# Brain vs. endocast: Does size differ? A unique experiment based on a cohort of 75 volunteers

Anna Maria Kubicka, Sylvain Prima, Andréa Filippo, Victor Giolland, Éric Bardinet, Mélanie Didier, Mathieu Santin, Antoine Balzeau

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Anna Maria Kubicka, Sylvain Prima, Andréa Filippo, Victor Giolland, Éric Bardinet, et al.. Brain vs. endocast: Does size differ? A unique experiment based on a cohort of 75 volunteers. Journal of Anatomy, 2025, 10.1111/joa.70032. hal-05346956

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Original Article

# Brain vs endocast: does size differ? A unique experiment based on a cohort of 75 volunteers

Submission ID 45dab65d-b9d5-4cb9-81eb-851375d8bf7f

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## Authors

Anna Maria Kubicka
*Corresponding Author*
*Submitting Author*

ORCID

https://orcid.org/0000-0002-7844-9225

### Affiliations

* Department of Zoology, Poznań University of Life Sciences, Poznań, Poland

* UMR 7194 Histoire Naturelle des Humanités
Préhistoriques, CNRS, PaleoFED team, Département
Homme et Environnement, Muséum national
d'Histoire naturelle, Paris, France

Sylvain Prima

### Affiliations

* UMR 7194 Histoire Naturelle des Humanités
Préhistoriques, CNRS, PaleoFED team, Département
Homme et Environnement, Muséum national
d'Histoire naturelle, Paris, France

* Inria, Rennes, France

Andréa Filippo

### Affiliations

* UMR 7194 Histoire Naturelle des Humanités
Préhistoriques, CNRS, PaleoFED team, Département
Homme et Environnement, Muséum national
d'Histoire naturelle, Paris, France

Victor Giolland

### Affiliations

* UMR 7194 Histoire Naturelle des Humanités
Préhistoriques, CNRS, PaleoFED team, Département
Homme et Environnement, Muséum national
d'Histoire naturelle, Paris, France
Éric Bardinet

Affiliations

* Centre de Neurolmagerie de Recherche (CENIR), ICM - Institut du Cerveau, Hôpital PitiéSalpêtrière, Paris, France

Mélanie Didier

Affiliations

* Centre de Neurolmagerie de Recherche (CENIR), ICM - Institut du Cerveau, Hôpital PitiéSalpêtrière, Paris, France

Mathieu Santin

Affiliations

* Centre de Neurolmagerie de Recherche (CENIR), ICM - Institut du Cerveau, Hôpital PitiéSalpêtrière, Paris, France

Antoine Balzeau

Affiliations

* UMR 7194 Histoire Naturelle des Humanités Préhistoriques, CNRS, PaleoFED team, Département Homme et Environnement, Muséum national d'Histoire naturelle, Paris, France

* Department of African Zoology, Royal Museum for Central Africa, Tervuren, Belgium

Additional Information

Keywords

MRI; 3D model; directional asymmetry; absolute asymmetry; prediction equation

Research Topics

General anatomy
Files for peer review

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1 Brain vs endocast: does size differ? A unique experiment based on a cohort of 75 volunteers

2

3

4 Anna Maria Kubicka¹,²*, Sylvain Prima²,³, Andréa Filippo², Victor Giolland², Éric Bardinet⁴,

5 Mélanie Didier⁴, Mathieu Santin⁴, Antoine Balzeau²,⁵

6

7 ¹Department of Zoology, Poznań University of Life Sciences, Poznań, Poland

8 ²UMR 7194 Histoire Naturelle des Humanités Préhistoriques, CNRS, PaleoFED team, Département

9 Homme et Environnement, Muséum national d'Histoire naturelle, Paris, France

10 ³Inria, Rennes, France

11 ⁴Centre de NeuroImagerie de Recherche (CENIR), ICM - Institut du Cerveau, Hôpital

12 PitiéSalpêtrière, Paris, France

13 ⁵Department of African Zoology, Royal Museum for Central Africa, Tervuren, Belgium

