Conduction velocity along a key white matter tract is associated with autobiographical memory recall ability

  1. Ian A Clark
  2. Siawoosh Mohammadi
  3. Martina F Callaghan
  4. Eleanor A Maguire  Is a corresponding author
  1. Wellcome Centre for Human Neuroimaging, Department of Imaging Neuroscience, UCL Queen Square Institute of Neurology, University College London, United Kingdom
  2. Institute of Systems Neuroscience, University Medical Centre Hamburg-Eppendorf, Germany

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.

Editor's evaluation

In this paper, the authors show that autobiographical memory recall is related to a specific biophysical property of the parahippocampal cingulum bundle, the MR g-ratio. The paper presents compelling data supporting a fundamental new insight about the relationship between autobiographical memory and its underlying neural anatomy. The paper will be of strong interest to memory researchers as well as neuroscientists studying associations between brain structure and cognitive processes more generally.

https://doi.org/10.7554/eLife.79303.sa0

Introduction

Communication between neurons in the brain is critical for cognition, and depends upon action potentials being conveyed along axons within white matter tracts. The speed at which these electrical signals travel along axons is known as the conduction velocity. It has been suggested that faster axonal conduction velocity promotes better cognition. For example, an increase in axonal conduction velocity is hypothesised to underpin the greater cognitive processing ability of vertebrates, in particular primates and humans (Brancucci, 2012; Miller, 1994), compared to invertebrates (Arancibia-Cárcamo et al., 2017; Bullock et al., 1984; Nave, 2010). In rats (Aston-Jones et al., 1985) and cats (Xi et al., 1999), faster axonal conduction velocity has been observed in younger compared to older animals. In a similar vein, axonal degradation that can lead to reduced conduction velocity has been identified in older compared to younger monkeys (Peters et al., 2000; Peters and Sethares, 2002).

Echoing these findings from non-humans, estimates of conduction velocity in humans from the latency of visual evoked potentials recorded over primary visual cortex (Reed and Jensen, 1992) and between the thalamus and parietal cortex (Reed and Jensen, 1993) have been positively correlated with nonverbal intelligence quotients. In addition, faster axonal conduction velocities are thought to better explain increases in intelligence compared to absolute and relative brain volumes (Dicke and Roth, 2016).

The conduction velocity of an axon is dependent upon the axon diameter, the presence and thickness of a myelin sheath, the distance between the nodes of Ranvier (periodic gaps in the myelin that facilitate action potential propagation), inter-nodal spacing, and electrical properties of the axonal and myelin membranes (Arancibia-Cárcamo et al., 2017; Drakesmith et al., 2019; Gasser and Grundfest, 1939; Hursh, 1939; Huxley and Stampfli, 1949; Rushton, 1951). A number of these features are not yet measurable in humans in vivo. However, seminal electrophysiological work has derived a relationship between axon morphology and conduction velocity using only axon diameter and myelin sheath thickness (Rushton, 1951). These two metrics are particularly key because a larger axon diameter results in less resistance to the action potential ion flow, resulting in faster conduction velocity. The presence of a myelin sheath around an axon is beneficial in two ways. First, the myelin sheath acts like an electrical insulating layer, reducing ion loss and preserving the action potential. Second, the presence of unmyelinated gaps in the myelin sheath (the nodes of Ranvier) enables a process called saltatory propagation to take place. As the majority of the axon is wrapped in myelin, the nodes of Ranvier are the only locations where action potentials can occur. This increases the strength of electrical signals because all the ions gather at these nodes instead of being dispersed along the length of the axon. Stronger action potentials are therefore sent along the myelinated portion of the axon at higher speeds, with this signal being boosted on arrival at the next node of Ranvier by another action potential, which helps to maintain a fast conduction velocity.

The conduction velocity of an axon is, therefore, not determined only by the axon diameter, but also by the relationship between the axon diameter and the thickness of the surrounding myelin sheath, a measure known as the g-ratio (Chomiak and Hu, 2009; Rushton, 1951; Schmidt and Knösche, 2019). Specifically, Rushton, 1951 derived an equation: conduction velocity d-ln(g) where d is the inner axon diameter, g is the g-ratio=d/D, and D is the outer fibre (axon plus myelin sheath) diameter. In other words, the g-ratio is computed as the ratio of the inner axon diameter relative to that of the axon plus the myelin sheath that encases it (Figure 1).

Schematic of a myelinated axon showing how the g-ratio is calculated.

Until recently, g-ratio measurements were restricted to invasive studies in non-human animals. However, by combining diffusion magnetic resonance imaging (MRI) with quantitative structural MRI scans optimised to assess myelination (e.g. magnetisation transfer saturation; Weiskopf et al., 2013), it is now possible to estimate the g-ratio in vivo in humans across the whole brain (Drakesmith et al., 2019; Mohammadi et al., 2015; Mohammadi and Callaghan, 2021; Stikov et al., 2015). This is achieved by measuring an aggregate g-ratio, which is an area-weighted ensemble average across a voxel of an underlying distribution of microscopic g-ratios of axons (Stikov et al., 2015; West et al., 2016). Whole brain MR g-ratio maps enable the investigation of the MR g-ratio of white matter fibre pathways at the group level. These MR g-ratio estimates have been optimised (Ellerbrock and Mohammadi, 2018; Jung et al., 2018; West et al., 2018) and used to investigate white matter development (Cercignani et al., 2017), changes in the g-ratio during aging (Berman et al., 2018), and as a potential neuroimaging marker in patients with multiple sclerosis (Yu et al., 2019). Of note, the MR g-ratio has been found to associate well with estimates of axonal conduction velocity (Berman et al., 2019; Drakesmith et al., 2019). Consequently, the MR g-ratio provides a non-invasive MRI method that can associate in vivo structural neuroimaging of humans with axonal conduction velocity.

Given that the MR g-ratio encompasses information about the inner axon diameter and myelin thickness, the identification of statistically significant relationships with the MR g-ratio can also guide as to which of these two features might be influencing variations in conduction velocity (Caeyenberghs et al., 2016; Kaller et al., 2017; Lakhani et al., 2016; Waxman, 1980; Xin and Chan, 2020). This is particularly useful in relation to the inner axon diameter. While measures of myelination can be obtained using conventional MRI scanners (e.g. via magnetisation transfer saturation maps), estimates of inner axon diameter cannot, and instead require ultra-strong gradient systems – 300 mT/m compared to the 10s of mT/m of conventional MRI scanners (Jones et al., 2018; Veraart et al., 2020). However, only four ultra-strong gradient Connectom MRI scanners exist in the world. Consequently, measuring the MR g-ratio with conventional MRI scanners can be useful in guiding inferences about inner axon diameter in the context of conduction velocity.

Adjudicating between the possible influence of inner axon diameter or myelination relies on knowledge, or an assumption, about whether the associated change in conduction velocity is faster or slower. This is because significant associations with the MR g-ratio only indicate the existence of a relationship with conduction velocity but not the direction. As noted previously, faster conduction velocity is often held to promote better cognition (e.g. Brancucci, 2012; Dicke and Roth, 2016; Miller, 1994; Reed and Jensen, 1992). Therefore, in Figure 2A, inner axon diameter, myelin thickness and (MR) g-ratio are plotted together to illustrate how different changes in the MR g-ratio are related to the underlying microstructural properties, given a faster conduction velocity. Myelin thickness is represented by the gradient in background colour and contours, with thinnest myelin at the bottom right, and thickest on the top left. The direction of the arrows describes the change in g-ratio for the microstructural variations presented. There are three main scenarios. (1) A decrease in MR g-ratio values. This would suggest that faster conduction velocity is due to greater thickness of the myelin sheath, with the inner axon diameter remaining constant (Figure 2A blue arrow, and Figure 2B). (2) A decrease in MR g-ratio values, but to a lesser extent than that observed in the first scenario. This would suggest that faster conduction velocity is due primarily to greater myelin sheath thickness, but one that is also accompanied by a larger inner axon diameter (Figure 2A red arrow, and Figure 2C). (3) An increase in MR g-ratio values. This would suggest that faster conduction velocity is predominantly due to a larger inner axon diameter, with only small differences, if any, in myelin thickness being present (Figure 2A orange arrow, and Figure 2D).

Illustration of how the MR g-ratio relates to specific microstructural properties given a faster conduction velocity.

(A) Graphical representation of the relationships between myelin thickness, inner axon diameter and MR g-ratio, assuming a faster conduction velocity (see Appendix 1 for details of the simulation). Myelin thickness is represented by the gradient in background colour and contours on the graph, with the thinnest myelin at the bottom right and thickest at the top left. The direction of the arrows describes the change in g-ratio for each microstructural variation presented in B-E. The positioning and colours of the arrows correspond to the text box outline colours in B-E. (B–E) Illustrations of how changes in the MR g-ratio relate to the underlying axonal microstructure, given a faster conduction velocity.

We note, for completeness, that a fourth scenario also exists where constant MR g-ratio values could be associated with faster conduction velocity. This would occur when both the inner axon diameter and myelin thickness change proportionally to each other (Figure 2A black arrow, and Figure 2E). However, this scenario could also mean that there is no variation in conduction velocity. One way to increase interpretability in this situation is by examining scans optimised to assess myelination (such as magnetisation transfer saturation values). Observing no relationship with the MR g-ratio, but a relationship with magnetisation transfer saturation values, would suggest a proportional change in the underlying myelin and, consequently, variation in conduction velocity. By contrast, no relationship with either the MR g-ratio or magnetisation transfer saturation values would suggest that there was no change in the underlying microstructure and therefore no variation in conduction velocity.

The MR g-ratio has, therefore, the potential to provide a number of novel insights into human cognition. One area where the MR g-ratio may be particularly helpful is in probing individual differences. Our particular interest is in the ability to recall past experiences from real life, known as autobiographical memories. The detailed recall of autobiographical memories is a critical cognitive function that serves to sustain our sense of self, enable independent living, and prolong survival (Tulving, 2002). While some healthy individuals can recollect decades-old autobiographical memories with great richness and clarity, others struggle to recall what they did last weekend (LePort et al., 2012; Palombo et al., 2015). In the context of the healthy population, we currently lack a clear biological explanation for the basis of these individual differences (Palombo et al., 2018).

There is no doubt that the hippocampus is central to the processing of autobiographical memories, and hippocampal damage is linked with autobiographical memory impairments (McCormick et al., 2018; Scoville and Milner, 1957; Winocur and Moscovitch, 2011). However, no consistent relationship between autobiographical memory recall ability and hippocampal grey matter volume or microstructure has been identified in healthy individuals (Clark et al., 2020; Clark et al., 2021a; LePort et al., 2012; Maguire et al., 2003; Van Petten, 2004). The hippocampus does not act alone, and functional neuroimaging studies have revealed that a distributed set of brain areas supports autobiographical memory recall along with the hippocampus, including the parahippocampal, retrosplenial, parietal and medial prefrontal cortices (Andrews-Hanna et al., 2014; Maguire, 2001; Spreng et al., 2009; Svoboda et al., 2006). Changes in MR g-ratio and, by inference, conduction velocity, might affect communication between these brain regions and so influence individual differences in autobiographical memory recall within the healthy population.

Three white matter pathways in particular enable communication with the hippocampal region – the fornix, the uncinate fasciculus and the parahippocampal cingulum bundle. The fornix (Figure 3A) is a major pathway in and out of the hippocampus and connects it to the orbital and medial prefrontal cortices, the basal forebrain, the anterior thalamus, the hypothalamus and the mammillary bodies (Aggleton et al., 2015; Croxson et al., 2005). The uncinate fasciculus (Figure 3B) originates in the uncus, entorhinal and parahippocampal cortices and passes over the lateral nucleus of the amygdala, arcs around the Sylvian fissure, terminating in various locations throughout the prefrontal cortex (Croxson et al., 2005; Von Der Heide et al., 2013). The parahippocampal cingulum bundle (Figure 3C) links the hippocampus with the entorhinal, parahippocampal, retrosplenial and parietal cortices, as well as providing another route between the hippocampus and anterior thalamus (Bubb et al., 2018; Jones et al., 2013b). It also links to the prefrontal cortex via its connections with other parts of the cingulum bundle.

The three white matter tracts of interest, given their relationship with the hippocampal region.

The fornix was defined using the ICBM-DTI-81 white-matter labels atlas (Mori et al., 2008). The uncinate fasciculus and parahippocampal cingulum bundle were defined using the Johns Hopkins probabilistic white matter tractography atlas (Hua et al., 2008), with the minimum probability threshold set to 25%.

In the current study, we calculated the MR g-ratio within these three pathways to ascertain whether this was related to autobiographical memory recall ability. A significant relationship with the MR g-ratio would suggest that variation in the conduction velocity of a pathway is associated with autobiographical memory recall ability. The relationship of MR g-ratio to the underlying microstructure as outlined in Figure 2, would further guide us as to whether any significant effects were more likely to be associated with the extent of myelination or the size of the inner axon diameter of the fibres in these three white matter tracts. These analyses were augmented by examining whether magnetisation transfer saturation values of the pathways (assessing myelination) were associated with autobiographical memory recall ability.

In addition, we also used the neurite orientation dispersion and density imaging (NODDI; Zhang et al., 2012) biophysical model to derive two complementary biological measures that could provide further insights into the arrangement of neurites in a voxel. A neurite is any projection from a neuron’s cell body, such as an axon or a dendrite. The neurite orientation dispersion index is an estimate of the organisation of the neurites in a voxel, where a small orientation dispersion index value indicates a low dispersion of neurites, in other words, that the neurites are coherently organised. The second property, neurite density, is a measure of the density of the neurites in a voxel.

For completeness, the commonly reported physical parameters from standard diffusion tensor imaging (DTI; e.g. fractional anisotropy and mean diffusivity; Basser, 1995) that are often derived from diffusion data were also computed (Oeschger et al., 2021). However, these metrics lack biological specificity (Jensen and Helpern, 2010; Jones et al., 2013a) and, consequently, could not speak to our research questions. For example, fractional anisotropy is a very general measure. Variations in fractional anisotropy values can occur for numerous reasons, including, but not limited to, changes in the extent of myelination, axon coherence, axon density, and the level of astrocytes. Consequently, standard DTI parameter results are only briefly summarised in the main text, with full details provided in Appendix 1 and Supplementary file 1, Supplementary file 2.

To ensure an appropriate sample size and a wide range of autobiographical memory recall ability, we examined a large group of healthy young adults from the general population (n=217; 109 females, 108 males; mean age of 29.0 years, SD = 5.60; age was restricted to between 20 and 41 years to limit the possible effects of aging).

All participants underwent the widely-used Autobiographical Interview (Levine et al., 2002). This task, which is the gold standard in the field, provides a detailed metric characterising a person’s ability to recall real-life past experiences, as well as providing a useful control measure. We also examined performance on another eight standard laboratory-based memory tests. Their inclusion allowed us to ascertain whether any relationships with conduction velocity were specific to recollecting detailed autobiographical memories from real life, or were also applicable to the recall of more constrained laboratory-based stimuli.

Diffusion and magnetisation transfer saturation MRI scans were obtained for each person to enable calculation of the MR g-ratio and the other measures. Our analyses were performed using weighted means from each of the three white matter tracts of interest rather than voxel-wise across the whole brain, reducing the potential for false positives (Marek et al., 2022).

Focusing on the fornix, uncinate fasciculus and parahippocampal cingulum bundle, we predicted that variations in the MR g-ratio from some or all of these tracts would be associated with autobiographical memory recall ability. Such a finding would, for the first time, suggest a link between variations in white matter tract conduction velocity and individual differences in autobiographical memory recall.

Under the assumption that a significant relationship between the MR g-ratio and autobiographical memory recall represents an association with faster conduction velocity (e.g. Brancucci, 2012; Dicke and Roth, 2016; Miller, 1994; Reed and Jensen, 1992), and aided by the analysis of the magnetisation transfer saturation values, we further sought to evaluate the scenarios presented in Figure 2. Specifically, we asked whether autobiographical memory recall ability was more likely to be associated with inner axon diameter or myelin thickness in the context of g-ratio and conduction velocity. A negative relationship between the MR g-ratio and autobiographical memory recall ability (Figure 2A blue and red arrows, and Figure 2B and C), along with a positive relationship between magnetisation transfer saturation and autobiographical memory recall ability, would suggest that myelin thickness was more relevant. By contrast, a positive relationship between the MR g-ratio and autobiographical memory recall ability (Figure 2A orange arrow, and Figure 2D) would highlight the potential relevance of inner axon diameters. Observing no associations between the MR g-ratio or magnetisation transfer saturation values and autobiographical memory recall, would suggest no relationships with the underlying microstructure or conduction velocity, and would speak against the possibility of a proportional change in microstructure (Figure 2A black arrow, and Figure 2E).

Finally, given that a previous functional MRI meta-analysis identified different neural substrates associated with autobiographical memory recall and the recall of laboratory-based stimuli (McDermott et al., 2009; see also Maguire, 2001; Maguire, 2012; Miller et al., 2022; Mobbs et al., 2021; Nastase et al., 2020; Spiers and Maguire, 2007), we expected that associations with the MR g-ratio might be specific to autobiographical memory recall. We reasoned that detailed, multimodal, autobiographical memories may rely on inter-regional connectivity to a greater degree than simpler, more constrained laboratory-based memory tests.

Results

Autobiographical memory recall scores

We employed the widely-used Autobiographical Interview (Levine et al., 2002) to score autobiographical memory recall (see Materials and methods for full details). The main measure of autobiographical memory recall ability was the mean number of ‘internal’ details from the freely recalled autobiographical memories. Internal details are those that describe the specific past event in question, and are considered to reflect episodic information. Across the participants, the mean number of internal details provided per memory was 23.95 (SD = 7.25; range = 4.60–44.60).

As a control measure, the mean number of “external” details was also calculated from the autobiographical memory descriptions. External details pertain to semantic information about the past event, and other non-event information. Across the participants, the mean number of external details provided per memory was 5.35 (SD = 3.20; range = 0.8–17.40).

Laboratory-based memory test performance

While our main interest was in autobiographical memory recall, eight commonly used laboratory-based memory tasks were also administered. Their inclusion allowed us to establish whether any associations identified with the main microstructure measure, MR g-ratio, were specific or not to the recollection of real-life autobiographical memories.

The ability to recall a short narrative was examined using the immediate and delayed recall tests of the Logical Memory subtest of the Wechsler Memory Scale IV (Wechsler, 2009). Across participants, the mean immediate recall scaled score was 12.95 (SD = 2.09, range = 6–18) and the mean delayed recall scaled score was 12.58 (SD = 2.62, range = 6–19). Verbal list recall ability was assessed using the immediate and delayed recall of the Rey Auditory Verbal Learning Test (see Strauss et al., 2006). The mean immediate recall (aggregate) score was 58.82 (SD = 7.42, range = 33–73) and the mean delayed recall score was 12.92 (SD = 2.17, range = 6–15). Visuospatial recall ability was examined using the delayed recall of the Rey–Osterrieth Complex Figure (Rey, 1941), with a mean delayed recall score of 22.28 (SD = 5.71, range = 8.5–35). Recognition memory ability was tested using the Warrington Recognition Memory Tests for Words and Faces (Warrington, 1984). The mean recognition memory scaled score for words was 12.75 (SD = 2.06, range = 3–15) and for faces was 11.00 (SD = 3.33, range = 3–18). Finally, participants also completed the ‘Dead or Alive’ task which probes general knowledge about whether famous people have died or are still alive, providing a measure of semantic memory (Kapur et al., 1989). The mean accuracy performance on this test was 81.32% (SD = 8.44, range = 57.14%–97.26%).

