imaging, which at the moment is lacking. This would provide a better picture of the results for a more general readership.
We agree, and additional consideration of interpretational and methodological limitations have now been included in the manuscript.
As one of the first works using an MRI-based microstructural measure of myelin, the g-ratio, to study cognition in a large cohort of subjects, I think this work will be a needed and significant step towards merging the neuroscience and MRI physics community - the methodology presented here is robust and could be used in many other applications.
Thank you.
Reviewer #3 (Public Review):
The manuscript adds useful information about how structural properties of the brain are related to individual differences in autobiographical memory. A novel metric is used to assess features of white matter in tracts that are important for information exchange between the hippocampus and other brain regions. In one of these, the parahippocampal bundle, a relationship between the MR g-ratio and autobiographical memory recall is identified. This represents new and interesting information. The authors interpret the results in line with the theory that speed of signal transmission is important for cognitive function.
Thank you for this positive summary.
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Evaluation Summary:
In this paper, the authors show that autobiographical memory recall is related to a specific biophysical property of the parahippocampal cingulum bundle, the so-called MR g-ratio. This paper will be of interest to neuroscientists studying associations between brain structure and cognitive processes. The data support the main conclusions of the paper. However, it is unclear how reliable the results are and whether the findings would generalize to situations beyond the specific one studied.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
This paper addresses an important question: whether the conduction velocity in white matter tracts is related to individual differences in memory performance. The authors use novel MRI techniques to estimate the "g-ratio" in vivo in humans - the ratio of the inner axon relative to the inner axon plus its outer myelin sheath. They find that autobiographical recall is positively related to the g-ratio in a specific white matter tract (the parahippocampal cingulum bundle) in a population of 217 healthy adults. This main finding is extended by showing that better memory is associated with larger inner axon diameters and lower neurite dispersion, which suggests more coherently organised neurites. The authors also argue that their results show that the magnetic resonance (MR) g-ratio can reveal novel insights into …
Reviewer #1 (Public Review):
This paper addresses an important question: whether the conduction velocity in white matter tracts is related to individual differences in memory performance. The authors use novel MRI techniques to estimate the "g-ratio" in vivo in humans - the ratio of the inner axon relative to the inner axon plus its outer myelin sheath. They find that autobiographical recall is positively related to the g-ratio in a specific white matter tract (the parahippocampal cingulum bundle) in a population of 217 healthy adults. This main finding is extended by showing that better memory is associated with larger inner axon diameters and lower neurite dispersion, which suggests more coherently organised neurites. The authors also argue that their results show that the magnetic resonance (MR) g-ratio can reveal novel insights into individual differences in cognition and how the human brain processes information.
The study is exploratory in nature and the analyses were not pre-registered. The technique has not been used before to associate cognitive performance with MR estimates of conduction velocity in candidate white matter tracts. It is therefore unknown how strong any associations are likely to be and what sort of sample size might be needed to observe them. Nevertheless, if the technique proves to be reliable, then it certainly offers a valuable new tool to understand individual differences in cognitive abilities. However, brain structure to behavior associations are notoriously variable across studies and have been argued to require very large sample sizes to obtain reproducible results.
The authors decided to analyse performance on a single task - the Autobiographical Memory Interview - and identified three candidate white matter tracts that connect the hippocampal region with other brain regions. While it is clear why these three tracts were chosen, it is less obvious why the authors chose to investigate associations with the Autobiographical Memory Interview and not other memory tests that were part of the battery of tests administered to the participants. It is reasonable to assume that something as general as the conduction velocity of a white matter tract would have an effect on memory ability across a range of tasks, so to single out one seems an unnecessarily narrow focus.