14

15 *corresponding author: amkkubicka@gmail.com
16 **Abstract**

17 Research on brain evolution centres mainly on internal mouldings of the skull, known as
18 endocasts; however, the relationship between the size and asymmetry of the brain and endocasts
19 has been poorly investigated in humans. Therefore, the main objective of this study was to
20 investigate whether endocasts can be reliable indicators of brain size and asymmetry. Magnetic
21 Resonance Imaging (MRI) of 75 participants was used to calculate the volume and surface area of
22 the brain, the endocast, and their respective hemispheres. Two asymmetry indices (i.e. directional
23 and absolute asymmetry) were used to assess the differences in volume and surface area between
24 the sides of the brain and endocast. The Pearson correlation coefficient was calculated to assess
25 the relationships between the parameters, and a Monte Carlo simulation for linear regression was
26 performed to generate prediction equations for brain volume. The relationships between the level
27 and direction of asymmetry indices were investigated using the Pearson correlation and
28 McNemar's test, respectively. All correlations were statistically significant; however, correlation
29 coefficients between volumes were stronger (0.894-0.931) than between volumes and surface
30 areas (0.783-0.834). Brain volume can be predicted with high accuracy (ranging between 0.80 and
31 0.87) using the endocast total volume or the volume of one of the sides. The associations between
32 the levels of asymmetry indices of the brain and endocast were non-significant; however, the
33 McNemar's test indicated that endocasts show the same left- or right-biased asymmetry as the
34 brain. This was the first study conducted on a large sample of brain and endocast data from the
35 same individuals. The results demonstrated that brain volume can be accurately reconstructed
36 using the volume of the endocast or one of its sides. This finding is especially important in the
37 context of reconstructing fossil skulls, which are usually fragmented. Conversely, the asymmetry
38 levels of endocast parameters are not reliable indicators of the actual level of brain volume
39 asymmetry. Future research on fossils should focus on endocast asymmetry direction (left- or
40 right-biased) as this closely corresponds with brain lateralisation.

41
42 **Keywords:** MRI, 3D model, directional asymmetry, absolute asymmetry, prediction equation
43 **Introduction**

44 As the brain never fossilises, anatomical studies focus on the internal surface of the skull, that is,
45 the endocast (Holloway et al., 2005). However, despite that the endocast has been used for over
46 150 years to infer the volume, shape and proportion of the brain lobes during human evolution,
47 knowledge of the relationship between these two objects remains limited. According to
48 Dumoncel et al., (2021), the morphology and structure of the brain and endocast correspond.
49 Other studies on hominins have focused on brain-endocast shape by comparing the morphology
50 of convolutions and sulci (Dumoncel et al., 2021; Labra et al., 2024; Zollikofer & De León, 2013).
51 However, comparisons between the sulci of the brain and the imprints visible on endocasts are
52 far more complex than previously imagined (Dumoncel et al., 2021; Labra et al., 2024).
53 Nevertheless still, little is known about the level of brain-endocast correspondence in terms of
54 size and bilateral variation.

55 A few articles have analysed the brain-to-endocast ratio, using reptiles and birds as
56 models (Clement et al., 2021; Iwaniuk & Nelson, 2002; Jirak & Janacek, 2017; Keirnan et al.,
57 2025; Morhardt et al., 2017; Watanabe et al., 2019). Recent studies found a strong correlation in
58 size and shape between the endocast and brain in birds (Keirnan et al., 2025) and the American
59 alligator (Watanabe et al., 2019), although the brain mass to endocast volume ratio differed
60 between species and during ontogeny in crocodiles (Jirak & Janacek, 2017). For example, in
61 amphibians, the correspondence between the brain and endocast is weak, as the brain only
62 partially fills the endocranial cavity (Clement et al., 2021). In terms of hominins, only one study
63 developed a formula for calculating brain volume using cranial capacity (Holloway et al., 2005).
64 This association was investigated on 12 human brains using a water displacement technique.