No relationships between memory measures and fornix or uncinate fasciculus microstructure

We first investigated the fornix and uncinate fasciculus. None of the biophysical measures from either tract were significantly associated with autobiographical memory recall ability. This was the case when using a corrected p<0.017 (see Materials and methods) or an uncorrected p<0.05 threshold. Full details of these results are provided in Appendix 1 (Appendix 1—figures 1 and 2; Appendix 1—tables 1–4), with the source data available in Supplementary file 1.

Standard DTI parameters (e.g. fractional anisotropy and mean diffusivity) were also extracted from the fornix and uncinate fasciculus. None of the standard DTI parameters, from either tract, were significantly associated with autobiographical memory recall ability, even when using an uncorrected p<0.05 threshold (see Appendix 1—tables 1–4 for full details, source data are available in Supplementary file 1).

There were no significant associations between fornix or uncinate fasciculus MR g-ratios or magnetisation transfer saturation values and any of the laboratory-based memory tests (see Appendix 1—table 5, Appendix 1—table 6 for full details, source data are available in Supplementary file 1).

Of note, and for completeness, we also performed exploratory analyses in six additional white matter tracts: the anterior thalamic radiation, the dorsal cingulum bundle, the forceps minor, the inferior longitudinal fasciculus, the inferior occipitofrontal fasciculus and the superior longitudinal fasciculus. However, as with the fornix and the uncinate fasciculus, none of the metrics from any of these tracts were associated with autobiographical memory recall ability, even when using an uncorrected p<0.05 threshold (see Appendix 1—figures 38 and Appendix 1—tables 7–18 for full details).

The parahippocampal cingulum bundle

We found that variations in autobiographical memory recall ability were uniquely related to the microstructure of the parahippocampal cingulum bundle. This tract connects the hippocampus with the entorhinal, parahippocampal, retrosplenial and parietal cortices, and the anterior thalamus (Figure 4). Moreover, via other subdivisions of the cingulum bundle, it is indirectly connected with prefrontal regions including the medial prefrontal cortex. The parahippocampal cingulum bundle is, therefore, well positioned for information transfer between the key regions involved in autobiographical memory recall (Andrews-Hanna et al., 2014; Maguire, 2001; Spreng et al., 2009; Svoboda et al., 2006).

Simplified schematic of the location and main connections of the parahippocampal cingulum bundle.

The blue lines indicate direct connections, and the dashed blue line an indirect connection.

As with the other tracts (see Materials and methods), the parahippocampal cingulum bundle region of interest (ROI) was defined bilaterally using the Johns Hopkins probabilistic white matter tractography atlas (Hua et al., 2008). To reduce partial volume effects, we used a conservative minimum probability of 25%, and the tract ROI was refined for each participant to ensure the mask was limited to each person’s white matter. The mean number of voxels in the parahippocampal cingulum bundle ROI was 129.11 (SD = 25.68), and the variance in number of voxels across individuals was accounted for in our analyses. As before, a corrected statistical threshold of p<0.017 was applied (see Materials and methods). Table 1 shows the summary statistics for the microstructure measures, with the source data for the parahippocampal cingulum bundle available in Supplementary file 2.

Table 1
Means and standard deviations for the microstructure measures from the parahippocampal cingulum bundle.
Microstructure measureMeanStandard deviation
MR g-ratio0.6470.043
Magnetisation transfer saturation0.9590.007
Neurite dispersion (ODI)0.1890.038
Neurite density0.4800.051
  1. Note. ODI = Orientation Dispersion Index.

Variation in MR g-ratio of the parahippocampal cingulum bundle was associated with autobiographical memory recall ability

We first investigated whether the MR g-ratio of the parahippocampal cingulum bundle was associated with autobiographical memory recall ability, performing partial correlation analyses with age, gender, scanner and the number of voxels in the ROI included as covariates. A significant positive association was observed between the parahippocampal cingulum bundle MR g-ratio and the number of internal details (Figure 5A; r(211) = 0.18, p=0.008, 95% CI=0.05, 0.29). This relationship was specific to internal details, with no association evident for the external details control measure (Figure 5B; r(211) = –0.09, p=0.17, 95% CI=−0.21, 0.019). Direct comparison of the correlations confirmed there was a significantly larger correlation between the MR g-ratio and internal details than for external details (Figure 5C; mean r difference = 0.28 (95% CI=0.11, 0.45), z=3.21, p=0.0013). This suggests that variations in the conduction velocity of the parahippocampal cingulum bundle are associated with individual differences in autobiographical memory recall ability. The positive nature of the correlation highlights the potential relevance of inner axon diameter rather than myelin thickness in the context of g-ratio and conduction velocity (Figure 2A orange arrow, and Figure 2D).

MR g-ratio and the parahippocampal cingulum bundle.

The relationship between parahippocampal cingulum bundle MR g-ratio and autobiographical memory recall ability (internal details), and the control measure (external details) are shown. (A) There was a significant positive correlation between the MR g-ratio and internal details (dashed lines indicate the confidence intervals). (B) There was no significant relationship between the MR g-ratio and external details. (C) Bar chart showing the partial correlation coefficients (with standard errors) between the MR g-ratio and internal and external details. There was a significant difference between the correlations when they were directly compared; ***p<0.001. Data points for this figure are provided in Figure 5—source data 1, n = 217 for all analyses.

To further aid the interpretation of the relationship with MR g-ratio in terms of the underlying axonal microstructure, we also investigated whether the magnetisation transfer saturation values (assessing myelination) of the parahippocampal cingulum bundle were associated with autobiographical memory recall ability. We performed partial correlation analyses with the same covariates as before. Magnetisation transfer saturation values were not significantly related to either internal (r(211) = 0.00, p=1.0, 95% CI=−0.12, 0.12), or external (r(211) = 0.14, p=0.048, 95% CI=−0.06, 0.30) details.

Overall, therefore, under the assumption that the significant relationship between the MR g-ratio and autobiographical memory recall ability is associated with faster conduction velocity, Rushton’s model of conduction velocity would indicate that better autobiographical memory recall is more likely to be related to parahippocampal cingulum bundle axons having larger inner axon diameters rather than thicker myelin sheaths (see Figure 2A orange arrow, and Figure 2D).

Variation in neurite dispersion within the parahippocampal cingulum bundle was associated with autobiographical memory recall

In addition to the MR g-ratio, we also examined the relationship between autobiographical memory recall ability and two complementary biophysical measures, the neurite orientation dispersion index and neurite density maps estimated using the NODDI biophysical model (Zhang et al., 2012). Partial correlations revealed a significant negative correlation between the neurite orientation dispersion index (a small orientation dispersion index value indicates low dispersion) and internal details (Figure 6A; r(211) = –0.19, p=0.005, 95% CI=−0.32,–0.06). This was again specific to internal details with no significant relationship between the neurite orientation dispersion index and external details (Figure 6B; r(211) = 0.07, p=0.28, 95% CI=−0.05, 0.20). Direct comparison of the correlations revealed a significantly larger correlation between the neurite orientation dispersion index and internal details than for external details (Figure 6C; mean r difference = 0.27 (95% CI=0.44, 0.10), z=3.13, p=0.0017). Neurite density was not significantly related to either internal (r(211) = 0.04, p=0.60, 95% CI=−0.09, 0.16), or external (r(211) = 0.01, p=0.93, 95% CI=−0.12, 0.13) details. Therefore, in addition to a higher MR g-ratio, when neurites in the parahippocampal cingulum bundle were less dispersed and thus more coherently organised, this was associated with better autobiographical memory recall.

Neurite dispersion and the parahippocampal cingulum bundle.

The relationship between parahippocampal cingulum bundle neurite dispersion (orientation dispersion index) and autobiographical memory recall ability (internal details), and the control measure (external details) are shown. (A) There was a significant negative correlation between neurite dispersion and internal details (dashed lines indicate the confidence intervals). (B) There was no significant relationship between neurite dispersion and external details. (C) Bar chart showing the partial correlation coefficients (with standard errors) between neurite dispersion and internal and external details. There was a significant difference between the correlations when they were directly compared; **p<0.01. Data points for this figure are provided in the Figure 6—source data 1, n = 217 for all analyses.

For completeness, we also examined a third measure from the NODDI biophysical model, the isotropic volume fraction. This models the space occupied by cerebrospinal fluid in a voxel, and therefore no relationship with autobiographical memory recall ability was expected, and none was found. Partial correlations showed that the isotropic volume fraction of the parahippocampal cingulum bundle (mean = 0.04, SD = 0.03) was not significantly related to either internal (r(211) = –0.03, p=0.71, 95% CI=−0.14, 0.10), or external (r(211) = 0.02, p=0.77, 95% CI=−0.11, 0.15) details. This confirms that it is the combination of these measures, in the form of the MR g-ratio, that is meaningful, rather than any single measure alone.

Standard DTI parameters of the parahippocampal cingulum bundle and autobiographical memory recall ability

Partial correlations using the same covariates as the previous analyses were also performed using the standard DTI parameters. As these metrics lack biological specificity (Jensen and Helpern, 2010; Jones et al., 2013a), and could not speak to our research questions, the results are summarised here, with full details in Appendix 1—table 19, Appendix 1—table 20 and Appendix 1—figure 9, Appendix 1—figure 10 and the source data are available in Supplementary file 2.

Two significant relationships were identified between the standard DTI parameters and autobiographical memory recall ability. First, there was a positive correlation between fractional anisotropy and the number of internal details (Appendix 1—figure 9A; r(211) = 0.20, p=0.003, 95% CI=0.07, 0.32). Second, a positive correlation was evident between diffusivities parallel and the number of internal details (Appendix 1—figure 10A; r(211) = 0.19, p=0.005, 95% CI=0.06, 0.32). As with the microstructure metrics, these relationships were specific to internal details with no relationships identified with external details for either fractional anisotropy (r(211) = –0.06, p=0.39, 95% CI=−0.19, 0.07) or diffusivities parallel (r(211) = –0.048, p=0.49, 95% CI=−0.19, 0.10). No significant relationships were found between mean diffusivity, mean kurtosis or diffusivities perpendicular and either internal or external details.

No relationship between microstructure measures of the parahippocampal cingulum bundle and scores on laboratory-based memory tests

Finally, we tested for associations between the key microstructure measures and performance on the eight laboratory-based memory tasks. No relationships with the MR g-ratio or magnetisation transfer saturation values were evident for any task, even when using an uncorrected p < 0.05 threshold (Appendix 1—table 21, source data are available in Supplementary file 2). This suggests that the parahippocampal cingulum bundle MR g-ratio, and by inference conduction velocity, was specifically associated with recall of autobiographical memories from real life rather than performance on the more constrained laboratory-based memory tests.

Discussion

The conduction velocity of action potentials along axons is crucial for neural communication. Until recently it was not possible to examine metrics associated with axonal conduction velocity, such as the g-ratio, in vivo in the human brain, with this being largely the preserve of studies involving non-human animals. However, by combining diffusion MRI with quantitative structural MRI scans optimised to assess myelination (Callaghan et al., 2014), it is now possible to estimate the MR g-ratio in vivo in humans (Drakesmith et al., 2019; Mohammadi et al., 2015; Mohammadi and Callaghan, 2021; Stikov et al., 2015). Here, in the first application to human cognition, we found that variations in the MR g-ratio specifically in the parahippocampal cingulum bundle were associated with individual differences in autobiographical memory recall ability in a large sample of healthy adults. Under various modelling assumptions related to MR g-ratio and conduction velocity (detailed below), this was associated with larger inner axon diameters rather than myelin content. Moreover, we identified a possible link between autobiographical memory recall ability and more coherently organised neurites. Our findings were also specific to autobiographical memory retrieval and were not evident for laboratory-based memory tests. These results offer a new perspective on individual differences in autobiographical memory recall ability. This is especially welcome given the current lack of a clear biological explanation for such variations in the healthy population (Clark et al., 2020; Clark et al., 2021a; LePort et al., 2012; Maguire et al., 2003; Palombo et al., 2018; Van Petten, 2004).

A key property of the MR g-ratio is that it provides a non-invasive methodology with which to relate in vivo structural neuroimaging of humans with axonal conduction velocity (Berman et al., 2019; Drakesmith et al., 2019). Moreover, the identification of a statistically significant relationship with the MR g-ratio can help to guide as to which of inner axon diameter or myelin thickness is more likely to be associated with variations in conduction velocity (Caeyenberghs et al., 2016; Kaller et al., 2017; Lakhani et al., 2016; Waxman, 1980; Xin and Chan, 2020).

Our inferences rested upon the assumption that a significant relationship with the MR g-ratio reflected faster conduction velocity, given previous work suggesting that faster conduction velocity might be associated with better cognition (e.g. Brancucci, 2012; Dicke and Roth, 2016; Miller, 1994; Reed and Jensen, 1992). As shown in Figure 2, there are three main scenarios describing how changes in the MR g-ratio are related to the underlying microstructural properties, given a faster conduction velocity. The positive relationship we observed between the parahippocampal cingulum bundle MR g-ratio and autobiographical memory recall ability suggests that this effect was associated predominantly with larger inner axon diameter (Figure 2A orange arrow, and Figure 2D). By contrast, had a negative correlation between the MR g-ratio and autobiographical memory recall ability been identified, we could instead have inferred that myelination was the relevant microstructural feature. The lack of relationship between parahippocampal cingulum bundle magnetisation transfer saturation values (optimised to assess myelination) and autobiographical memory recall ability provided further corroboration that myelin may not have been influential in this context. Greater myelination is often held to be a prominent influence on behavioural and cognitive performance (Caeyenberghs et al., 2016; Fields and Bukalo, 2020; Kaller et al., 2017; Lakhani et al., 2016; Waxman, 1980; Xin and Chan, 2020). By contrast, our results highlight the potentially important role that the inner axon diameter could be playing in autobiographical memory recall.

We also found that lower neurite dispersion, suggesting more coherent neurite organisation, was related to better autobiographical memory recall ability. Our measure of neurite dispersion was obtained using the NODDI biophysical model (Zhang et al., 2012), which aims to isolate the organisation of the neurites in a voxel from the density of the neurites in a voxel. While neurite dispersion was significantly related to autobiographical memory recall, no relationship was observed with neurite density.

A larger inner axon diameter reduces resistance to action potential signals, enabling greater conduction velocities (Gasser and Grundfest, 1939; Hursh, 1939), and coherently organised fibres may decrease the distance signals need to travel, further reducing communication times (Salami et al., 2003; Steriade, 1995). This combination of features might optimise a fibre bundle for faster communication, and this may benefit autobiographical memory recall.

These results were specific to one white matter tract, the parahippocampal cingulum bundle (Bubb et al., 2018). MR g-ratio measures from no other tract, including the dorsal part of the cingulum bundle, showed any association with autobiographical memory recall ability. The parahippocampal cingulum bundle directly connects the hippocampus, parahippocampal, retrosplenial and parietal cortices, the anterior thalamus and, through other subdivisions of the cingulum bundle, the medial prefrontal cortex. These regions are typically engaged during fMRI studies of autobiographical memory recall (Andrews-Hanna et al., 2014; Maguire, 2001; Spreng et al., 2009; Svoboda et al., 2006), and damage to them is often associated with autobiographical memory impairments (Berryhill et al., 2007; McCormick et al., 2018; Scoville and Milner, 1957; Vann et al., 2009). The retrosplenial and parahippocampal cortices are thought to provide visuospatial elements of autobiographical memories (Dalton and Maguire, 2017; Epstein and Higgins, 2007; Mullally and Maguire, 2011; Vann et al., 2009), while the medial prefrontal cortex may initiate autobiographical retrieval and support schema-guided recall (Gilboa and Marlatte, 2017; McCormick et al., 2018; McCormick et al., 2020). The parahippocampal cingulum bundle is, therefore, uniquely positioned as a transmission highway enabling this information to reach the hippocampus, where memories can be reconstructed (Bartlett, 1932; Hassabis and Maguire, 2007; Schacter et al., 2012). Larger inner axon diameters and coherently organised neurites could facilitate rapid information flow along the parahippocampal cingulum bundle leading to more memory elements being available simultaneously, which in turn may result in increased detail and better integration of a memory representation.

There have only been a small number of previous studies investigating white matter tracts and individual differences in autobiographical memory recall ability in healthy people. These focused on standard DTI parameters, such as fractional anisotropy and mean diffusivity, and not the MR g-ratio. Two such studies were suggestive of a relationship between parahippocampal cingulum bundle fractional anisotropy and autobiographical memory recall (Irish et al., 2014; Memel et al., 2020). Our analyses of the standard DTI parameters, therefore, replicated these previous results. Direct comparison between these studies and our findings is difficult, however, given the relatively small sample sizes, older age of participants in some of the extant studies, and the testing of mixed groups of healthy older people and patients with dementia. In addition, fractional anisotropy and other physical parameters lack biological specificity (Jensen and Helpern, 2010; Jones et al., 2013a) and, consequently, they cannot speak to questions concerning axonal conduction velocity, which is our main interest here. In a similar vein, we are not aware of any reports of bilateral lesions that selectively compromise or sever the parahippocampal cingulum bundle in humans. Given our findings, we would predict that such lesions would adversely affect the ability to recall autobiographical memories.

Despite its prime location and connectivity at the heart of the brain’s autobiographical memory system, the dearth of studies in humans and the rarity of selective bilateral lesions to the parahippocampal cingulum bundle have perhaps obscured its importance when compared to other, more celebrated, memory-related white matter tracts. We also examined two such tracts, the fornix and the uncinate fasciculus, but in both cases no significant relationships between any of our neuroimaging metrics and autobiographical memory recall ability were evident in our large cohort of young healthy adults. As outlined in Figure 2, there was one possible scenario where a null relationship with the MR g-ratio could reflect an association with conduction velocity – if both the inner axon diameter and myelin thickness increased proportionally to each other (Figure 2A black arrow, and Figure 2E). However, we found no associations between autobiographical memory recall and both the MR g-ratio and magnetisation transfer saturation values of the fornix and uncinate fasciculus, which speaks against this explanation. In terms of standard DTI parameters, unlike a previous study (Hodgetts et al., 2017), we did not find a relationship between fornix fractional anisotropy and autobiographical memory recall ability, which may be due to the larger sample that we examined.

Both the fornix and parahippocampal cingulum bundle are vulnerable to partial volume effects (Concha et al., 2005). However, to mitigate this issue we took steps to ensure the data were extracted only from white matter voxels (see Materials and methods). Diffusion data are also susceptible to distortions which can particularly affect the uncinate fasciculus. We addressed this challenge by using a new technique that improves distortion correction in this region (Clark et al., 2021b). The absence of fornix findings in our study could echo those relating to hippocampal volume (Clark et al., 2020; Clark et al., 2021a), whereby the structure is widely acknowledged to be involved in autobiographical memory recall, and damage impedes retrieval (Aggleton et al., 2000; D’Esposito et al., 1995; Gaffan and Gaffan, 1991; Tsivilis et al., 2008), but microstructural variations have limited impact within the healthy adult population. Regarding the uncinate fasciculus, unilateral lesions do not seem to significantly impair performance on laboratory-based memory tests (Papagno et al., 2011) or the recall of premorbid autobiographical memories (Levine et al., 2009). Bilateral uncinate fasciculus lesions are very rare in humans, but might result in greater memory impairment. Alternatively, hippocampal-prefrontal connections may be better served by other pathways, for example, via the fornix or parts of the cingulum bundle.