The results of the study are interesting and highlight a key role of the parahippocampal cingulum bundle in autobiographical memory recall. The results are corrected for multiple comparisons across the three fiber tracts of interest and the recall of "external details" provides a nice control compared to the "internal details" which are the measure of interest. The main findings are extended to show that it is likely to be an increase in axon diameter and an increase in neurite coherency that characterize those individuals with better autobiographical recall. Despite these positives, it remains unclear whether memory recall, in general, is better in people with higher g-ratios in this tract (as implied in the Abstract), or if this effect is specific to scores on the Autobiographical Memory Interview.
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Reviewer #2 (Public Review):
In this study, Clark and colleagues tackle a very intriguing question: how differences in autobiographical recall abilities reflect in the human brain structure and function? To answer this question, they interviewed a large cohort of subjects and proceeded to acquire MRI data, specifically diffusion-weighted imaging and magnetization transfer data, to estimate the g-ratio, a measure of myelination deeply linked to conduction velocity. Looking at three specific white matter pathways of interest, all interconnecting the hippocampus with other brain structures, they studied the relationship between the g-ratio and the autobiographical recall abilities, together with many more measures from MRI. They found a significant positive association between the g-ratio of the parahippocampal cingulum bundle and the …
Reviewer #2 (Public Review):
In this study, Clark and colleagues tackle a very intriguing question: how differences in autobiographical recall abilities reflect in the human brain structure and function? To answer this question, they interviewed a large cohort of subjects and proceeded to acquire MRI data, specifically diffusion-weighted imaging and magnetization transfer data, to estimate the g-ratio, a measure of myelination deeply linked to conduction velocity. Looking at three specific white matter pathways of interest, all interconnecting the hippocampus with other brain structures, they studied the relationship between the g-ratio and the autobiographical recall abilities, together with many more measures from MRI. They found a significant positive association between the g-ratio of the parahippocampal cingulum bundle and the number of inner details from the interviews. These results can provide new potential directions to further study the underlying neural features beyond memory.
I think that this is a very interesting article, it is well written, the methods are extensively explained, and the appendix provides further details for more expert readers. The authors put an effort into providing a comprehensive context in the introduction and in the discussion, and as a result, the paper seems overall quite suitable for both general and specialistic readerships.
The main issue I can currently see in the paper is that the mentioned relationship between g-ratio and recall abilities is then used to infer that better recall abilities are associated with higher conduction velocity and larger axons. The authors' line of reasoning is that given the hypothesized association, the increase in the g-ratio implies increases in myelin and axonal diameter. Despite this scenario being indeed possible given the current result, an increased g-ratio may also not indicate higher conduction velocity. In fact, the first potential inference would be that, without having any information on the axon size, the quantify of myelin can indeed be lower and as result, the conduction velocity would decrease. I understand that the authors expected higher conduction velocity associated with better autobiographical memory recall, but it is hard to see any experimental outcome that could have disproved this hypothesis: from the possible scenarios depicted in the introduction, any change in the g-ratio (and even not any change at all) could indicate higher conduction velocity. What would be then needed to corroborate one of these scenarios is some independent or complementary measure, which unfortunately is missing.
The mentioned issue does not mean that the paper loses relevance - I think that it should focus on the very practical result, a change in myelination and microstructure, and discuss what are the potential implications, including the one that currently dominates the discussion section. It would also be helpful to include some paragraphs on both interpretation and methodological issues when it comes to MRI-based microstructural imaging, which at the moment is lacking. This would provide a better picture of the results for a more general readership.
As one of the first works using an MRI-based microstructural measure of myelin, the g-ratio, to study cognition in a large cohort of subjects, I think this work will be a needed and significant step towards merging the neuroscience and MRI physics community - the methodology presented here is robust and could be used in many other applications.
-
Reviewer #3 (Public Review):
The manuscript adds useful information about how structural properties of the brain are related to individual differences in autobiographical memory. A novel metric is used to assess features of white matter in tracts that are important for information exchange between the hippocampus and other brain regions. In one of these, the parahippocampal bundle, a relationship between the MR g-ratio and autobiographical memory recall is identified. This represents new and interesting information. The authors interpret the results in line with the theory that speed of signal transmission is important for cognitive function.
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