65 Variations in overall brain dimensions influence brain areas that have important
66 functional implications, especially in hominins. The trajectory in hominins over the past 7
67 million years has involved a general and overall increase in endocranial size, with some
68 exceptions (DeSilva et al., 2023; Tattersall, 2023). This general increase in size is insufficient to
69 explain the emergence and diversity of human behaviour, as brain structure certainly played a
70 central role. Indeed, research has revealed variations between hominin species in anatomical
71 areas with strong functional implications; however, this complex picture of brain size and
72 structural variation is linked to major modifications in human capacity. In addition, the
73 emergence of anatomical asymmetries and their functional implications is a debated topic in
74 paleoneurology (Balzeau et al., 2012, 2014; Bruner, 2025; Neubauer et al., 2020). In this context,
75 it is important to improve our ability to characterize the relationship between the brain and the
76 endocast, our only available proxy for studying human brain evolution.
77

78 This is why reconstruction of brain volume using endocast parameters could expand
79 what is currently known about fossil hominins. With the development of virtual anthropology, it
80 is possible to investigate the strength of the correlation between brain and endocast size. In
81 addition, three-dimensional data enable analysis of the associations between the entire organ
82 and the endocast, and evaluation of the extent to which the endocast and brain hemispheres
correspond.
Until recently, the automatic segmentation of bone tissues using Magnetic Resonance

Imaging (MRI) was not sufficiently accurate (White et al., 2008); moreover, white and grey

matter show low contrast in computed tomography (CT) scans (Irimia et al., 2019). This is why

comparisons of the brain and endocast required two types of imaging for the same datasets:

MRI, used for brain segmentation; and CT, used for endocast reconstruction. Although these two

imaging techniques can be performed on non-human specimens without major restrictions,

collecting similar data on non-pathological living humans proves difficult. These technical

challenges were recently overcome through the use of a deep learning model for bone tissue

segmentation based on MRI input volume (Valabregue et al., 2025). Therefore, this study

focused on comparing brain and endocast parameters using only MRIs of 75 living individuals

and a semi-automatic skull segmentation tool.

This is the first study to analyse the direct size relationship between the brain and

endocast in humans using a large sample of brain and endocast data from the same individuals.

The first objective of this study was to analyse the strength of the correlation between the actual

volume of an individual's brain, and the volume and surface area of its endocast, including

hemispheric volumes, thus quantifying whether endocranial volume reflects brain volume at the

individual and sample levels. Regression equations were generated for reconstructing brain

volume based on endocast total and hemispheric volumes. The final objective was to evaluate

the correlation of the level and direction of asymmetry between the brain and endocast. These

results, in determining whether endocast volume and surface area are good indicators of brain

morphology, and may be useful in future research on fossils.
## 104 Materials and methods

A total of 75 patients (36 females, 39 males, age range: 18-75 years) were recruited during the
PaleoBRAIN project for complementary biological and behavioural experiments. MRI
acquisitions occurred at the Center for Neuroimaging Research, Brain Institute, Pitié-Salpêtrière
Hospital, Paris, France, in 2022 and 2023. The 'Comité de Protection des Personnes Sud-
Méditerranée II' approved the research protocol for the imaging centre used for this study
(comity reference 221 B38, identification number 2021-A02404-37). All volunteers underwent,
in particular, T1 and ultrashort time-to-echo (UTE) sequences.

The brains of the 75 participants were segmented into subcortical and cortical structures
using the volBrain open-access platform, which allows for automatic and rapid processing of
high-resolution T1-weighted MR images. The AssemblyNet pipeline (Coupé et al., 2020) was
used to provide grey and white matter volumes for the different lobes of the left and right
hemispheres. Brain structures were defined according to the Neuromorphometrics protocol
(http://www.neuromorphometrics.com/), which provides a consensus between the standard
practice in several research centres and different neuroanatomical atlases. The final brain
volume included separate hemispherical parameters for the cerebrum and cerebellum
separately for the sides, allowing for the calculation of asymmetry indices.

The endocast of each participant was reconstructed using the image obtained from a UTE
MRI sequence following a previously published protocol (Labra et al., 2024). A total of 49
endocasts were automatically obtained using a specifically adapted pipeline in Morphologist
(Fischer et al., 2012). This method was less successful with the 26 other specimens, which were
manually segmented using Avizo software (ver. 5.4.5).