Our findings were not only specific to the parahippocampal cingulum bundle, but also to the internal details of autobiographical memories, which reflect the episodicity of past experiences. By contrast, our control measure of external details, also from the same task but which concerns non-episodic information in the autobiographical memories, did not correlate with any white matter microstructure metrics. Moreover, no relationships were identified with any of the eight laboratory-based memory tasks examined, highlighting the specific nature of the relationship between parahippocampal cingulum bundle MR g-ratio and, by inference, conduction velocity, and autobiographical memory recall ability. It may be that vivid, detailed, multimodal, autobiographical memories rely on inter-regional connectivity, particularly that supported by the parahippocampal cingulum bundle, to a greater degree than simpler, more constrained laboratory-based memory tests. This result aligns with previous work involving an fMRI meta-analysis which showed that recall of autobiographical memories and laboratory-based memory stimuli were associated with substantially different neural substrates (McDermott et al., 2009). More generally, our findings add to the increasingly-recognised importance of studying real-world cognition in order to fully characterise brain-behaviour relationships (Maguire, 2001; Maguire, 2012; Miller et al., 2022; Mobbs et al., 2021; Nastase et al., 2020; Spiers and Maguire, 2007).

Age, gender, scanner and the number of voxels within an ROI were included as covariates in all analyses, limiting the potential confounding effects of these variables. Our analyses were also performed using weighted means from each of the three white matter tracts of interest rather than voxel-wise across the whole brain, reducing the potential for false positives (Marek et al., 2022). We also tested a sample of over 200 participants, which has been suggested as sufficient for correlational neuroimaging research such as that performed here (Cecchetti and Handjaras, 2022; DeYoung et al., 2022). Relationships with autobiographical memory recall ability were also specific to the MR g-ratio, and were not evident for any of its components (magnetisation transfer saturation, neurite density or isotropic volume fraction), suggesting that it is the combination of these measures, in the form of the MR g-ratio, that is meaningful rather than any single measure alone.

Nevertheless, as with all neuroimaging techniques, methodological limitations need to be considered when measuring the MR g-ratio (see Campbell et al., 2018; Mohammadi and Callaghan, 2021 for in depth methodological reviews). First, the MR g-ratio is an area-weighted average of all microscopic axons in an MRI-voxel that is slightly weighted towards larger axons. Second, MR proxies are required to estimate myelin and axonal volumes for the calculation of the MR g-ratio. Multiple methodologies are available to estimate myelin and axonal volumes, with no consensus yet reached as to the best combination (Mohammadi and Callaghan, 2021). Third, a calibration step is required to more closely align the MR proxies with the estimated volume fractions. Here, we used the standard single-point calibration method to estimate the slope of the myelin-based proxy, assuming that the offset can be neglected. Future work may be able to improve these calibrations. But, of note, since a non-negligible offset in the myelin-based proxy can increase the error in the MR g-ratio, any calibration improvements would likely serve to increase the observed correlation. Fourth, although the model of the MR g-ratio allows for fibre dispersion (Stikov et al., 2015), this is not accounted for in mapping to conduction velocity. Going forward, more advanced models may help to further elaborate on these relationships. Fifth, our myelin measure can be influenced by any factor, cognitive or demographic, that leads to a difference in absolute myelination. In principle, unexplained variance could obscure a true underlying relationship with autobiographical memory. To mitigate this, our analyses controlled for age, gender and any potential scanner-related differences. The MR g-ratio, however, is less affected by this limitation because it is a relative measure and does not depend on absolute myelin content but on the balance between absolute myelin and axonal volumes.

Finally, our inference suggesting that the positive correlation between the MR g-ratio and autobiographical memory recall ability is potentially related to inner axon diameter is specifically in the context of g-ratio and conduction velocity, and is based upon Rushton’s (1951) model rather than direct measurements of axon diameter. The use of Connectom MRI scanners (Jones et al., 2018) and more advanced biophysical models may be able to expand upon this relationship in the future.

While we examined the parahippocampal cingulum bundle as a unitary pathway, it comprises both long and short association fibres with differing connectivity (Bubb et al., 2018). Some fibres will form long range connections between, for example, the hippocampus and retrosplenial cortex, whereas others will make shorter range connections between neighbouring regions. Connectom MRI is starting to make examination of short range ‘u-fibres’ possible in vivo in humans (Movahedian Attar et al., 2020; Shastin et al., 2022). While there are currently only four of these scanners in the world, future studies using Connectom MRI could seek to identify specific connections within the parahippocampal cingulum bundle that relate to individual differences in autobiographical memory recall.

In conclusion, white matter microstructure measures related to conduction velocity are now possible to derive in vivo in humans. This has the potential to provide novel insights into how the brain processes and integrates information (Berman et al., 2019; Drakesmith et al., 2019), deepening our understanding of the information flow that underpins critical cognitive functions such as autobiographical memory recall.

Materials and methods

Participants

Two hundred and seventeen healthy people took part in the study, including 109 females and 108 males. The age range was restricted to 20–41 years old to limit the possible effects of aging (mean age = 29.0 years, SD = 5.60). Participants had English as their first language and reported no history of psychological, psychiatric or neurological conditions. Our aim was to assess people from the general population who would not be classed as having extreme expertise on classic hippocampal tasks, as this could affect hippocampal structure (Maguire et al., 2000; Woollett and Maguire, 2011). Consequently, people with vocations such as taxi driving (or those training to be taxi drivers), ship navigators, aeroplane pilots, or those with regular hobbies including orienteering, or taking part in memory sports and competitions, were excluded. Of the approximately 2000 people who contacted us, 23 were explicitly excluded on this basis. Participants were reimbursed £10 per hour for taking part which was paid at study completion. All participants gave written informed consent and the study was approved by the University College London Research Ethics Committee (project ID: 6743/001).

A sample size of 217 was determined during study design to be robust to employing different statistical approaches when answering multiple questions of interest. Specifically, the sample 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). Samples of over 200 participants have also been suggested as sufficient for correlational neuroimaging research similar to that performed here (Cecchetti and Handjaras, 2022; DeYoung et al., 2022).

Procedure

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Participants completed the study over multiple visits. Diffusion imaging and magnetisation transfer saturation scans were acquired on two separate days, and the Autobiographical Interview was conducted during a third visit. All participants completed all parts of the study.

The autobiographical interview

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This widely-used test (Levine et al., 2002) was employed to measure autobiographical memory recall ability. Participants are asked to provide autobiographical memories from a specific time and place over four time periods – early childhood (up to age 11), teenage years (aged from 11 to 17), adulthood (from age 18 years to 12 months prior to the interview; two memories are requested), and the last year (a memory from the last 12 months); therefore, five memories in total are harvested. Recordings of the memory descriptions are transcribed for later scoring.

The main outcome measure of the Autobiographical Interview is the mean number of internal details included in the description of an event from across the five autobiographical memories. Internal details are those describing the event in question (i.e. episodic details) and include event, place, time and perceptual information, as well as thoughts and emotions relating to the event itself. We used the secondary outcome measure of the Autobiographical Interview, the mean number of external details included in the five autobiographical memories, as a control measure. External details include semantic information concerning the event, or other non-event information, and are not considered to reflect autobiographical memory recall ability.

Double scoring was performed on 20% of the data. Inter-class correlation coefficients, with a two-way random effects model looking for absolute agreement were calculated for both internal and external details. This was performed both for individual memories and as an average of all five memories across each participant. For internal details the coefficients were 0.94 and 0.97, respectively, and for external details they were 0.84 and 0.87 respectively. For reference, a score of 0.8 or above is considered excellent agreement beyond chance.

Laboratory-based memory tests

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Eight laboratory-based memory tasks were also administered to participants. These are standard memory tests that are often used in neuropsychological settings. Tasks were performed and scored in line with their standardised and published protocols.

The ability to recall a short narrative was examined using the immediate and delayed recall tests of the Logical Memory subtest of the Wechsler Memory Scale IV (Wechsler, 2009). Verbal list recall was assessed using the immediate and delayed recall tests of the Rey Auditory Verbal Learning Test (see Strauss et al., 2006). Visuospatial recall was examined using the delayed recall of the Rey–Osterrieth Complex Figure (Rey, 1941). Recognition memory was investigated using the Warrington Recognition Memory Tests for Words and Faces (Warrington, 1984). Finally, participants also underwent the ‘Dead or Alive’ task which probes general knowledge about whether famous individuals have died or are still alive, providing a measure of semantic memory (Kapur et al., 1989).

Diffusion MRI data acquisition

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Three MRI scanners were used to collect the neuroimaging data. All scanners were Siemens Magnetom TIM Trio systems with 32 channel head coils and were located at the same neuroimaging centre, running the same software. The sequences were loaded identically onto the individual scanners. Participant set-up and positioning followed the same protocol for each scanner.

Diffusion-weighted images were collected using the multiband accelerated EPI pulse sequence developed by the Centre for Magnetic Resonance Research at the University of Minnesota (R012a-c, R013a on VB17, https://www.cmrr.umn.edu/multiband/; Feinberg et al., 2010; Xu et al., 2013). Acquisition parameters were: resolution = 1.7 mm isotropic; FOV = 220 mm × 220 mm × 138 mm; 60 directions with 6 interleaved b0 images, echo time (TE)=112ms, repetition time (TR)=4.84 s, with a multiband acceleration factor of 3. The sequence was performed 4 times – twice with b-values of 1000 and twice with b-values of 2500. The first acquisition of each set of b-values was performed with phase-encoding in the anterior to posterior direction (blip-up), the second in the posterior to anterior direction (blip-down). The total acquisition time was 22 min.

Magnetisation transfer saturation data acquisition

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The specific scanner used to collect a participant’s diffusion-weighted images was also used to obtain their magnetisation transfer saturation map.

Whole brain structural maps of magnetisation transfer saturation, at an isotropic resolution of 800 μm, were derived from a multi-parameter mapping quantitative imaging protocol (Callaghan et al., 2015; Callaghan et al., 2019; Weiskopf et al., 2013). This protocol consisted of the acquisition of three multi-echo gradient-echo acquisitions with either proton density, T1 or magnetisation transfer weighting. Each acquisition had a TR of 25ms. Proton density weighting was achieved with an excitation flip angle of 60, which was increased to 210 to achieve T1 weighting. Magnetisation transfer weighting was achieved through the application of a Gaussian RF pulse 2 kHz off resonance with 4ms duration and a nominal flip angle of 2200. This acquisition had an excitation flip angle of 60. The field of view was 256 mm head-foot, 224 mm anterior-posterior, and 179 mm right-left. The multiple gradient echoes per contrast were acquired with alternating readout gradient polarity at eight equidistant echo times ranging from 2.34 to 18.44ms in steps of 2.30ms using a readout bandwidth of 488 Hz/pixel. Only six echoes were acquired for the magnetisation transfer weighted volume to facilitate the off-resonance pre-saturation pulse and subsequent spoiling gradient within the TR. To accelerate the data acquisition, partially parallel imaging using the GRAPPA algorithm was employed in each phase-encoded direction (anterior-posterior and right-left) with forty integrated reference lines and a speed up factor of two. Calibration data were also acquired at the outset of each session to correct for inhomogeneities in the RF transmit field (Lutti et al., 2010). The total acquisition time was 27 min.

Diffusion MRI pre-processing

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The diffusion MRI data were processed using the ACID toolbox (https://www.diffusiontools.com) within SPM12 (https://www.fil.ion.ucl.ac.uk/spm). The weighted average consecutive HySCO pipeline described in Clark et al., 2021b was followed, with the addition of multi-shell Position-Orientation Adaptive Smoothing (msPOAS; Becker et al., 2012) and Rician bias correction (Andrews-Hanna et al., 2014). In brief, the blip-up and blip-down data were first separately corrected for motion and eddy current artefacts. Next, msPOAS was performed, followed by correction for susceptibility-related distortion artefacts using the HySCO2 module (Macdonald and Ruthotto, 2018; Ruthotto et al., 2012). Tensor fitting (Mohammadi et al., 2013) was then implemented separately on each of the distortion corrected blip-up and blip-down datasets to estimate FA maps. HySCO2 was then repeated using the distortion corrected and brain-masked FA maps as input instead of b0 images; the second HySCO2 field map being consecutively applied to the ‘pre-corrected’ diffusion MRI data. Finally, Rician bias noise correction was employed on the distortion corrected data (André et al., 2014), before the data were combined using a weighted average to minimise information loss due to susceptibility distortion blurring induced by local spatial compression.

Magnetisation transfer saturation pre-processing

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The magnetisation transfer saturation data were processed for each participant using the hMRI toolbox (Tabelow et al., 2019) within SPM12. The default toolbox configuration settings were used, with the exception that correction for imperfect spoiling was additionally enabled (Corbin and Callaghan, 2021). The output magnetisation transfer saturation map quantified the degree of saturation of the steady state signal induced by the application of the off-resonance pre-pulse, having accounted for spatially varying T1 times and RF field inhomogeneity (Weiskopf et al., 2013).

Each participant’s magnetisation transfer saturation map was segmented into white matter probability maps using the unified segmentation approach (Ashburner and Friston, 2005), but with no bias field correction (since the magnetisation transfer saturation map does not suffer from any bias field modulation) and using the tissue probability maps developed by Lorio et al., 2016.

Diffusion model fitting

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The MR g-ratio was calculated according to Ellerbrock and Mohammadi, 2018:

gMR=1-MVFMRMVFMR+AVFMR

with MVFMR being the myelin-volume fraction estimated from the magnetisation transfer saturation map and AVFMR being the axonal-volume fraction. The AVFMR was estimated as AVFMR=1-MVFMR AWF according to Stikov et al., 2015, where AWF was obtained by combining the intra-cellular fraction (νicvf) and isotropic fraction (νiso) maps from NODDI (Zhang et al., 2012) as AWF=1- νiso νicvf . The magnetisation transfer saturation map was obtained from the hMRI toolbox as described above. For calibration of the magnetisation transfer saturation map to a myelin-volume fraction map (MVFMR= α MTsat), we used the g-ratio based calibration method as reported in Ellerbrock and Mohammadi, 2018 and Mohammadi and Callaghan, 2021, with α=0.1683.

The NODDI biophysical model (Zhang et al., 2012) was also used to obtain maps of the neurite orientation dispersion index and neurite density using the NODDI toolbox (http://mig.cs.ucl.ac.uk/index.php?n=Tutorial.NODDImatlab).

Finally, for completeness, Axial-Symmetric DKI (Oeschger et al., 2021) was performed on the pre-processed diffusion data using the ACID toolbox to generate maps of the more commonly reported physical parameters of fractional anisotropy, mean diffusivity, mean kurtosis, diffusivities parallel and diffusivities perpendicular.

Microstructure data extraction

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Microstructure data extraction was performed in Montreal Neurological Institute (MNI) space. The diffusion and magnetisation transfer saturation maps were transformed from native to MNI space using the hMRI toolbox (Tabelow et al., 2019). This involved performing inter-subject registration using DARTEL (Ashburner, 2007) on the segmented magnetisation transfer saturation grey and white matter probability maps, with the resulting DARTEL template and deformations then used to normalize the diffusion and magnetisation transfer saturation maps to MNI space at 1.5 x 1.5 x 1.5mm.

Bilateral tract ROIs were defined using the Johns Hopkins probabilistic white matter tractography atlas (Hua et al., 2008), with the exception of the fornix which was defined using the ICBM-DTI-81 white-matter labels atlas (Mori et al., 2008) as the fornix is not available in the probabilistic atlas. Our primary foci were the fornix, uncinate fasciculus and parahippocampal cingulum bundle. However, we also performed exploratory analyses on six other tracts - the anterior thalamic radiation, the dorsal cingulum bundle, forceps minor, inferior longitudinal fasciculus, inferior occipitofrontal fasciculus and superior longitudinal fasciculus. To reduce partial volume effects, for all tracts (with the exception of the fornix as the available fornix tract was not probabilistic) the minimum probability threshold was set to 25%. In addition, all of the tract ROIs were refined for each participant using their segmented magnetisation transfer saturation white matter probability map, with a minimum probability of 90% to limit the mask to white matter. This also served to remove any residual mis-alignment from the maps being transformed into MNI space, as no smoothing was performed to preserve the quantitative values. As this resulted in differing tract ROI sizes for each participant, the number of voxels in each tract for each participant was calculated. Mean values of the extracted microstructure metrics from the tract ROIs were determined using a weighted average, where voxels with higher white matter probabilities contributed more to the mean.

We used the well-established ROI approach (e.g. Ellerbrock and Mohammadi, 2018; Memel et al., 2020) rather than, for example, a tract-based pipeline, in order to reduce the influence of seed and target region selection. This is because small changes to these selections can result in different tracts being identified. We also wanted to avoid the inclusion of excess grey matter in the tracts themselves, because it is not possible to estimate the MR g-ratio in grey matter tissue. In addition, an ROI approach reduced the potential for false positives in comparison to performing tract-based voxel-wise analyses.

Statistical analyses

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Analyses were performed in SPSS v27 unless otherwise stated. Data were summarised using means and standard deviations. There were no missing data, and no data needed to be removed from any analysis.

As we had different tract ROI sizes for each participant, we first assessed whether there were any relationships between the number of voxels in the tract ROIs and autobiographical memory recall ability. We performed partial correlations for each tract between the number of voxels in the tract ROI and the number of internal details on the Autobiographical Interview, with age, gender and scanner as covariates. No significant relationships were identified (all r<0.12, all p>0.1). However, to ensure no residual effects were present, the number of voxels in a tract ROI was included as a covariate in the analyses.

In our main analyses, we first investigated the relationships between each microstructure measure and the number of internal details from the Autobiographical Interview using partial correlations, with bootstrapping performed 10,000 times to calculate confidence intervals. Four covariates were included in each partial correlation: age, gender, scanner, and the number of voxels in a tract ROI. For these primary analyses, similar partial correlations were performed for the external details control measure. If an internal details correlation was significant, the internal and external details correlations were then directly compared in order to test for statistical difference using the technique described by Meng et al., 1992. This approach extends the Fisher z transformation, allowing for more accurate testing and comparison of two related correlations. The correlation comparison was performed using the R cocor package v1.1.3 (Diedenhofen and Musch, 2015).

We also investigated the relationship between the MR g-ratio and the magnetisation transfer saturation values and eight laboratory-based memory tests. As with the main analyses, partial correlations were performed between the MR g-ratio and magnetisation transfer saturation values and the outcome measures of the memory tests with age, gender, scanner and the number of voxels in a tract ROI included as covariates, and bootstrapping performed 10,000 times to calculate confidence intervals.

As the microstructure measures were investigated across several tracts, we corrected for the repeated testing of the same measures across our three main tracts of interest (the fornix, the uncinate fasciculus and the parahippocampal cingulum bundle) using the Bonferroni method; dividing alpha = 0.05 by 3. Consequently, associations with a two-sided p-value <0.017 were considered significant. As the comparison of correlations was performed only when a significant correlation was identified, a two-sided p-value <0.05 was deemed significant.

Appendix 1

Details of the simulation performed for Figure 2A

In Figure 2A, inner axon diameter, myelin thickness and g-ratio are plotted together. The range of g-ratio values used in the simulation spanned two standard deviations about the mean MR g-ratio observed for the parahippocampal cingulum bundle in the current study (mean = 0.647, standard deviation = 0.043). The axon diameter was computed for this MR g-ratio range by re-arranging the equation presented in Berman et al., 2019 such that axon diameter=exp(gratio0.5060.22). Fibre dimeter was then calculated as fibre diameter=axon diamterg-ratio , enabling myelin thickness to be computed as myelin thickness=fibre diameter-axon diameter2 .

We note that discrepancies between reported microscopic parameters (i.e. g-ratio, modelled axon diameter and myelin thickness) derived from in vivo and ex vivo histology may arise for two reasons. (1) The in vivo MR g-ratio is computed from volume-fractions unlike the microscopic g-ratio measured with histology. (2) The heuristic equation by Berman et al., 2019 that is relating the in vivo MR g-ratio to axon diameter is rather capturing the tail of the axon radii distribution.

Investigation of the MR g-ratio, magnetisation transfer saturation values, neurite orientation dispersion index, neurite density and standard DTI parameters in the fornix and uncinate fasciculus

As can be observed in the tables below, there were no significant correlations between microstructural measures or standard DTI parameters and autobiographical memory recall ability for either of the tracts when using the corrected (p<0.017) threshold.

Fornix

The mean number of voxels in the region of interest (ROI) was 249.55 (SD = 23.09).

Appendix 1—figure 1
The location of the fornix.
Appendix 1—table 1
Means and standard deviations for the microstructure measures and standard DTI parameters extracted from the fornix.
MeasureMeanStandard deviation
MR g-ratio0.7200.017
Magnetisation transfer saturation0.9730.003
Neurite dispersion (ODI)0.1430.021
Neurite density0.6010.045
Fractional anisotropy0.6050.035
Mean diffusivity (10–3 mm2/s)0.9010.036
Mean kurtosis0.9090.100
Diffusivities parallel (10–3 mm2/s)1.6450.072
Diffusivities perpendicular (10–3 mm2/s)0.5290.042
  1. Note. ODI = Orientation Dispersion Index.

Appendix 1—table 2
Partial correlations between the microstructure measures or standard DTI parameters extracted from the fornix and autobiographical memory recall ability (internal details).
Measurer(211)p95% Confidence interval
LowerUpper
MR g-ratio–0.040.53–0.160.08
Magnetisation transfer saturation–0.080.23–0.200.03
Neurite dispersion (ODI)–0.030.62–0.160.10
Neurite density–0.030.69–0.150.10
Fractional anisotropy0.020.80–0.120.15
Mean diffusivity0.070.35–0.080.21
Mean kurtosis–0.030.66–0.160.10
Diffusivities parallel0.050.46–0.090.19
Diffusivities perpendicular0.020.74–0.120.15
  1. Note. ODI = Orientation Dispersion Index.

Uncinate fasciculus

The mean number of voxels in the ROI was 191.98 (SD = 29.77).

Appendix 1—figure 2
The location of the uncinate fasciculus.
Appendix 1—table 3
Means and standard deviations for the microstructure measures and standard DTI parameters extracted from the uncinate fasciculus.
MeasureMeanStandard deviation
MR g-ratio0.7230.016
Magnetisation transfer saturation0.9720.003
Neurite dispersion (ODI)0.1890.022
Neurite density0.5620.045
Fractional anisotropy0.5120.036
Mean diffusivity (10–3 mm2/s)0.8770.304
Mean kurtosis0.9130.100
Diffusivities parallel (10–3 mm2/s)1.4560.055
Diffusivities perpendicular (10–3 mm2/s)0.5880.039
  1. Note. ODI = Orientation Dispersion Index.

Appendix 1—table 4
Partial correlations between the microstructure measures or standard DTI parameters extracted from the uncinate fasciculus and autobiographical memory recall ability (internal details).
Measurer(211)p95% Confidence interval
LowerUpper
MR g-ratio0.100.15–0.030.22
Magnetisation transfer saturation–0.020.81–0.140.11
Neurite dispersion (ODI)–0.010.94–0.140.13
Neurite density0.010.89–0.140.16
Fractional anisotropy–0.010.94–0.140.13
Mean diffusivity–0.010.87–0.140.13
Mean kurtosis–0.010.91–0.130.18
Diffusivities parallel–0.010.87–0.140.13
Diffusivities perpendicular0.000.96–0.150.14
  1. Note. ODI = Orientation Dispersion Index.

Investigation of associations between the MR g-ratio and magnetisation transfer saturation values of the fornix and uncinate fasciculus and the laboratory-based memory tests

As can be observed in the tables below, there were no significant correlations between either the MR g-ratio or magnetisation transfer saturation values of the fornix or uncinate fasciculus and any of the laboratory-based memory tasks for either of the tracts, even when using a p<0.05 uncorrected threshold.

Appendix 1—table 5
Partial correlations between the fornix MR g-ratio and magnetisation transfer saturation values and the laboratory-based memory tests.
Measurer(211)p95% Confidence interval
LowerUpper
MR g-ratio
Logical Memory immediate recall–0.010.85–0.140.11
Logical Memory delayed recall–0.070.33–0.190.06
RAVLT immediate recall–0.060.42–0.200.09
RAVLT delayed recall0.000.98–0.140.15
Rey-Osterrieth Complex Figure delayed recall0.100.16–0.040.23
Warrington RMT for Words0.040.59–0.080.16
Warrington RMT for Faces–0.050.52–0.170.09
Dead or Alive Test–0.050.50–0.160.09
Magnetisation transfer saturation
Logical Memory immediate recall0.040.53–0.110.19
Logical Memory delayed recall0.110.11–0.040.26
RAVLT immediate recall0.010.92–0.110.13
RAVLT delayed recall0.030.71–0.090.15
Rey-Osterrieth Complex Figure delayed recall0.070.33–0.060.19
Warrington RMT for Words0.060.41–0.050.17
Warrington RMT for Faces0.040.61–0.090.16
Dead or Alive Test0.080.25–0.060.21
  1. Note. RAVLT = Rey Auditory Verbal Learning Test; RMT = Recognition Memory Test.

Appendix 1—table 6
Partial correlations between the uncinate fasciculus MR g-ratio and magnetisation transfer saturation values and the laboratory-based memory tests.
Measurer(211)p95% Confidence interval
LowerUpper
MR g-ratio
Logical Memory immediate recall0.070.34–0.060.19
Logical Memory delayed recall0.040.34–0.090.17
RAVLT immediate recall0.000.98–0.140.13
RAVLT delayed recall0.060.40–0.100.21
Rey-Osterrieth Complex Figure delayed recall0.010.94–0.130.15
Warrington RMT for Words–0.010.86–0.160.15
Warrington RMT for Faces–0.070.34–0.200.06
Dead or Alive Test–0.040.60–0.150.08
Magnetisation transfer saturation
Logical Memory immediate recall–0.040.53–0.170.09
Logical Memory delayed recall–0.050.49–0.180.09
RAVLT immediate recall–0.130.06–0.260.01
RAVLT delayed recall–0.160.02–0.27–0.03
Rey-Osterrieth Complex Figure delayed recall–0.070.33–0.200.07
Warrington RMT for Words–0.140.04–0.26–0.01
Warrington RMT for Faces–0.050.44–0.180.09
Dead or Alive Test–0.010.93–0.140.13
  1. Note. RAVLT = Rey Auditory Verbal Learning Test; RMT = Recognition Memory Test.

Exploratory analyses of the MR g-ratio, magnetisation transfer saturation values, neurite orientation dispersion index, neurite density and standard DTI parameters in other white matter tracts

As can be observed in the tables below, there were no significant correlations between microstructural measures or standard DTI parameters and autobiographical memory recall ability for any of the tracts when using the corrected (p<0.017) threshold.

Anterior thalamic radiation

The mean number of voxels in the ROI was 2090.21 (SD = 67.43).

Appendix 1—figure 3
The location of the anterior thalamic radiation.
Appendix 1—table 7
Means and standard deviations for the microstructure measures and standard DTI parameters extracted from the anterior thalamic radiation.
MeasureMeanStandard deviation
MR g-ratio0.7240.014
Magnetisation transfer saturation0.9860.001
Neurite dispersion (ODI)0.2520.017
Neurite density0.5980.041
Fractional anisotropy0.4300.028
Mean diffusivity (10–3 mm2/s)0.8610.029
Mean kurtosis0.9860.063
Diffusivities parallel (10–3 mm2/s)1.3280.041
Diffusivities perpendicular (10–3 mm2/s)0.6270.034
  1. Note. ODI = Orientation Dispersion Index.

Appendix 1—table 8
Partial correlations between the microstructure measures or standard DTI parameters extracted from the anterior thalamic radiation and autobiographical memory recall ability (internal details).
Measurer(211)p95% Confidence interval
LowerUpper
MR g-ratio0.050.47–0.060.17
MT sat–0.080.26–0.200.04
Neurite dispersion (ODI)–0.050.46–0.180.09
Neurite density0.100.16–0.040.23
Fractional anisotropy0.080.26–0.060.21
Mean diffusivity0.030.67–0.110.17
Mean kurtosis0.070.28–0.070.22
Diffusivities parallel0.090.20–0.040.21
Diffusivities perpendicular–0.020.77–0.160.12
  1. Note. MT sat = Magnetisation Transfer saturation; ODI = Orientation Dispersion Index.

Dorsal cingulum bundle

The mean number of voxels in the ROI was 611.48 (SD = 25.29).

Appendix 1—figure 4
The location of the dorsal cingulum bundle.
Appendix 1—table 9
Means and standard deviations for the microstructure measures and standard DTI parameters extracted from the dorsal cingulum bundle.
MeasureMeanStandard deviation
MR g-ratio0.7100.016
Magnetisation transfer saturation0.9840.003
Neurite dispersion (ODI)0.1470.019
Neurite density0.5600.038
Fractional anisotropy0.5700.039
Mean diffusivity (10–3 mm2/s)0.8620.026
Mean kurtosis0.8620.093
Diffusivities parallel (10–3 mm2/s)1.5310.061
Diffusivities perpendicular (10–3 mm2/s)0.5270.040
  1. Note. ODI = Orientation Dispersion Index.

Appendix 1—table 10
Partial correlations between the microstructure measures or standard DTI parameters extracted from the dorsal cingulum bundle and autobiographical memory recall ability (internal details).
Measurer(211)p95% Confidence interval
LowerUpper
MR g-ratio0.090.22–0.040.21
MT sat0.080.23–0.040.21
Neurite dispersion (ODI)0.090.17–0.050.23
Neurite density0.090.17–0.050.23
Fractional anisotropy0.010.85–0.130.16
Mean diffusivity0.060.43–0.080.19
Mean kurtosis0.130.050.000.27
Diffusivities parallel0.050.48–0.080.18
Diffusivities perpendicular0.010.91–0.140.15
  1. Note. MT sat = Magnetisation Transfer saturation; ODI = Orientation Dispersion Index.

Forceps minor

The mean number of voxels in the ROI was 4613.67 (SD = 78.02).

Appendix 1—figure 5
The location of the forceps minor.
Appendix 1—table 11
Means and standard deviations for the microstructure measures and standard DTI parameters extracted from the forceps minor.
MeasureMeanStandard deviation
MR g-ratio0.6980.026
Magnetisation transfer saturation0.9930.002
Neurite dispersion (ODI)0.2010.016
Neurite density0.6010.042
Fractional anisotropy0.5000.027
Mean diffusivity (10–3 mm2/s)0.8810.031
Mean kurtosis0.9470.128
Diffusivities parallel (10–3 mm2/s)1.4670.052
Diffusivities perpendicular (10–3 mm2/s)0.5880.034
  1. Note. ODI = Orientation Dispersion Index.

Appendix 1—table 12
Partial correlations between the microstructure measures or standard DTI parameters extracted from the forceps minor and autobiographical memory recall ability (internal details).
Measurer(211)p95% Confidence interval
LowerUpper
MR g-ratio0.040.53–0.070.18
MT sat0.070.34–0.060.19
Neurite dispersion (ODI)–0.060.38–0.210.07
Neurite density0.090.19–0.040.22
Fractional anisotropy0.100.17–0.030.23
Mean diffusivity–0.040.56–0.170.09
Mean kurtosis0.000.97–0.110.21
Diffusivities parallel0.030.67–0.090.18
Diffusivities perpendicular–0.070.32–0.190.05
  1. Note. MT sat = Magnetisation Transfer saturation; ODI = Orientation Dispersion Index.

Inferior longitudinal fasciculus

The mean number of voxels in the ROI was 2844.03 (SD = 52.97).

Appendix 1—figure 6
The location of the inferior longitudinal fasciculus.
Appendix 1—table 13
Means and standard deviations for the microstructure measures and standard DTI parameters extracted from the inferior longitudinal fasciculus.
MeasureMeanStandard deviation
MR g-ratio0.7240.013
Magnetisation transfer saturation0.9940.002
Neurite dispersion (ODI)0.1840.017
Neurite density0.5580.041
Fractional anisotropy0.4860.028
Mean diffusivity (10–3 mm2/s)0.9020.029
Mean kurtosis0.9180.061
Diffusivities parallel (10–3 mm2/s)1.4730.045
Diffusivities perpendicular (10–3 mm2/s)0.6160.035
  1. Note. ODI = Orientation Dispersion Index.

Appendix 1—table 14
Partial correlations between the microstructure measures or standard DTI parameters extracted from the inferior longitudinal fasciculus and autobiographical memory recall ability (internal details).
Measurer(211)p95% Confidence interval
LowerUpper
MR g-ratio0.070.35–0.060.19
MT sat0.070.35–0.050.18
Neurite dispersion (ODI)–0.030.64–0.170.10
Neurite density0.070.35–0.070.19
Fractional anisotropy0.100.14–0.040.23
Mean diffusivity–0.010.87–0.150.13
Mean kurtosis0.100.16–0.030.23
Diffusivities parallel0.070.29–0.070.21
Diffusivities perpendicular–0.070.34–0.190.07
  1. Note. MT sat = Magnetisation Transfer saturation; ODI = Orientation Dispersion Index.

Inferior occipitofrontal fasciculus

The mean number of voxels in the ROI was 3344.31 (SD = 46.0).

Appendix 1—figure 7
The location of the inferior occipitofrontal fasciculus.
Appendix 1—table 15
Means and standard deviations for the microstructure measures and standard DTI parameters extracted from the inferior occipitofrontal fasciculus.
MeasureMeanStandard deviation
MR g-ratio0.7290.011
Magnetisation transfer saturation0.9950.001
Neurite dispersion (ODI)0.1790.012
Neurite density0.5630.036
Fractional anisotropy0.5080.024
Mean diffusivity (10–3 mm2/s)0.8890.026
Mean kurtosis0.9120.057
Diffusivities parallel (10–3 mm2/s)1.4880.039
Diffusivities perpendicular (10–3 mm2/s)0.5900.031
  1. Note. ODI = Orientation Dispersion Index.

Appendix 1—table 16
Partial correlations between the microstructure measures or standard DTI parameters extracted from the inferior occipitofrontal fasciculus and autobiographical memory recall ability (internal details).
Measurer(211)p95% Confidence interval
LowerUpper
MR g-ratio–0.010.93–0.120.12
MT sat0.080.22–0.030.19
Neurite dispersion (ODI)–0.010.89–0.140.13
Neurite density0.060.42–0.070.18
Fractional anisotropy0.060.38–0.080.20
Mean diffusivity0.000.99–0.130.13
Mean kurtosis0.070.31–0.060.19
Diffusivities parallel0.050.50–0.090.18
Diffusivities perpendicular–0.030.62–0.170.10
  1. Note. MT sat = Magnetisation Transfer saturation; ODI = Orientation Dispersion Index.

Superior longitudinal fasciculus

The mean number of voxels in the ROI was 4243.22 (SD = 39.80).

Appendix 1—figure 8
The location of the superior longitudinal fasciculus.
Appendix 1—table 17
Means and standard deviations for the microstructure measures and standard DTI parameters extracted from the superior longitudinal fasciculus.
MeasureMeanStandard deviation
MR g-ratio0.7510.011
Magnetisation transfer saturation0.9960.001
Neurite dispersion (ODI)0.2180.012
Neurite density0.6340.034
Fractional anisotropy0.4710.026
Mean diffusivity (10–3 mm2/s)0.8250.025
Mean kurtosis1.0290.041
Diffusivities parallel (10–3 mm2/s)1.3240.035
Diffusivities perpendicular (10–3 mm2/s)0.5750.041
  1. Note. ODI = Orientation Dispersion Index.

Appendix 1—table 18
Partial correlations between microstructure measures or standard DTI parameters extracted from the superior longitudinal fasciculus and autobiographical memory recall ability (internal details).
Measurer(211)p95% Confidence interval
LowerUpper
MR g-ratio0.080.28–0.050.20
MT sat–0.040.54–0.160.08
Neurite dispersion (ODI)–0.090.17–0.230.05
Neurite density0.120.09–0.010.24
Fractional anisotropy0.130.050.010.26
Mean diffusivity–0.020.80–0.140.11
Mean kurtosis0.110.12–0.030.24
Diffusivities parallel0.120.09–0.030.25
Diffusivities perpendicular–0.080.23–0.200.03
  1. Note. MT sat = Magnetisation Transfer saturation; ODI = Orientation Dispersion Index.

Investigation of the standard DTI parameters extracted from the parahippocampal cingulum bundle

As reported in the main text, significant correlations between a number of microstructural measures from the parahippocampal cingulum bundle and autobiographical memory recall ability were evident. This was also the case for several of the standard DTI parameters – see Appendix 1—table 19, Appendix 1—table 20 and Appendix 1—figure 9, Appendix 1—figure 10 below.

Appendix 1—table 19
Means and standard deviations for the standard DTI parameters extracted from the parahippocampal cingulum bundle.
MeasureMeanStandard deviation
Fractional anisotropy0.4660.053
Mean diffusivity (10–3 mm2/s)0.9310.041
Mean kurtosis0.7790.122
Diffusivities parallel (10–3 mm2/s)1.4790.071
Diffusivities perpendicular (10–3 mm2/s)0.6560.057
Appendix 1—table 20
Partial correlations between the standard DTI parameters extracted from the parahippocampal cingulum bundle and autobiographical memory recall ability (internal details).
Measurer(211)p95% Confidence interval
LowerUpper
Fractional anisotropy0.200.003*0.070.32
Mean diffusivity–0.020.72–0.150.11
Mean kurtosis0.080.23–0.050.21
Diffusivities parallel0.190.005*0.060.32
Diffusivities perpendicular0.150.03–0.27–0.02
  1. *

    p < 0.017 (two-sided Bonferroni corrected threshold).

Specifically, partial correlation analyses, with age, gender, scanner and the number of voxels in the ROI included as covariates revealed a significant positive correlation between internal details and fractional anisotropy (FA) (Appendix 1—figure 9A; r(211) = 0.20, p=0.003, 95% CI=0.07, 0.32). This relationship was specific to internal details, and was not evident for the external details control measure (Appendix 1—figure 9B; r(211) = –0.06, p=0.39, 95% CI=−0.19, 0.07). Direct comparison of the two correlations confirmed a significant difference between them, showing that parahippocampal cingulum bundle FA was related to internal details to a greater extent than external details (Appendix 1—figure 9C; mean r difference = 0.26 (95% CI=0.10, 0.44), z=3.08, p=0.002).