Two parameters were calculated for the endocast and hemispheres: volume and surface
area. These measurements were performed using Avizo software (ver. 5.4.5). The left and right
sides of the endocasts were determined based on a plane located at three points: between the
frontal poles (at the most anterior protruding points of both frontal poles); on the endobregma;
and between the occipital poles (at the most posterior protruding points of both occipital poles,
Figure 1). This was carried out using GomInspect software (ver. 2.0.1). The plane's location and
endocast parameters were calculated twice for each participant by the same researcher (AMK),
and intra-observer error determined using the Intraclass correlation coefficient (ICC).

## 134 Statistical analysis

All brain and endocast parameters were checked for normality of distribution and
homogeneity of variance using the Shapiro-Wilk and Bartlett's tests, respectively. This analysis
was carried out separately for body side parameters. All measurements of the endocast and
brain followed a normal distribution and homogeneity of variance; therefore, further analyses
were carried out using parametric tests. Descriptive statistics such as the mean, maximum,
minimum, and standard deviation were calculated for all parameters.

The Pearson correlation coefficient was used to evaluate the association between brain
and endocast volume and surface area. In assessing the volume and surface area association, the
cube root of the volume was compared with the square root of the surface area. The associations
between the hemispherical parameters of the brain and endocast were also calculated. A Monte
Carlo simulation for linear regression was performed on the entire dataset (i.e. 75 individuals) to generate a regression equation for reconstructing brain volume using endocast parameters. For this purpose, three simulations were performed: between the brain and endocast volumes, and between the brain volume and the volume of each endocast side. All three analyses were performed with 10,000 permutations. The accuracy of each regression equation was estimated using the R², which is the proportion of variance accounted for by the regression.

Two asymmetry indices were calculated for the brain and endocast parameters. The directional asymmetry index (%DA) was calculated using the equation:
$$ \%DA = (\text{right} - \text{left})/(\text{average of left and right}) \times 100 $$
Positive %DA values indicate right-side asymmetry, with negative values indicating left-side asymmetry. The second index was an absolute asymmetry index (%AA) calculated using the equation:

$$ \%AA = (\text{maximum} - \text{minimum})/(\text{average of maximum and minimum}) \times 100 $$
(Auerbach & Ruff, 2006). A paired samples t-test was performed to test the significance of differences in brain volume and endocast parameters between body sides.

The concluding part of the analysis focused on the asymmetry and correlations between values and directions of the asymmetry indices. The association of %DA and %AA values between the brain and endocast was calculated using the Pearson correlation. The final analysis focused on the %DA directions, using McNemar's test for paired dichotomous variables. This assessed whether the endocasts exhibited the same left- or right-biased asymmetry as brains. All statistical analyses were carried out using R software and the following packages: dplyr (Wickham et al., 2014), ggpubr (Kassambara, 2023), psych (Revelle, 2025), MASS (Ripley & Venables, 2025), with p-values at a significance level of <0.05. The R script and measurements of the endocasts and brains are in the supplementary material. The 3D models of endocasts and brains are available in the repository of the Histoire Naturelle des Humanités Préhistoriques (Balzeau, 2025).
170 **Results**

171 The ICC (intra-class correlation coefficient) values for each endocast parameter (i.e. the volume
172 and surface area of the endocasts and sides) were greater than 0.98, indicating excellent
173 repeatability of the plane's location and endocast measurements. The ICC value of the %AA
174 (absolute asymmetry index) was 0.68, considered moderate; however, this value includes the
175 cumulated measurement errors of the metrical traits. This illustrates that measurement errors
176 in bilateral data do not impede the ability to distinguish anatomical variations between
177 hemispheres. Further statistical analysis was performed on the average of the two
178 measurements. No outliers were detected for any of the parameters.