Appendix 1—figure 9
Fractional anisotropy (FA) and the parahippocampal cingulum bundle.

The relationships between parahippocampal cingulum bundle FA and autobiographical memory recall ability (internal details), and the control measure (external details) are shown. (A) There was a significant positive correlation between FA and internal details (dashed lines indicate the confidence intervals). (B) There was no significant relationship between FA and external details. (C) Bar chart showing the partial correlation coefficients (with standard errors) between FA and internal and external details. There was a significant difference between the correlations when they were directly compared; **p<0.01. Data points for this figure are provided in Supplementary file 2.

In addition, a significant positive correlation between diffusivities parallel and the number of internal details was also apparent (Appendix 1—figure 10A; r(211) = 0.19, p=0.005, 95% CI=0.06, 0.32). As with FA, no significant relationship was observed between diffusivities parallel and external details (Appendix 1—figure 10B; r(211) = –0.048, p=0.49, 95% CI=−0.19, 0.10). Direct comparison of the correlations confirmed that diffusivities parallel was related to internal details to a greater extent than external details (Appendix 1—figure 10C; mean r difference = 0.24 (95% CI=0.07, 0.41), z=2.81, p=0.0049).

Appendix 1—figure 10
Dpara and the parahippocampal cingulum bundle.

The relationships between parahippocampal cingulum bundle diffusivities parallel (Dpara) and autobiographical memory recall ability (internal details), and the control measure (external details) are shown. (A) There was a significant positive correlation between Dpara and internal details (dashed lines indicate the confidence intervals). (B) There was no significant relationship between Dpara and external details. (C) Bar chart showing the partial correlation coefficients (with standard errors) between Dpara and internal and external details. There was a significant difference between the correlations when they were directly compared; **p<0.01. Data points for this figure are provided in Supplementary file 2.

In contrast, no relationships were observed when examining the partial correlations between either internal or external details and mean diffusivity (internal: r(211) = –0.02, p=0.72, 95% CI=−0.15, 0.11; external: r(211) = 0.01, p=0.86, 95% CI=−0.11, 0.14), the mean kurtosis (internal: r(211) = 0.08, p=0.23, 95% CI=−0.05, 0.21; external: r(211) = 0.03, p=0.62, 95% CI=−0.01, 0.16) or diffusivities perpendicular (internal: r(211) = –0.15, p=0.03, 95% CI=−0.27,–0.02; external: r(211) = 0.44, p=0.52, 95% CI=−0.08, 0.17), when using the corrected (p<0.017) threshold. This suggests that none of these parameters were strongly associated with individual differences in autobiographical memory recall.

Investigation of the parahippocampal cingulum bundle MR g-ratio and magnetisation transfer saturation values and the laboratory-based memory tests

Investigation of associations between the MR g-ratio and magnetisation transfer saturation values and the eight laboratory-based memory tests was also undertaken. No relationships were evident for any test, even when using an uncorrected p<0.05 threshold, see Appendix 1—table 21.

Appendix 1—table 21
Partial correlations between the parahippocampal cingulum bundle MR g-ratio and magnetisation transfer saturation values and the laboratory-based memory tests.
Measurer(211)p95% Confidence interval
LowerUpper
MR g-ratio
Logical Memory immediate recall0.010.93–0.130.13
Logical Memory delayed recall–0.050.46–0.180.08
RAVLT immediate recall–0.060.41–0.180.07
RAVLT delayed recall–0.090.17–0.210.04
Rey-Osterrieth Complex Figure delayed recall0.070.34–0.060.19
Warrington RMT for Words0.020.80–0.110.16
Warrington RMT for Faces–0.040.53–0.170.10
Dead or Alive Test0.020.79–0.110.15
Magnetisation transfer saturation
Logical Memory immediate recall0.070.35–0.060.19
Logical Memory delayed recall0.010.91–0.120.14
RAVLT immediate recall–0.010.90–0.140.14
RAVLT delayed recall–0.020.80–0.140.11
Rey-Osterrieth Complex Figure delayed recall–0.090.21–0.230.05
Warrington RMT for Words–0.090.21–0.220.04
Warrington RMT for Faces–0.050.49–0.170.09
Dead or Alive Test0.110.11–0.010.23
  1. Note. RAVLT = Rey Auditory Verbal Learning Test; RMT = Recognition Memory Test.

Data availability

The data for every participant are provided in Figure 5—source data 1, Figure 6—source data 1, Supplementary file 1 and Supplementary file 2.

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Decision letter

  1. Anna C Schapiro
    Reviewing Editor; University of Pennsylvania, United States
  2. Laura L Colgin
    Senior Editor; University of Texas at Austin, United States

Our editorial process produces two outputs: (i) public reviews designed to be posted alongside the preprint for the benefit of readers; (ii) feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.

Decision letter after peer review:

Thank you for submitting your article "Signalling speed along a key white matter tract influences memory recall ability in humans" for consideration by eLife. Your article has been reviewed by 3 peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Laura Colgin as the Senior Editor. The reviewers have opted to remain anonymous.

We are sorry to say that, after consultation with the reviewers, we have decided that the work as described in the current manuscript will not be considered for publication by eLife. However, eLife might consider a very substantial revision, if the authors are interested in undertaking it. The new version would need to address all of the reviewers' concerns, including incorporating reviewer 1's suggestion to report correlations between white matter tracts and all cognitive measures collected, addressing concerns about the g-ratio measurement, as well as changing claims about measuring signaling speed and removing language suggesting causal relationships.

Reviewer #1 (Recommendations for the authors):

My main recommendation is that the authors report the raw correlations between other memory tests and the MR g-ratios of their candidate white matter tracts (assuming that this is possible). This will either show that increased g-ratios in the parahippocampal cingulum bundle are a general feature of individuals who perform better on memory tests, or it is something more specific to the scores on the Autobiographical Memory Interview. It might be the case that other tracts show associations with other tests. Any of these scenarios would help contextualize the results of the paper as they stand.

I am not particularly concerned about correcting for multiple comparisons or arbitrary thresholds for significance. I think that the study is important, novel, and well carried out and that the findings will be important to researchers in several fields. If it is the case that reliable associations between cognitive measures and the MR g-ratio cannot be established in a sample of 217 people then this is really useful information!

I have probably misunderstood the interpretation of the findings with respect to the examples shown in figure 1. It seemed that the authors interpreted their positive correlation between internal details and the g-ratio in the parahippocampal cingulum bundle as evidence for option D – people with better memory recall scores are likely to have larger inner axon diameters and relatively smaller increases in myelin. However, since example 1E involves no change in the g-ratio, I couldn't understand why the finding of no relationship between memory recall ability and g-ratio from the fornix or uncinate fasciculus was not taken as support for option E. It might help if the authors could clarify which situation(s) would lead to them accepting option E as the best explanation of their results.

The following paper by Hodgetts et al., seems very relevant – the present study fails to replicate their findings related to the fornix.

Hodgetts, C. J., Postans, M., Warne, N., Varnava, A., Lawrence, A. D., and Graham, K. S. (2017). Distinct contributions of the fornix and inferior longitudinal fasciculus to episodic and semantic autobiographical memory. cortex, 94, 1-14.

Reviewer #2 (Recommendations for the authors):

– Following what I mentioned in the public review, given the lack of any other measure to quantitatively or even qualitatively assess either conduction velocity/delays or axon size, the authors should refrain from directly claiming that larger axons mean better memory recall abilities, which instead is done in the abstract (page 2, "(…) two tract features seemed to favour better memory retrieval – large inner axon diameters (…)" – despite the axon diameters not being measured or estimated), and in the discussion (page 18, "(…) we were able to identify two particular features (…) that might favour better memory recall, namely larger inner axon diameters (…)").

– Related to the previous point, a suggestion that I have is to include, among the exhaustive comparisons performed in the appendix, the ones with the MTsat values. As an absolute measure of myelin, MTsat could further help the authors by providing a complete picture of their results.

– It is rather peculiar that the abstract does not mention at all myelin (which in the end is the main protagonist of the study) and that does not briefly define the g-ratio. I understand the authors' focus on the conduction velocity, but these additions would surely benefit a more general audience.

– Related to the previous point, the authors may also consider rethinking the use of "signalling speed", which basically appears only in the title and in the abstract, in favour of "conduction velocity" which is used extensively in the text.

– On page 3, the authors stated: "The scope for signals to travel quickly and efficiently between brain regions could make all the differences for an individual's survival". Although the idea that faster conduction velocity constitutes an evolutionary advantage could be appealing and the peripheral nervous system (PNS) supports the concept extremely well (a very famous example is depicted in Wedel, Acta Palaeontologica 2011), there are several reasons to be cautious with such a statement. In contrast to what happens in the PNS (where faster propagation reflects in faster sensory processing and faster motor responses), in the central nervous system conduction phenomena serve the purpose of guaranteeing synchrony in the activity of different neuronal populations (Seidtl, Neuroscience 2014; Gollo et al., NeuroImage 2017; Pariz et al., Plos Computational Biology 2021) and the role of delays could be more subtle. Unless the authors can integrate the statement with some references to experimental evidence, I would remove such a statement.

– Still on page 3, the authors mentioned that the conduction velocity "is dependent upon two biological features – the axonal diameter and the presence and thickness of a myelin sheath". This picture is too approximative as experimental work (Arancibia-Carcamo et al., eLife 2017) and simulations (Drakesmith et al., NeuroImage 2019) have shown how several parameters influence conduction velocity, potentially even with a larger impact than the g-ratio. It would be appropriate for a more general audience to add more details. Similarly, on page 4 it would help to refer to saltatory propagation when explaining the effect of myelin as an insulator.

– On page 7, there is a bit of a leap between the section on the uses and potentials of the MRI-based g-ratio and the proposed application in autobiographical memory. It would help to provide a couple of sentences to link those together or to rearrange a bit the paragraph in-between pages 7 and 8, where at the very end the case for g-ratio and memory is made.

– The considerations in figure 1 made on pages 4-5 are at the moment very hard without referring to an actual relationship between conduction velocity, axonal diameter, and g-ratio. Even though the authors are not actually computing conduction velocity, it would help to refer to established formulas such as the one from Rushton (Rushton, Journal of Physiology 1951) or the one form Waxman and Bennet (Waxman and Bennet, Nature New Biology 1972).

– I noticed that in Figures 4 and 5 the scatterplots are based on the residuals rather than the actual g-ratio and neurite dispersion values. Can I ask what is the reason behind this choice? This representation makes actually harder to get a visual sense of the dynamics of the reported relationships.

– On page 18, the authors mentioned how these results can provide a new perspective on the underlying neural substrate of autographical memory, and stated: "This is especially welcome given the dearth of consistent findings linking hippocampal grey matter volume or microstructure with autobiographical memory recall ability in the healthy population". Can the authors expand their argument here? I am missing the link between the current findings (on white matter microstructure) with previous ones on grey matter features.

– On page 22, there is a reference to the CONNECTOM MRI scanners (misspelled as "connectome MRI scanners") – as the general audience is not familiar with those it would help to add a brief sentence explaining what they are and maybe a reference (for example, Jones et al., NeuroImage 2018).

– Can the authors comment on the advantages of the proposed ROI-based approach compared with a tract-based approach?

– I may have missed it, but I am not sure of what is the reason for the fornix tract being "not probabilistic" (page 29) – are not all the tract ROIs obtained from the John Hopkins probabilistic atlas?

– I could not find any mention of the main methodological limitations (e.g., the use of signal fractions rather than volume fractions, the bias towards larger axons, and the need for single-point calibration). There is only a brief mention in the appendix on page 43. I think these limitations should be part of the discussion to put these results in the right context.

Reviewer #3 (Recommendations for the authors):

I have some suggestions the authors may consider, presented in chronological order.

Title

The title suggests a causal relationship, while this is based on an association. Maybe better to use a neutral word, i.e. replace "influences" with e.g. "is associated with" or something similar?

As I understand MR g-ratio, it reflects structural aspects of nerve fibers, and although probably related to conduction velocity/ signaling speed, it is not a direct measure of this. Hence, I believe the title is overstating this relationship by referring to "signalling speed" directly. I fully understand the need for short and focused titles, but I believe this is a bit misleading. The same point applies to a couple of other places in the manuscript too. Of course fine to discuss this as an interpretation.

Abstract

Not all readers are probably familiar with the MR g-ratio, so maybe it can be defined in the abstract?

Since this is a cross-sectional study, I suggest avoiding phrases that imply change, e.g. "increased MR g-ratio". Maybe replace it with something neutral, such as "higher MR g-ratio"? The same is the case in several places in the manuscript, e.g. ln 195.

As with the title, the results reflect associations, not causation. This does not render them less interesting, but I would recommend replacing "favour better memory …" with e.g. "is associated with better memory …". I also wonder whether "offer a new perspective on drivers of individual differences in memory recall ability" is overstating a bit, since (a) we don't know whether g-ratio (or signal speed) is driving anything, and (b) this is a rather well-established theory (as also explained in the introduction, and it is stated ln 44 "it is perhaps no surprise that speed may be of the essence")?

Introduction

ln 51-54: Why was aging discussed? Reading the introductory paragraph, I expected aging to be part of the study, which it was not.

Ln 123-125: "While some healthy individuals can recollect decades-old autobiographical memories with great richness and clarity, others struggle to recall what they did last weekend" Yes, but as the authors surely know, this reflects different memory systems or processes, and therefore can happen within the same individual too, not only as a feature of inter-individual differences.

Ln 195-200: Figure 1 clearly illustrates different scenarios, which is very useful. However, the hypothesis that better autobiographical memory is related to more myelin could also be consistent with no relationship with the MR g-ratio if the axon diameter is larger in participants with a good memory, right? And vice versa for the hypothesis about axon diameter? I don't see how the ratio measure can distinguish between the different accounts since the measures per definition are related to two possibly independent properties which both can be of importance? The authors multiple times mention that other relevant metrics, such as those derived from DTI, lack biological specificity. But the MR g-ratio measure seems also to be unspecific in this regard. If axon diameter and myelin thickness can be estimated separately, why not use them directly in the analyses instead of the MR g-ratio? There may be a methodological reason for this, but I think this could be more clearly explained as MR g-ratio is not often reported in the literature and so will be novel to many readers. Relatedly, although there are methods papers on this topic, maybe a brief justification of how can ratios between these small compartments on the micrometer scale can be calculated from voxels on the millimeter scale already in the introduction?

Results

I understand that the authors don't want to provide the full description of results for FA and MD in the main text, but it would be convenient to report a brief summary of the main results also in the text. As far as I can see from Appendix 1, none even approach significance for fornix and uncinated fasciculus, so maybe at least state that?

This may be a matter of taste, but I would suggest moving the section on why the parahippocampal cingulum bundle should be important for autobiographical memory from the Results section (ln 236 and onwards) to the introduction or the discussion.

Ln 279: A positive relationship between MR g-ratio and memory is interpreted as reflecting larger inner axon diameters. Ref Figure 1, this can also be due to thinner myelin sheets, right, as it is a ratio measure? Multiple comparison correction was mentioned for some analyses above, was this done here two, and if so, how? Would be useful to state explicitly.

Inspecting the Appendix, it seems that the relationships between autobiographic memory and PCB FA and MD were also significant, with r-values that were at least as large as for MR g-ratio. Why not include this in the main text? These are metrics of interest to many researchers. You could also run a multiple regression analysis, and test whether each metric gives unique information or whether they are redundant. I think this would be a very useful addition to the manuscript, regardless of the outcome. If MR g-ratio is still significantly related to autobiographical memory, this would strengthen the main argument in the paper. If not, we will know more about the interrelationships between these different tract metrics, which also will be very useful.

Discussion

Ln 336: Is it correct to say that the MR g-ratio – memory correlation represents "neural instantiation of autobiographical memory"? To me, it seems to overstate the results, as this is an association, and we do not know whether there is any causality involved. The same goes for the last part of the sentence "drivers of individual differences in recall ability". I think the results are of sufficient interest, without such statements.

Methods, Participants

Ln 456-457: "People with hobbies or vocations known to be associated with the hippocampus (e.g. licenced London taxi drivers) were excluded." Could you please be a little more specific, most activities will be associated with the hippocampus? How many were excluded based on this?

[Editors’ note: further revisions were suggested prior to acceptance, as described below.]

The authors put an amazing effort into taking into account the reviewers' comments and into improving the paper with further details and analysis. The finding that magnetization transfer saturation does not correlate with the score of interest while the g-ratio instead does is quite interesting - I think that for the sake of fully characterizing the relationship what is missing at the moment is correlating the isotropic volume fraction with the recall score: since the g-ratio is computed using MTsat, Viso and Vic, double-checking that a correlation does not exist with Viso is the last step needed to show that indeed is the combination of all these measures that is meaningful rather than the single measures themselves.

https://doi.org/10.7554/eLife.79303.sa1

Author response

Reviewer #1 (Recommendations for the authors):

My main recommendation is that the authors report the raw correlations between other memory tests and the MR g-ratios of their candidate white matter tracts (assuming that this is possible). This will either show that increased g-ratios in the parahippocampal cingulum bundle are a general feature of individuals who perform better on memory tests, or it is something more specific to the scores on the Autobiographical Memory Interview. It might be the case that other tracts show associations with other tests. Any of these scenarios would help contextualize the results of the paper as they stand.

As noted in our response to the Reviewer’s Public Review, 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. We used the current, gold standard approach to measuring autobiographical memory recall ability (Levine’s Autobiographical Interview). Nevertheless, at the Reviewer’s request we have now analysed data from eight additional laboratory-based memory tests. Scores from these tests did not correlate with the MR g-ratio for any of our three white matter tracts of interest. 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, our findings now also contribute to wider discussions about real-world compared to laboratory-based memory tests. We thank the Reviewer again for making the excellent suggestion to include these additional data, analyses and discussion points, as noted below.

Introduction, p. 10: “All participants underwent the widely-used Autobiographical Interview (Levine et al., 2002). This task, which is the gold standard in the field, provides a detailed metric characterising a person’s ability to recall real-life past experiences, as well as providing a useful control measure. We also examined performance on another eight standard laboratory-based memory tests. Their inclusion allowed us to ascertain whether any relationships with conduction velocity were specific to recollecting detailed autobiographical memories from real life, or were also applicable to the recall of more constrained laboratory-based stimuli.”

Introduction, pp. 11-12: “Finally, given that a previous functional MRI meta-analysis identified different neural substrates associated with autobiographical memory recall and the recall of laboratory-based stimuli (McDermott et al., 2009; see also Maguire, 2001, 2012; Miller et al., 2022; Mobbs et al., 2021; Nastase et al., 2020; Spiers and Maguire, 2007), we expected that associations with the MR g-ratio might be specific to autobiographical memory recall. We reasoned that detailed, multimodal, autobiographical memories may rely on inter-regional connectivity to a greater degree than simpler, more constrained laboratory-based memory tests.”

Results, pp. 12-13:

“Laboratory-based memory test performance

While our main interest was in autobiographical memory recall, eight commonly used laboratory-based memory tasks were also administered. Their inclusion allowed us to establish whether any associations identified with the main microstructure measure, MR g-ratio, were specific or not to the recollection of real-life autobiographical memories.

The ability to recall a short narrative was examined using the immediate and delayed recall tests of the Logical Memory subtest of the Wechsler Memory Scale IV (Wechsler, 2009). Across participants, the mean immediate recall scaled score was 12.95 (SD = 2.09, range = 6-18) and the mean delayed recall scaled score was 12.58 (SD = 2.62, range = 6-19). Verbal list recall ability was assessed using the immediate and delayed recall of the Rey Auditory Verbal Learning Test (see Strauss et al., 2006). The mean immediate recall (aggregate) score was 58.82 (SD = 7.42, range = 33-73) and the mean delayed recall score was 12.92 (SD = 2.17, range = 6-15). Visuospatial recall ability was examined using the delayed recall of the Rey–Osterrieth Complex Figure (Rey, 1941), with a mean delayed recall score of 22.28 (SD = 5.71, range = 8.5-35). Recognition memory ability was tested using the Warrington Recognition Memory Tests for Words and Faces (Warrington, 1984). The mean recognition memory scaled score for words was 12.75 (SD = 2.06, range = 3-15) and for faces was 11.00 (SD = 3.33, range = 3-18). Finally, participants also completed the “Dead or Alive” task which probes general knowledge about whether famous people have died or are still alive, providing a measure of semantic memory (Kapur et al., 1989). The mean accuracy performance on this test was 81.32% (SD = 8.44, range = 57.14%-97.26%).”

Results, p. 14: “There were no significant associations between fornix or uncinate fasciculus MR g-ratios or magnetisation transfer saturation values and any of the laboratory-based memory tests (see Appendix 1– tables 5 and 6 for full details, source data are available in Supplementary file 1).”

Results, p. 18:

“No relationship between microstructure measures of the parahippocampal cingulum bundle and scores on laboratory-based memory tests

Finally, we tested for associations between the key microstructure measures and performance on the eight laboratory-based memory tasks. No relationships with the MR g-ratio or magnetisation transfer saturation values were evident for any task, even when using an uncorrected p < 0.05 threshold (Appendix 1-table 21, source data are available in Supplementary file 2). This suggests that the parahippocampal cingulum bundle MR g-ratio, and by inference conduction velocity, was specifically associated with recall of autobiographical memories from real life rather than performance on the more constrained laboratory-based memory tests.”

Discussion, p. 24: “Moreover, no relationships were identified with any of the eight laboratory-based memory tasks examined, highlighting the specific nature of the relationship between parahippocampal cingulum bundle MR g-ratio and, by inference, conduction velocity, and autobiographical memory recall ability. It may be that vivid, detailed, multimodal, autobiographical memories rely on inter-regional connectivity, particularly that supported by the parahippocampal cingulum bundle, to a greater degree than simpler, more constrained laboratory-based memory tests. This result aligns with previous work involving an fMRI meta-analysis which showed that recall of autobiographical memories and laboratory-based memory stimuli were associated with substantially different neural substrates (McDermott et al., 2009). More generally, our findings add to the increasingly-recognised importance of studying real-world cognition in order to fully characterise brain-behaviour relationships (Maguire, 2001, 2012; Miller et al., 2022; Mobbs et al., 2021; Nastase et al., 2020; Spiers and Maguire, 2007).”

Materials and methods, pp. 28-29:

“Laboratory-based memory tests

Eight laboratory-based memory tasks were also administered to participants. These are standard memory tests that are often used in neuropsychological settings. Tasks were performed and scored in line with their standardised and published protocols.

The ability to recall a short narrative was examined using the immediate and delayed recall tests of the Logical Memory subtest of the Wechsler Memory Scale IV (Wechsler, 2009). Verbal list recall was assessed using the immediate and delayed recall tests of the Rey Auditory Verbal Learning Test (see Strauss et al., 2006). Visuospatial recall was examined using the delayed recall of the Rey–Osterrieth Complex Figure (Rey, 1941). Recognition memory was investigated using the Warrington Recognition Memory Tests for Words and Faces (Warrington, 1984). Finally, participants also underwent the “Dead or Alive” task which probes general knowledge about whether famous individuals have died or are still alive, providing a measure of semantic memory (Kapur et al., 1989).”

Materials and methods, p. 35: “We also investigated the relationship between the MR g-ratio and the magnetisation transfer saturation values and eight laboratory-based memory tests. As with the main analyses, partial correlations were performed between the MR g-ratio and magnetisation transfer saturation values and the outcome measures of the memory tests with age, gender, scanner and the number of voxels in a tract ROI included as covariates, and bootstrapping performed 10,000 times to calculate confidence intervals.”

I am not particularly concerned about correcting for multiple comparisons or arbitrary thresholds for significance. I think that the study is important, novel, and well carried out and that the findings will be important to researchers in several fields. If it is the case that reliable associations between cognitive measures and the MR g-ratio cannot be established in a sample of 217 people then this is really useful information!

Thank you.

I have probably misunderstood the interpretation of the findings with respect to the examples shown in figure 1. It seemed that the authors interpreted their positive correlation between internal details and the g-ratio in the parahippocampal cingulum bundle as evidence for option D – people with better memory recall scores are likely to have larger inner axon diameters and relatively smaller increases in myelin. However, since example 1E involves no change in the g-ratio, I couldn't understand why the finding of no relationship between memory recall ability and g-ratio from the fornix or uncinate fasciculus was not taken as support for option E. It might help if the authors could clarify which situation(s) would lead to them accepting option E as the best explanation of their results.

We are grateful for the opportunity to clarify the situation regarding option E (Figure 2A black arrow, and Figure 2E), and agree it requires further unpacking.

In fact, there are three main scenarios. (1) A decrease in MR g-ratio values. This would suggest that faster conduction velocity is due to greater thickness of the myelin sheath, with the inner axon diameter remaining constant (Figure 2A blue arrow, and Figure 2B). (2) A decrease in MR g-ratio values, but to a lesser extent than that observed in the first scenario. This would suggest that faster conduction velocity is due primarily to greater myelin sheath thickness, but one that is also accompanied by a larger inner axon diameter (Figure 2A red arrow, and Figure 2C). (3) An increase in MR g-ratio values. This would suggest that faster conduction velocity is predominantly due to a larger inner axon diameter, with only small increases in myelin thickness also being present (Figure 2A orange arrow, and Figure 2D).

A fourth scenario also exists in which constant MR g-ratio values could be associated with faster conduction velocity. This would occur when both the inner axon diameter and myelin thickness change proportionally to each other (Figure 2A black arrow, and Figure 2E). However, this scenario could also mean that there is no variation in conduction velocity. One way to increase interpretability in this situation, is by examining scans optimised to assess myelination (such as magnetisation transfer saturation maps). Observing no relationship with the MR g-ratio, but a relationship with magnetisation transfer saturation values, would suggest a proportional change in the underlying myelin and, consequently, variation in conduction velocity. By contrast, no relationship with either the MR g-ratio or magnetisation transfer saturation values would suggest that there was no change in the underlying microstructure, and therefore no variation in conduction velocity. In fact, we observed no associations between the magnetisation transfer saturation values and autobiographical memory recall, suggesting no relationships with myelin or conduction velocity.

We now explicitly consider Figure 2E (black arrow) and its interpretation in the revised manuscript, as detailed below.

Introduction, p. 4: “The conduction velocity of an axon is, therefore, not determined only by the axon diameter, but also by the relationship between the axon diameter and the thickness of the surrounding myelin sheath, a measure known as the g-ratio (Chomiak and Hu, 2009; Rushton, 1951; Schmidt and Knösche, 2019). Specifically, Rushton (1951) derived an equation: conduction velocitydln(g), where d is the inner axon diameter, g is the g-ratio = d/D, and D is the outer fibre (axon plus myelin sheath) diameter. In other words, the g-ratio is computed as the ratio of the inner axon diameter relative to that of the axon plus the myelin sheath that encases it (Figure 1).”

Introduction, p. 5: “Of note, the MR g-ratio has been found to associate well with estimates of axonal conduction velocity (Berman et al., 2019; Drakesmith et al., 2019). Consequently, the MR g-ratio provides a non-invasive MRI method that can associate in vivo structural neuroimaging of humans with axonal conduction velocity.”

Introduction, p. 7: “We note, for completeness, that a fourth scenario also exists where constant MR g-ratio values could be associated with faster conduction velocity. This would occur when both the inner axon diameter and myelin thickness change proportionally to each other (Figure 2A black arrow, and Figure 2E). However, this scenario could also mean that there is no variation in conduction velocity. One way to increase interpretability in this situation, is by examining scans optimised to assess myelination (such as magnetisation transfer saturation values). Observing no relationship with the MR g-ratio, but a relationship with magnetisation transfer saturation values, would suggest a proportional change in the underlying myelin and, consequently, variation in conduction velocity. By contrast, no relationship with either the MR g-ratio or magnetisation transfer saturation values would suggest that there was no change in the underlying microstructure and therefore no variation in conduction velocity.”

Introduction, p. 9: “The relationship of MR g-ratio to the underlying microstructure as outlined in Figure 2, would further guide us as to whether any significant effects were more likely to be associated with the extent of myelination or the size of the inner axon diameter of the fibres in these three white matter tracts. These analyses were augmented by examining whether magnetisation transfer saturation values of the pathways (assessing myelination) were associated with autobiographical memory recall ability.”

Introduction, pp. 10-11: “Focusing on the fornix, uncinate fasciculus and parahippocampal cingulum bundle, we predicted that variations in the MR g-ratio from some or all of these tracts would be associated with autobiographical memory recall ability. Such a finding would, for the first time, suggest a link between variations in white matter tract conduction velocity and individual differences in autobiographical memory recall.

Under the assumption that a significant relationship between the MR g-ratio and autobiographical memory recall represents an association with faster conduction velocity (e.g. Brancucci, 2012; Dicke and Roth, 2016; Miller, 1994; Reed and Jensen, 1992), and aided by the analysis of the magnetisation transfer saturation values, we further sought to evaluate the scenarios presented in Figure 2. Specifically, we asked whether autobiographical memory recall ability was more likely to be associated with inner axon diameters or myelin thickness. A negative relationship between the MR g-ratio and autobiographical memory recall ability (Figure 2A blue and red arrows, and Figures 2B and 2C), along with a positive relationship between magnetisation transfer saturation and autobiographical memory recall ability, would suggest that myelin thickness was more relevant. By contrast, a positive relationship between the MR g-ratio and autobiographical memory recall ability (Figure 2A orange arrow, and Figure 2D) would highlight the potential relevance of inner axon diameters. Observing no associations between the MR g-ratio or magnetisation transfer saturation values and autobiographical memory recall, would suggest no relationships with the underlying microstructure or conduction velocity, and would speak against the possibility of a proportional change in microstructure (Figure 2A black arrow, and Figure 2E).”

Results, p. 16: “To further aid the interpretation of the relationship with MR g-ratio in terms of the underlying axonal microstructure, we also investigated whether the magnetisation transfer saturation values (assessing myelination) of the parahippocampal cingulum bundle were associated with autobiographical memory recall ability. We performed partial correlation analyses with the same covariates as before. Magnetisation transfer saturation values were not significantly related to either internal (r(211) = 0.00, p = 1.0, 95% CI = -0.12, 0.12), or external (r(211) = 0.14, p = 0.048, 95% CI = -0.06, 0.30) details.”

Discussion, p. 20: “The positive relationship we observed between the parahippocampal cingulum bundle MR g-ratio and autobiographical memory recall ability suggests that this effect was associated predominantly with larger inner axon diameter (Figure 2A orange arrow, and Figure 2D). By contrast, had a negative correlation between the MR g-ratio and autobiographical memory recall ability been identified, we could instead have inferred that myelination was the relevant microstructural feature. The lack of relationship between parahippocampal cingulum bundle magnetisation transfer saturation values (optimised to assess myelination) and autobiographical memory recall ability provided further corroboration that myelin may not have been influential in this context.”

Discussion, pp. 22-23: “We also examined two such tracts, the fornix and the uncinate fasciculus, but in both cases no significant relationships between any of our neuroimaging metrics and autobiographical memory recall ability were evident in our large cohort of young healthy adults. As outlined in Figure 2, there was one possible scenario where a null relationship with the MR g-ratio could reflect an association with conduction velocity – if both the inner axon diameter and myelin thickness increased proportionally to each other (Figure 2A black arrow, and Figure 2E). However, we found no associations between autobiographical memory recall and both the MR g-ratio and magnetisation transfer saturation values of the fornix and uncinate fasciculus, which speaks against this explanation.”

The following paper by Hodgetts et al., seems very relevant – the present study fails to replicate their findings related to the fornix.

Hodgetts, C. J., Postans, M., Warne, N., Varnava, A., Lawrence, A. D., and Graham, K. S. (2017). Distinct contributions of the fornix and inferior longitudinal fasciculus to episodic and semantic autobiographical memory. cortex, 94, 1-14.

Thank you for highlighting this paper, which we now reference.

Discussion, p. 23: “In terms of standard DTI parameters, unlike a previous study (Hodgetts et al., 2017), we did not find a relationship between fornix fractional anisotropy and autobiographical memory recall ability, which may be due to the larger sample that we examined.”

Reviewer #2 (Recommendations for the authors):

– Following what I mentioned in the public review, given the lack of any other measure to quantitatively or even qualitatively assess either conduction velocity/delays or axon size, the authors should refrain from directly claiming that larger axons mean better memory recall abilities, which instead is done in the abstract (page 2, "(…) two tract features seemed to favour better memory retrieval – large inner axon diameters (…)" – despite the axon diameters not being measured or estimated), and in the discussion (page 18, "(…) we were able to identify two particular features (…) that might favour better memory recall, namely larger inner axon diameters (…)").

Changes have been made throughout the manuscript to avoid any direct claims of this nature, and to emphasise inferences and associations, where appropriate.

– Related to the previous point, a suggestion that I have is to include, among the exhaustive comparisons performed in the appendix, the ones with the MTsat values. As an absolute measure of myelin, MTsat could further help the authors by providing a complete picture of their results.

As noted in our response to the Reviewer’s Public Review, thank you, we think this is an excellent suggestion. We now include analyses examining relationships between the magnetisation transfer saturation values and autobiographical memory recall ability for all tracts. No significant associations were evident. We also note in the revised manuscript that these findings support the inference that there seems to be no relationship between conduction velocity and autobiographical memory recall for the fornix and uncinate fasciculus. It also aligns with our assumption that here, relationships with the MR g-ratio were indicative of faster, not slower, conduction velocity, and that for the parahippocampal cingulum bundle inner axon diameter might be of more relevance than myelin thickness in relation to autobiographical memory recall ability.

Introduction, p. 7: “We note, for completeness, that a fourth scenario also exists where constant MR g-ratio values could be associated with faster conduction velocity. This would occur when both the inner axon diameter and myelin thickness change proportionally to each other (Figure 2A black arrow, and Figure 2E). However, this scenario could also mean that there is no variation in conduction velocity. One way to increase interpretability in this situation, is by examining scans optimised to assess myelination (such as magnetisation transfer saturation values). Observing no relationship with the MR g-ratio, but a relationship with magnetisation transfer saturation values, would suggest a proportional change in the underlying myelin and, consequently, variation in conduction velocity. By contrast, no relationship with either the MR g-ratio or magnetisation transfer saturation values would suggest that there was no change in the underlying microstructure and therefore no variation in conduction velocity.”

Introduction, p. 9: “The relationship of MR g-ratio to the underlying microstructure as outlined in Figure 2, would further guide us as to whether any significant effects were more likely to be associated with the extent of myelination or the size of the inner axon diameter of the fibres in these three white matter tracts. These analyses were augmented by examining whether magnetisation transfer saturation values of the pathways (assessing myelination) were associated with autobiographical memory recall ability.”

Introduction, p. 11: “Under the assumption that a significant relationship between the MR g-ratio and autobiographical memory recall represents an association with faster conduction velocity (e.g. Brancucci, 2012; Dicke and Roth, 2016; Miller, 1994; Reed and Jensen, 1992), and aided by the analysis of the magnetisation transfer saturation values, we further sought to evaluate the scenarios presented in Figure 2. Specifically, we asked whether autobiographical memory recall ability was more likely to be associated with inner axon diameters or myelin thickness. A negative relationship between the MR g-ratio and autobiographical memory recall ability (Figure 2A blue and red arrows, and Figures 2B and 2C), along with a positive relationship between magnetisation transfer saturation and autobiographical memory recall ability, would suggest that myelin thickness was more relevant. By contrast, a positive relationship between the MR g-ratio and autobiographical memory recall ability (Figure 2A orange arrow, and Figure 2D) would highlight the potential relevance of inner axon diameters. Observing no associations between the MR g-ratio or magnetisation transfer saturation values and autobiographical memory recall, would suggest no relationships with the underlying microstructure or conduction velocity, and would speak against the possibility of a proportional change in microstructure (Figure 2A black arrow, and Figure 2E).”

Results, p. 14: “There were no significant associations between fornix or uncinate fasciculus MR g-ratios or magnetisation transfer saturation values and any of the laboratory-based memory tests (see Appendix 1– tables 5 and 6 for full details, source data are available in Supplementary file 1).”

Results, p. 16: “To further aid the interpretation of the relationship with MR g-ratio in terms of the underlying axonal microstructure, we also investigated whether the magnetisation transfer saturation values (assessing myelination) of the parahippocampal cingulum bundle were associated with autobiographical memory recall ability. We performed partial correlation analyses with the same covariates as before. Magnetisation transfer saturation values were not significantly related to either internal (r(211) = 0.00, p = 1.0, 95% CI = -0.12, 0.12), or external (r(211) = 0.14, p = 0.048, 95% CI = -0.06, 0.30) details.”

Results, p. 18:

“No relationship between microstructure measures of the parahippocampal cingulum bundle and scores on laboratory-based memory tests

Finally, we tested for associations between the key microstructure measures and performance on the eight laboratory-based memory tasks. No relationships with the MR g-ratio or magnetisation transfer saturation values were evident for any task, even when using an uncorrected p < 0.05 threshold (Appendix 1-table 21, source data are available in Supplementary file 2). This suggests that the parahippocampal cingulum bundle MR g-ratio, and by inference conduction velocity, was specifically associated with recall of autobiographical memories from real life rather than performance on the more constrained laboratory-based memory tests.”

Discussion, p. 20: “The positive relationship we observed between the parahippocampal cingulum bundle MR g-ratio and autobiographical memory recall ability suggests that this effect was associated predominantly with larger inner axon diameter (Figure 2A orange arrow, and Figure 2D). By contrast, had a negative correlation between the MR g-ratio and autobiographical memory recall ability been identified, we could instead have inferred that myelination was the relevant microstructural feature. The lack of relationship between parahippocampal cingulum bundle magnetisation transfer saturation values (optimised to assess myelination) and autobiographical memory recall ability provided further corroboration that myelin may not have been influential in this context.”

Discussion, pp. 22-23: “We also examined two such tracts, the fornix and the uncinate fasciculus, but in both cases no significant relationships between any of our neuroimaging metrics and autobiographical memory recall ability were evident in our large cohort of young healthy adults. As outlined in Figure 2, there was one possible scenario where a null relationship with the MR g-ratio could reflect an association with conduction velocity – if both the inner axon diameter and myelin thickness increased proportionally to each other (Figure 2A black arrow, and Figure 2E). However, we found no associations between autobiographical memory recall and both the MR g-ratio and magnetisation transfer saturation values of the fornix and uncinate fasciculus, which speaks against this explanation.”

– It is rather peculiar that the abstract does not mention at all myelin (which in the end is the main protagonist of the study) and that does not briefly define the g-ratio. I understand the authors' focus on the conduction velocity, but these additions would surely benefit a more general audience.

– Related to the previous point, the authors may also consider rethinking the use of "signalling speed", which basically appears only in the title and in the abstract, in favour of "conduction velocity" which is used extensively in the text.

The abstract has now been updated to include reference to myelination and to define the g-ratio. The phrase “signalling speed” has also been replaced in the title with “conduction velocity”. Thank you for these suggestions.

– On page 3, the authors stated: "The scope for signals to travel quickly and efficiently between brain regions could make all the differences for an individual's survival". Although the idea that faster conduction velocity constitutes an evolutionary advantage could be appealing and the peripheral nervous system (PNS) supports the concept extremely well (a very famous example is depicted in Wedel, Acta Palaeontologica 2011), there are several reasons to be cautious with such a statement. In contrast to what happens in the PNS (where faster propagation reflects in faster sensory processing and faster motor responses), in the central nervous system conduction phenomena serve the purpose of guaranteeing synchrony in the activity of different neuronal populations (Seidtl, Neuroscience 2014; Gollo et al., NeuroImage 2017; Pariz et al., Plos Computational Biology 2021) and the role of delays could be more subtle. Unless the authors can integrate the statement with some references to experimental evidence, I would remove such a statement.

We agree, and have now removed this statement from the Introduction.

– Still on page 3, the authors mentioned that the conduction velocity "is dependent upon two biological features – the axonal diameter and the presence and thickness of a myelin sheath". This picture is too approximative as experimental work (Arancibia-Carcamo et al., eLife 2017) and simulations (Drakesmith et al., NeuroImage 2019) have shown how several parameters influence conduction velocity, potentially even with a larger impact than the g-ratio. It would be appropriate for a more general audience to add more details. Similarly, on page 4 it would help to refer to saltatory propagation when explaining the effect of myelin as an insulator.

In the revised manuscript we now include additional details about how the conduction velocity of an axon is dependent upon its physiology, and what factors are measurable in vivo in humans. We also refer to saltatory propagation when explaining the effect of myelin as an insulator. We agree that these additions provide a more informative context.

Introduction, pp. 3-4:

“The conduction velocity of an axon is dependent upon the axon diameter, the presence and thickness of a myelin sheath, the distance between the nodes of Ranvier (periodic gaps in the myelin that facilitate action potential propagation), inter-nodal spacing, and electrical properties of the axonal and myelin membranes (Arancibia-Cárcamo et al., 2017; Drakesmith et al., 2019; Gasser and Grundfest, 1939; Hursh, 1939; Huxley and Stämpeli, 1949; Rushton, 1951). A number of these features are not yet measurable in humans in vivo. However, seminal electrophysiological work has derived a relationship between axon morphology and conduction velocity using only axon diameter and myelin sheath thickness (Rushton, 1951). These two metrics are particularly key because a larger axon diameter results in less resistance to the action potential ion flow, resulting in faster conduction velocity. The presence of a myelin sheath around an axon is beneficial in two ways. First, the myelin sheath acts like an electrical insulating layer, reducing ion loss and preserving the action potential. Second, the presence of unmyelinated gaps in the myelin sheath (the nodes of Ranvier) enables a process called saltatory propagation to take place. As the majority of the axon is wrapped in myelin, the nodes of Ranvier are the only locations where action potentials can occur. This increases the strength of electrical signals because all the ions gather at these nodes instead of being dispersed along the length of the axon. Stronger action potentials are therefore sent along the myelinated portion of the axon at higher speeds, with this signal being boosted on arrival at the next node of Ranvier by another action potential, which helps to maintain a fast conduction velocity.

The conduction velocity of an axon is, therefore, not determined only by the axon diameter, but also by the relationship between the axon diameter and the thickness of the surrounding myelin sheath, a measure known as the g-ratio (Chomiak and Hu, 2009; Rushton, 1951; Schmidt and Knösche, 2019). Specifically, Rushton (1951) derived an equation: conduction velocitydln(g), where d is the inner axon diameter, g is the g-ratio = d/D, and D is the outer fibre (axon plus myelin sheath) diameter. In other words, the g-ratio is computed as the ratio of the inner axon diameter relative to that of the axon plus the myelin sheath that encases it (Figure 1).”

– On page 7, there is a bit of a leap between the section on the uses and potentials of the MRI-based g-ratio and the proposed application in autobiographical memory. It would help to provide a couple of sentences to link those together or to rearrange a bit the paragraph in-between pages 7 and 8, where at the very end the case for g-ratio and memory is made.

We have now finessed the text further to provide a smoother link.

Introduction, p. 7: “The MR g-ratio has, therefore, the potential to provide a number of novel insights into human cognition. One area where the MR g-ratio may be particularly helpful is in probing individual differences. Our particular interest is in the ability to recall past experiences from real life, known as autobiographical memories.”

– The considerations in figure 1 made on pages 4-5 are at the moment very hard without referring to an actual relationship between conduction velocity, axonal diameter, and g-ratio. Even though the authors are not actually computing conduction velocity, it would help to refer to established formulas such as the one from Rushton (Rushton, Journal of Physiology 1951) or the one form Waxman and Bennet (Waxman and Bennet, Nature New Biology 1972).

We now refer explicitly to the Rushton (1951) formulae for calculating conduction velocity.

Introduction, p. 4: “The conduction velocity of an axon is, therefore, not determined only by the axon diameter, but also by the relationship between the axon diameter and the thickness of the surrounding myelin sheath, a measure known as the g-ratio (Chomiak and Hu, 2009; Rushton, 1951; Schmidt and Knösche, 2019). Specifically, Rushton (1951) derived an equation: conduction velocitydln(g), where d is the inner axon diameter, g is the g-ratio = d/D, and D is the outer fibre (axon plus myelin sheath) diameter. In other words, the g-ratio is computed as the ratio of the inner axon diameter relative to that of the axon plus the myelin sheath that encases it (Figure 1).”

– I noticed that in Figures 4 and 5 the scatterplots are based on the residuals rather than the actual g-ratio and neurite dispersion values. Can I ask what is the reason behind this choice? This representation makes actually harder to get a visual sense of the dynamics of the reported relationships.

The scatterplots are based on the residuals because we included a number of covariates – age, gender, scanner, number of voxels in the ROI – in the correlation analyses. Plotting the actual g-ratio (or neurite dispersion) values against autobiographical memory recall would not present an accurate plot of the relationship, as calculated with the conservative statistics we employed.

– On page 18, the authors mentioned how these results can provide a new perspective on the underlying neural substrate of autographical memory, and stated: "This is especially welcome given the dearth of consistent findings linking hippocampal grey matter volume or microstructure with autobiographical memory recall ability in the healthy population". Can the authors expand their argument here? I am missing the link between the current findings (on white matter microstructure) with previous ones on grey matter features.

This sentence was simply meant to highlight the fact that we currently lack a clear biological explanation for individual differences in autobiographical memory recall in the healthy population. We have now re-worded this to better reflect the point being made.

p. 19: “These results offer a new perspective on individual differences in autobiographical memory recall ability. This is especially welcome given the current lack of a clear biological explanation for such variations in the healthy population (Clark et al., 2020; Clark et al., 2021a; LePort et al., 2012; Maguire et al., 2003; Palombo et al., 2018; Van Petten, 2004).”

– On page 22, there is a reference to the CONNECTOM MRI scanners (misspelled as "connectome MRI scanners") – as the general audience is not familiar with those it would help to add a brief sentence explaining what they are and maybe a reference (for example, Jones et al., NeuroImage 2018).

We have now included an explanation of Connectom MRI scanners.

Introduction, pp. 5-6: “While measures of myelination can be obtained using conventional MRI scanners (e.g. via magnetisation transfer saturation maps), estimates of inner axon diameter cannot, and instead require ultra-strong gradient systems – 300 mT/m compared to the 10s of mT/m of conventional MRI scanners (Jones et al., 2018; Veraart et al., 2020). However, only four ultra-strong gradient Connectom MRI scanners exist in the world. Consequently, measuring the MR g-ratio with conventional MRI scanners can be useful in guiding inferences about inner axon diameter.”

– Can the authors comment on the advantages of the proposed ROI-based approach compared with a tract-based approach?

We now mention the advantages of the ROI compared to a tract-based approach in the Materials and methods.

Materials and methods, p. 34: “We used the well-established ROI approach (e.g. Ellerbrock and Mohammadi, 2018; Memel et al., 2020) rather than, for example, a tract-based pipeline, in order to reduce the influence of seed and target region selection. This is because small changes to these selections can result in different tracts being identified. We also wanted to avoid the inclusion of excess grey matter in the tracts themselves, because it is not possible to estimate the MR g-ratio in grey matter tissue. In addition, an ROI approach reduced the potential for false positives in comparison to performing tract-based voxel-wise analyses.”

– I may have missed it, but I am not sure of what is the reason for the fornix tract being "not probabilistic" (page 29) – are not all the tract ROIs obtained from the John Hopkins probabilistic atlas?

Thank you for noting this. The fornix was defined using the ICBM-DTI-81 white-matter labels atlas (Mori et al., 2008, NeuroImage), which is a non-probabilistic atlas. The uncinate fasciculus and parahippocampal cingulum bundle were defined using the Johns Hopkins probabilistic atlas. This latter atlas does not include the fornix. The manuscript text has been updated accordingly.

Materials and methods, p. 33: “Bilateral tract ROIs were defined using the Johns Hopkins probabilistic white matter tractography atlas (Hua et al., 2008), with the exception of the fornix which was defined using the ICBM-DTI-81 white-matter labels atlas (Mori et al., 2008) as the fornix is not available in the probabilistic atlas.”

Figure 3 legend: “The three white matter tracts of interest, given their relationship with the hippocampal region. The fornix was defined using the ICBM-DTI-81 white-matter labels atlas (Mori et al., 2008). The uncinate fasciculus and parahippocampal cingulum bundle were defined using the Johns Hopkins probabilistic white matter tractography atlas (Hua et al., 2008), with the minimum probability threshold set to 25%”.

– I could not find any mention of the main methodological limitations (e.g., the use of signal fractions rather than volume fractions, the bias towards larger axons, and the need for single-point calibration). There is only a brief mention in the appendix on page 43. I think these limitations should be part of the discussion to put these results in the right context.

The main methodological limitations are now outlined in the revised manuscript.

Discussion, p. 25: “Nevertheless, as with all neuroimaging techniques, methodological limitations need to be considered when measuring the MR g-ratio (see Campbell et al., 2018; Mohammadi and Callaghan, 2021 for in depth methodological reviews). First, the MR g-ratio is an area-weighted average of all microscopic axons in an MRI-voxel that is slightly weighted towards larger axons. Second, MR proxies are required to estimate myelin and axonal volumes for the calculation of the MR g-ratio. Multiple methodologies are available to estimate myelin and axonal volumes, with no consensus yet reached as to the best combination (Mohammadi and Callaghan, 2021). Third, a calibration step is required to more closely align the MR proxies with the estimated volume fractions. Here, we used the standard single-point calibration method to estimate the slope of the myelin-based proxy, assuming that the offset can be neglected. Future work may be able to improve these calibrations. But, of note, since a non-negligible offset in the myelin-based proxy can increase the error in the MR g-ratio, any calibration improvements would likely serve to increase the observed correlation. Fourth, although the model of the MR g-ratio allows for fibre dispersion (Stikov et al., 2015), this is not accounted for in mapping to conduction velocity. Going forward, more advanced models may help to further elaborate on these relationships. Finally, our myelin measure can be influenced by any factor, cognitive or demographic, that leads to a difference in absolute myelination. In principle, unexplained variance could obscure a true underlying relationship with autobiographical memory. To mitigate this, our analyses controlled for age, gender and any potential scanner-related differences. The MR g-ratio, however, is less affected by this limitation because it is a relative measure and does not depend on absolute myelin content but on the balance between absolute myelin and axonal volumes.”

Reviewer #3 (Recommendations for the authors):

I have some suggestions the authors may consider, presented in chronological order.

Title

The title suggests a causal relationship, while this is based on an association. Maybe better to use a neutral word, i.e. replace "influences" with e.g. "is associated with" or something similar?

As I understand MR g-ratio, it reflects structural aspects of nerve fibers, and although probably related to conduction velocity/ signaling speed, it is not a direct measure of this. Hence, I believe the title is overstating this relationship by referring to "signalling speed" directly. I fully understand the need for short and focused titles, but I believe this is a bit misleading. The same point applies to a couple of other places in the manuscript too. Of course fine to discuss this as an interpretation.

The title has now been revised to replace “signalling speed” with Reviewer #2’s suggestion of “conduction velocity”, and Reviewer #3’s suggestion to replace “influences” with “associated with”.

Title, p. 1: “Conduction velocity along a key white matter tract is associated with autobiographical memory recall ability”

Any references to causal relationships have also been removed throughout the manuscript.

Abstract

Not all readers are probably familiar with the MR g-ratio, so maybe it can be defined in the abstract?

A definition of the g-ratio has now been included.

Abstract, p. 2: “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.”

Since this is a cross-sectional study, I suggest avoiding phrases that imply change, e.g. "increased MR g-ratio". Maybe replace it with something neutral, such as "higher MR g-ratio"? The same is the case in several places in the manuscript, e.g. ln 195.

As with the title, the results reflect associations, not causation. This does not render them less interesting, but I would recommend replacing "favour better memory …" with e.g. "is associated with better memory …". I also wonder whether "offer a new perspective on drivers of individual differences in memory recall ability" is overstating a bit, since (a) we don't know whether g-ratio (or signal speed) is driving anything, and (b) this is a rather well-established theory (as also explained in the introduction, and it is stated ln 44 "it is perhaps no surprise that speed may be of the essence")?

Throughout the manuscript we have replaced phrases that imply change with more neutral associative statements, and generally tempered the language.

Introduction

ln 51-54: Why was aging discussed? Reading the introductory paragraph, I expected aging to be part of the study, which it was not.

The literature examining conduction velocity in relation to individual differences is relatively sparse, especially as most work in this area is performed in non-human animals, and involves ageing, which is why we cited it. We have now removed the aging-related summary sentence at the end of that paragraph to prevent confusion.

Ln 123-125: "While some healthy individuals can recollect decades-old autobiographical memories with great richness and clarity, others struggle to recall what they did last weekend" Yes, but as the authors surely know, this reflects different memory systems or processes, and therefore can happen within the same individual too, not only as a feature of inter-individual differences.

We do not deny that variability in recall occurs within the same person as well across people. However, the current study was set up to examine individual differences across people, and the two references cited in relation to that statement (LePort et al., 2012; Palombo et al., 2015) also refer to inter-individual differences.

Ln 195-200: Figure 1 clearly illustrates different scenarios, which is very useful. However, the hypothesis that better autobiographical memory is related to more myelin could also be consistent with no relationship with the MR g-ratio if the axon diameter is larger in participants with a good memory, right? And vice versa for the hypothesis about axon diameter? I don't see how the ratio measure can distinguish between the different accounts since the measures per definition are related to two possibly independent properties which both can be of importance? The authors multiple times mention that other relevant metrics, such as those derived from DTI, lack biological specificity. But the MR g-ratio measure seems also to be unspecific in this regard.

As we now note in the revised manuscript, the conduction velocity of an axon is not determined by the axon diameter or myelin sheath thickness individually, but by the relationship between them – the g-ratio. Given that the MR g-ratio encompasses information about the inner axon diameter and myelin thickness, the identification of statistically significant relationships with the MR g-ratio can help to guide as to which of these two features might be associated variations in conduction velocity. One way to further increase interpretability is by examining scans optimised to assess myelination (such as magnetisation transfer saturation values), as suggested by Reviewer #2. We observed no relationship between autobiographical memory recall ability and magnetisation transfer saturation values. This finding is supportive of the parahippocampal cingulum bundle inner axon diameter being of potentially more relevance than myelin thickness. Consequently, by measuring the MR g-ratio and magnetisation transfer saturation, we can make biologically-relevant inferences about the relationship between autobiographical memory recall ability and conduction velocity. This is in contrast to metrics derived from DTI. In the revised manuscript, we now explain that fractional anisotropy, for example, is a very general measure. Variations in fractional anisotropy values can occur for numerous reasons, including, but not limited to, changes in the extent of myelination, axon coherence, axon density, the level of astrocytes, and so forth.

Introduction, p. 6: “Adjudicating between the possible influence of inner axon diameter or myelination relies on knowledge, or an assumption, about whether the associated change in conduction velocity is faster or slower. This is because significant associations with the MR g-ratio only indicate the existence of a relationship with conduction velocity but not the direction. As noted previously, faster conduction velocity is often held to promote better cognition (e.g. Brancucci, 2012; Dicke and Roth, 2016; Miller, 1994; Reed and Jensen, 1992). Therefore, in Figure 2A, inner axon diameter, myelin thickness and (MR) g-ratio are plotted together to illustrate how different changes in the MR g-ratio are related to the underlying microstructural properties, given a faster conduction velocity. Myelin thickness is represented by the gradient in background colour and contours, with thinnest myelin at the bottom right, and thickest on the top left. The direction of the arrows describes the change in g-ratio for the microstructural variations presented. There are three main scenarios. (1) A decrease in MR g-ratio values. This would suggest that faster conduction velocity is due to greater thickness of the myelin sheath, with the inner axon diameter remaining constant (Figure 2A blue arrow, and Figure 2B). (2) A decrease in MR g-ratio values, but to a lesser extent than that observed in the first scenario. This would suggest that faster conduction velocity is due primarily to greater myelin sheath thickness, but one that is also accompanied by a larger inner axon diameter (Figure 2A red arrow, and Figure 2C). (3) An increase in MR g-ratio values. This would suggest that faster conduction velocity is predominantly due to a larger inner axon diameter, with only small differences, if any, in myelin thickness being present (Figure 2A orange arrow, and Figure 2D).”

Introduction, pp. 9-10: “For completeness, the commonly reported physical parameters from standard diffusion tensor imaging (DTI; e.g. fractional anisotropy and mean diffusivity; Basser, 1995) that are often derived from diffusion data were also computed (Oeschger et al., 2021). However, these metrics lack biological specificity (Jensen and Helpern, 2010; Jones et al., 2013a) and, consequently, could not speak to our research questions. For example, fractional anisotropy is a very general measure. Variations in fractional anisotropy values can occur for numerous reasons, including, but not limited to, changes in the extent of myelination, axon coherence, axon density, and the level of astrocytes.”

Discussion, pp. 19-20: “A key property of the MR g-ratio is that it provides a non-invasive methodology with which to relate in vivo structural neuroimaging of humans with axonal conduction velocity (Berman et al., 2019; Drakesmith et al., 2019). Moreover, the identification of a statistically significant relationship with the MR g-ratio can help to guide as to which of inner axon diameter or myelin thickness is more likely to be associated with variations in conduction velocity (Caeyenberghs et al., 2016; Kaller et al., 2017; Lakhani et al., 2016; Waxman, 1980; Xin and Chan, 2020).

Our inferences rested upon the assumption that a significant relationship with the MR g-ratio reflected faster conduction velocity, given previous work suggesting that faster conduction velocity might be associated with better cognition (e.g. Brancucci, 2012; Dicke and Roth, 2016; Miller, 1994; Reed and Jensen, 1992). As shown in Figure 2, there are three main scenarios describing how changes in the MR g-ratio are related to the underlying microstructural properties, given a faster conduction velocity. The positive relationship we observed between the parahippocampal cingulum bundle MR g-ratio and autobiographical memory recall ability suggests that this effect was associated predominantly with larger inner axon diameter (Figure 2A orange arrow, and Figure 2D). By contrast, had a negative correlation between the MR g-ratio and autobiographical memory recall ability been identified, we could instead have inferred that myelination was the relevant microstructural feature. The lack of relationship between parahippocampal cingulum bundle magnetisation transfer saturation values (optimised to assess myelination) and autobiographical memory recall ability provided further corroboration that myelin may not have been influential in this context. Greater myelination is often held to be a prominent influence on behavioural and cognitive performance (Caeyenberghs et al., 2016; Fields and Bukalo, 2020; Kaller et al., 2017; Lakhani et al., 2016; Waxman, 1980; Xin and Chan, 2020). By contrast, our results highlight the potentially important role that the inner axon diameter could be playing in autobiographical memory recall.”

If axon diameter and myelin thickness can be estimated separately, why not use them directly in the analyses instead of the MR g-ratio? There may be a methodological reason for this, but I think this could be more clearly explained as MR g-ratio is not often reported in the literature and so will be novel to many readers.

As we now note in the revised manuscript, the conduction velocity of an axon is not determined by the axon diameter or myelin sheath thickness individually, but by the relationship between them – the g-ratio. The MR g-ratio, therefore, is the only measure able to provide a link with conduction velocity.

While measures of myelination can be obtained using conventional MRI scanners (e.g. via the magnetisation transfer saturation values that we also acquired), estimates of inner axon diameter cannot, and instead require ultra-strong gradient systems – 300 mT/m in comparison to the 10s of mT/m of conventional MRI scanners (Jones et al., 2018; Veraart et al., 2020). However, only four ultra-strong gradient Connectom MRI scanners exist in the world. Consequently, measuring the MR g-ratio and interpreting these results together with magnetisation transfer saturation values can be useful in guiding inferences about inner axon diameter with conventional MRI scanners.

Introduction, p. 4: “The conduction velocity of an axon is, therefore, not determined only by the axon diameter, but also by the relationship between the axon diameter and the thickness of the surrounding myelin sheath, a measure known as the g-ratio (Chomiak and Hu, 2009; Rushton, 1951; Schmidt and Knösche, 2019). Specifically, Rushton (1951) derived an equation: conduction velocitydln(g), where d is the inner axon diameter, g is the g-ratio = d/D, and D is the outer fibre (axon plus myelin sheath) diameter. In other words, the g-ratio is computed as the ratio of the inner axon diameter relative to that of the axon plus the myelin sheath that encases it (Figure 1).”

Introduction, p. 5: “Of note, the MR g-ratio has been found to associate well with estimates of axonal conduction velocity (Berman et al., 2019; Drakesmith et al., 2019). Consequently, the MR g-ratio provides a non-invasive MRI method that can associate in vivo structural neuroimaging of humans with axonal conduction velocity.”

Introduction, p. 5-6: “Given that the MR g-ratio encompasses information about the inner axon diameter and myelin thickness, the identification of statistically significant relationships with the MR g-ratio can also guide as to which of these two features might be influencing variations in conduction velocity (Caeyenberghs et al., 2016; Kaller et al., 2017; Lakhani et al., 2016; Waxman, 1980; Xin and Chan, 2020). This is particularly useful in relation to the inner axon diameter. While measures of myelination can be obtained using conventional MRI scanners (e.g. via magnetisation transfer saturation maps), estimates of inner axon diameter cannot, and instead require ultra-strong gradient systems – 300 mT/m compared to the 10s of mT/m of conventional MRI scanners (Jones et al., 2018; Veraart et al., 2020). However, only four ultra-strong gradient Connectom MRI scanners exist in the world. Consequently, measuring the MR g-ratio with conventional MRI scanners can be useful in guiding inferences about inner axon diameter.”

Discussion, pp. 19-20: “A key property of the MR g-ratio is that it provides a non-invasive methodology with which to relate in vivo structural neuroimaging of humans with axonal conduction velocity (Berman et al., 2019; Drakesmith et al., 2019). Moreover, the identification of a statistically significant relationship with the MR g-ratio can help to guide as to which of inner axon diameter or myelin thickness is more likely to be associated with variations in conduction velocity (Caeyenberghs et al., 2016; Kaller et al., 2017; Lakhani et al., 2016; Waxman, 1980; Xin and Chan, 2020).”

Relatedly, although there are methods papers on this topic, maybe a brief justification of how can ratios between these small compartments on the micrometer scale can be calculated from voxels on the millimeter scale already in the introduction?

We now briefly expand this explanation in the revised manuscript.

Introduction, p. 5: “Until recently, g-ratio measurements were restricted to invasive studies in non-human animals. However, by combining diffusion magnetic resonance imaging (MRI) with quantitative structural MRI scans optimised to assess myelination (e.g. magnetisation transfer saturation; Weiskopf et al., 2013), it is now possible to estimate the g-ratio in vivo in humans across the whole brain (Drakesmith et al., 2019; Mohammadi et al., 2015; Mohammadi and Callaghan, 2021; Stikov et al., 2015). This is achieved by measuring an aggregate g-ratio, which is an area-weighted ensemble average across a voxel of an underlying distribution of microscopic g-ratios of axons (Stikov et al., 2015; West et al., 2016).”

Results

I understand that the authors don't want to provide the full description of results for FA and MD in the main text, but it would be convenient to report a brief summary of the main results also in the text. As far as I can see from Appendix 1, none even approach significance for fornix and uncinated fasciculus, so maybe at least state that?

Brief summaries of the standard DTI parameters are now provided in the Results section, and are mentioned in the Discussion.

Results, pp. 13-14: “Standard DTI parameters (e.g. fractional anisotropy and mean diffusivity) were also extracted from the fornix and uncinate fasciculus. None of the standard DTI parameters, from either tract, were significantly associated with autobiographical memory recall ability, even when using an uncorrected p < 0.05 threshold (see Appendix 1–tables 1-4 for full details, source data are available in Supplementary file 1).”

Results, pp. 17-18:

“Standard DTI parameters of the parahippocampal cingulum bundle and autobiographical memory recall ability

Partial correlations using the same covariates as the previous analyses were also performed using the standard DTI parameters. As these metrics lack biological specificity (Jensen and Helpern, 2010; Jones et al., 2013a), and could not speak to our research questions, the results are summarised here, with full details in Appendix 1–tables 19 and 20 and Appendix 1–figures 9 and 10, and the source data are available in Supplementary file 2.

Two significant relationships were identified between the standard DTI parameters and autobiographical memory recall ability. First, there was a positive correlation between fractional anisotropy and the number of internal details (Appendix 1–figure 9A; r(211) = 0.20, p = 0.003, 95% CI = 0.07, 0.32). Second, a positive correlation was evident between diffusivities parallel and the number of internal details (Appendix 1–figure 10A; r(211) = 0.19, p = 0.005, 95% CI = 0.06, 0.32). As with the microstructure metrics, these relationships were specific to internal details with no relationships identified with external details for either fractional anisotropy (r(211) = -0.06, p = 0.39, 95% CI = -0.19, 0.07) or diffusivities parallel (r(211) = -0.048, p = 0.49, 95% CI = -0.19, 0.10). No significant relationships were found between mean diffusivity, mean kurtosis or diffusivities perpendicular and either internal or external details.”

Discussion, p. 22: “There have only been a small number of previous studies investigating white matter tracts and individual differences in autobiographical memory recall ability in healthy people. These focused on standard DTI parameters, such as fractional anisotropy and mean diffusivity, and not the MR g-ratio. Two such studies were suggestive of a relationship between parahippocampal cingulum bundle fractional anisotropy and autobiographical memory recall (Irish et al., 2014; Memel et al., 2020). Our analyses of the standard DTI parameters, therefore, replicated these previous results.”

Discussion, p. 23: “In terms of standard DTI parameters, unlike a previous study (Hodgetts et al., 2017), we did not find a relationship between fornix fractional anisotropy and autobiographical memory recall ability, which may be due to the larger sample that we examined.”

This may be a matter of taste, but I would suggest moving the section on why the parahippocampal cingulum bundle should be important for autobiographical memory from the Results section (ln 236 and onwards) to the introduction or the discussion.

We understand the Reviewer’s point, and did consider this idea before the original submission. We have elected to keep this section within the Results to act as a primer for readers when they reach the parahippocampal cingulum bundle findings, to remind them about why this tract may be especially relevant. However, consideration of the parahippocampal cingulum bundle and its possible role in autobiographical memory recall is also included in both the Introduction and Discussion.

Ln 279: A positive relationship between MR g-ratio and memory is interpreted as reflecting larger inner axon diameters. Ref Figure 1, this can also be due to thinner myelin sheets, right, as it is a ratio measure?

A positive relationship between MR g-ratio and autobiographical memory recall would only reflect thinner myelin sheaths if the conduction velocity was slower (rather than faster, which is the basis of our interpretations). In addition, we have now also included analyses with a measure of myelination (magnetisation transfer saturation) and found no relationship between myelin and autobiographical memory recall ability. This supports our suggestion that the MR g-ratio finding might be related to inner axon diameter rather than myelination, and consequently also the assumption of faster rather than slower conduction velocity.

Multiple comparison correction was mentioned for some analyses above, was this done here two, and if so, how? Would be useful to state explicitly.

Multiple comparison correction was performed for all partial correlation analyses using the Bonferroni method; dividing α = 0.05 by 3 (because there were three tracts of interest). This means that associations with a two-sided p-value < 0.017 were considered significant. This information is included in the Materials and methods on p. 35.

Inspecting the Appendix, it seems that the relationships between autobiographic memory and PCB FA and MD were also significant, with r-values that were at least as large as for MR g-ratio. Why not include this in the main text? These are metrics of interest to many researchers.

Brief summaries of the standard DTI parameters are now provided in the Results section, and are mentioned in the Discussion.

Results, pp. 17-18:

“Standard DTI parameters of the parahippocampal cingulum bundle and autobiographical memory recall ability

Partial correlations using the same covariates as the previous analyses were also performed using the standard DTI parameters. As these metrics lack biological specificity (Jensen and Helpern, 2010; Jones et al., 2013a), and could not speak to our research questions, the results are summarised here, with full details in Appendix 1–tables 19 and 20 and Appendix 1–figures 9 and 10, and the source data are available in Supplementary file 2.

Two significant relationships were identified between the standard DTI parameters and autobiographical memory recall ability. First, there was a positive correlation between fractional anisotropy and the number of internal details (Appendix 1–figure 9A; r(211) = 0.20, p = 0.003, 95% CI = 0.07, 0.32). Second, a positive correlation was evident between diffusivities parallel and the number of internal details (Appendix 1–figure 10A; r(211) = 0.19, p = 0.005, 95% CI = 0.06, 0.32). As with the microstructure metrics, these relationships were specific to internal details with no relationships identified with external details for either fractional anisotropy (r(211) = -0.06, p = 0.39, 95% CI = -0.19, 0.07) or diffusivities parallel (r(211) = -0.048, p = 0.49, 95% CI = -0.19, 0.10). No significant relationships were found between mean diffusivity, mean kurtosis or diffusivities perpendicular and either internal or external details.”

Discussion, p. 22: “There have only been a small number of previous studies investigating white matter tracts and individual differences in autobiographical memory recall ability in healthy people. These focused on standard DTI parameters, such as fractional anisotropy and mean diffusivity, and not the MR g-ratio. Two such studies were suggestive of a relationship between parahippocampal cingulum bundle fractional anisotropy and autobiographical memory recall (Irish et al., 2014; Memel et al., 2020). Our analyses of the standard DTI parameters, therefore, replicated these previous results.”

You could also run a multiple regression analysis, and test whether each metric gives unique information or whether they are redundant. I think this would be a very useful addition to the manuscript, regardless of the outcome. If MR g-ratio is still significantly related to autobiographical memory, this would strengthen the main argument in the paper. If not, we will know more about the interrelationships between these different tract metrics, which also will be very useful.

Unfortunately, it is not possible to implement this suggestion. Each of the metrics available has varying specificity in relation to the underlying microstructure. Fractional anisotropy, for example, is a very general measure that simply describes the directionality of water molecule movement. High fractional anisotropy values can occur, therefore, for a variety of reasons including increased myelination, axon coherence and axon density. This means that fractional anisotropy will always be able to explain more of the variance than the more specific measures. However, this does not mean it has greater explanatory power, because fractional anisotropy cannot inform about the actual variations in microstructure, while the more specific metrics can.

To illustrate, in the current study, we see relationships between autobiographical memory recall and fractional anisotropy, axonal coherence and the MR g-ratio, and no relationship with axonal density. As the fractional anisotropy metric is the most general measure, placing the four measures together into a regression model results in fractional anisotropy explaining the majority of the model variance. However, even if we had observed instead, for example, relationships between autobiographical memory recall and fractional anisotropy, axonal density and the MR g-ratio, and no relationship with axonal coherence, exactly the same result would emerge from the regression analysis. Fractional anisotropy would again seem to explain the majority of the model variance, even though different inferences would be drawn from investigating the individual measures alone.

Discussion

Ln 336: Is it correct to say that the MR g-ratio – memory correlation represents "neural instantiation of autobiographical memory"? To me, it seems to overstate the results, as this is an association, and we do not know whether there is any causality involved. The same goes for the last part of the sentence "drivers of individual differences in recall ability". I think the results are of sufficient interest, without such statements.

These statements have now been removed.

Methods, Participants

Ln 456-457: "People with hobbies or vocations known to be associated with the hippocampus (e.g. licenced London taxi drivers) were excluded." Could you please be a little more specific, most activities will be associated with the hippocampus? How many were excluded based on this?

Additional information has now been included in the revised manuscript.

Materials and methods, pp. 26-27: “Our aim was to assess people from the general population who would not be classed as having extreme expertise on classic hippocampal tasks, as this could affect hippocampal structure (Maguire et al., 2000; Woollett and Maguire, 2011). Consequently, people with vocations such as taxi driving (or those training to be taxi drivers), ship navigators, aeroplane pilots, or those with regular hobbies including orienteering, or taking part in memory sports and competitions, were excluded. Of the approximately 2000 people who contacted us, 23 were explicitly excluded on this basis.”

[Editors’ note: what follows is the authors’ response to the second round of review.]

The authors put an amazing effort into taking into account the reviewers' comments and into improving the paper with further details and analysis. The finding that magnetization transfer saturation does not correlate with the score of interest while the g-ratio instead does is quite interesting -

Thank you.

I think that for the sake of fully characterizing the relationship what is missing at the moment is correlating the isotropic volume fraction with the recall score: since the g-ratio is computed using MTsat, Viso and Vic, double-checking that a correlation does not exist with Viso is the last step needed to show that indeed is the combination of all these measures that is meaningful rather than the single measures themselves.

Author response: Thank you for this suggestion. The correlation between autobiographical memory recall ability and Viso (isotropic volume fraction) has now been computed and included in the manuscript (and the associated data are now included in the relevant supplementary file). As expected, no significant relationship was observed, confirming that it is the combination of the measures, in the form of the MR g-ratio, that is meaningful rather than any single measure alone. We have modified the text as follows:

Results, pp. 17-18: “For completeness, we also examined a third measure from the NODDI biophysical model, the isotropic volume fraction. This models the space occupied by cerebrospinal fluid in a voxel, and therefore no relationship with autobiographical memory recall ability was expected, and none was found. Partial correlations showed that the isotropic volume fraction of the parahippocampal cingulum bundle (mean = 0.04, SD = 0.03) was not significantly related to either internal (r(211) = -0.03, p = 0.71, 95% CI = -0.14, 0.10), or external (r(211) = 0.02, p = 0.77, 95% CI = -0.11, 0.15) details. This confirms that it is the combination of these measures, in the form of the MR g-ratio, that is meaningful, rather than any single measure alone.”

Discussion, p. 25: “Relationships with autobiographical memory recall ability were also specific to the MR g-ratio, and were not evident for any of its components (magnetisation transfer saturation, neurite density or isotropic volume fraction), suggesting that it is the combination of these measures, in the form of the MR g-ratio, that is meaningful rather than any single measure alone.”

https://doi.org/10.7554/eLife.79303.sa2

Article and author information

Author details

  1. Ian A Clark

    Wellcome Centre for Human Neuroimaging, Department of Imaging Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
    Contribution
    Conceptualization, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5678-2190
  2. Siawoosh Mohammadi

    Institute of Systems Neuroscience, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Contribution
    Formal analysis, Writing - review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1311-9636
  3. Martina F Callaghan

    Wellcome Centre for Human Neuroimaging, Department of Imaging Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
    Contribution
    Formal analysis, Writing - review and editing
    Competing interests
    No competing interests declared
  4. Eleanor A Maguire

    Wellcome Centre for Human Neuroimaging, Department of Imaging Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
    Contribution
    Conceptualization, Formal analysis, Supervision, Funding acquisition, Methodology, Writing - original draft, Writing - review and editing
    For correspondence
    e.maguire@ucl.ac.uk
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9470-6324

Funding

Wellcome Trust (101759/Z/13/Z)

  • Eleanor A Maguire

Wellcome Trust (210567/Z/18/Z)

  • Eleanor A Maguire

Wellcome Trust (203147/Z/16/Z)

  • Eleanor A Maguire

ERA-NET NEURON (hMRI-ofSCI)

  • Siawoosh Mohammadi
  • Martina F Callaghan

Federal Ministry of Education and Research (01EW1711A and B)

  • Siawoosh Mohammadi

German Research Foundation (MO 2397/5‐1)

  • Siawoosh Mohammadi

German Research Foundation (MO 2397/4‐1)

  • Siawoosh Mohammadi

Forschungszentrums Medizintechnik Hamburg (01fmthh2017)

  • Siawoosh Mohammadi

MRC and Spinal Research Charity (MR/R000050/1)

  • Martina F Callaghan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

Acknowledgements

Thanks to Anna Monk, Victoria Hotchin, Gloria Pizzamiglio and Alice Liefgreen for assistance with data collection and scoring. Thanks also to Mohammad Ashtarayeh and Jan Malte Oeschger for their support with implementing the diffusion model fitting and g-ratio calculations.

Ethics

All participants gave written informed consent, including consent to publish, and the study was approved by the University College London Research Ethics Committee (project ID: 6743/001).

Senior Editor

  1. Laura L Colgin, University of Texas at Austin, United States

Reviewing Editor

  1. Anna C Schapiro, University of Pennsylvania, United States

Publication history

  1. Received: April 6, 2022
  2. Preprint posted: April 7, 2022 (view preprint)
  3. Accepted: September 12, 2022
  4. Version of Record published: September 27, 2022 (version 1)

Copyright

© 2022, Clark et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ian A Clark
  2. Siawoosh Mohammadi
  3. Martina F Callaghan
  4. Eleanor A Maguire
(2022)
Conduction velocity along a key white matter tract is associated with autobiographical memory recall ability
eLife 11:e79303.
https://doi.org/10.7554/eLife.79303
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