179 Table 1 outlines brain and endocast descriptive statistics. All correlations were
180 statistically significant, with high coefficient values (Table 2, Figure 2); however, coefficient
181 values were stronger for the associations between volumes than between volumes and surface
182 areas. These findings were similar when comparing cube root values for the volumes and square
183 root values for the surface areas. The strongest correlation coefficient obtained was between
184 brain volume and endocranial volume. Correlation values were weaker, but still significant,
185 when brain volume was compared with endocranial surface area. The correlations between the
186 brain and endocast hemispheres were also significant and at high levels.

187 Table 3 shows the constant and regression coefficients of the three linear regressions
188 calculated using the Monte Carlo simulation from which the prediction equations were
189 generated. Fitted regression lines from the Monte Carlo simulations with 10,000 permutations
190 are illustrated in Figure 3. Brain volume can be predicted using the following equations:

1. Predicted brain volume = Endocast volume × 0.82 + 83.07

192 2. Predicted brain volume = Volume of the left endocast hemisphere × 1.59 + 122.89

193 3. Predicted brain volume = Volume of the right endocast hemisphere × 1.51 + 163.66

194 The accuracy of these regressions ranged between 0.80 and 0.87 (R² values reported in
195 Table 3). The largest part of the variation was explained by the prediction equation, which
196 included the entire endocast volume (i.e. R² = 0.87).

197 Table 4 shows %DA (directional asymmetry index) and %AA values, and paired t-test
198 results. The differences in all analysed measurements were statistically significant between
199 hemispheres. The Pearson correlations of %DA and %AA between brain volume and both
200 endocast parameters (volume and surface area) were non-significant (Table 5). Regarding the
201 %DA direction (left- or right-biased asymmetry), the McNemar's test showed no significant
202 differences between both endocast parameters and the brain (Table 6). This indicates that
203 endocasts show the same left- or right-biased asymmetry as the brain.

204
205 **Discussion**

206 The results of the current study, obtained from a large dataset (i.e. 75 participants),
207 confirm a previous study (Holloway et al., 2005) that endocranial volume reflects brain volume
208 at the individual level. Moreover, this study demonstrates that endocranial surface area is also a
209 good indicator of brain size; despite that the correlation coefficient values were weaker than
210 with volumes, they were significant and positive nonetheless (Table 2).

211 Owing to advancements in imaging techniques and virtual anthropology methods, it was
212 also possible to evaluate the strength of the relationship between endocast and brain
213 hemispheres. This approach is important in the context of reconstructing fossil skulls, which are
214 usually fragmented (Gunz et al., 2009; Ogihara et al., 2015; Senck et al., 2015). The relationship
215 between endocast sides and brain hemispheres was significant; however, the coefficient values
216 for the volume were stronger than for the surface area (Table 2). This suggests that, as much as
217 investigating lobe surface area could inform on their contribution to hemispherical anatomy
218 (Balzeau et al., 2012), research on brain evolution should ideally focus on endocast volume, as
219 this provides more direct information on brain size.

220 Considering the strong correlation between the parameters (Table 2), this study
221 calculated regression equations allowing for the reconstruction of brain volume based on the
222 volume of the entire endocast and its hemispheres. The Monte Carlo simulations with 10,000
223 permutations produced three equations (Table 3). The highest accuracy was obtained for a
224 regression which used the endocast volume parameter to predict the brain volume of an
225 individual. As this analysis was performed on a larger dataset than the cranial capacity and brain
226 volume study previously discussed (Holloway et al., 2005), and utilised the volBrain open-access
227 platform which accurately measures grey and white matter volumes (Coupé et al., 2020), in our
228 opinion, the revised equation may be applicable in future fossil research.

229 A high regression accuracy was also observed for the equations in which the volume of
230 the left or right endocast side was a predictor of brain volume (Table 3). This is interesting from
231 the perspective of analysing partial endocasts and attempting to estimate volume. Due to the
232 fragmentation of many cranial remains, endocasts of other individuals are used as models to
233 reconstruct the missing parts of some fossils (Falk et al., 2000; Kochiyama et al., 2018; Ogihara
234 et al., 2018). In our opinion, the equations proposed in this study will allow the reconstruction of
235 the brain volume in the case of fragmented endocasts, with a high degree of accuracy. This is
236 especially the case as the approach of dividing the endocasts into left and right sides using a
237 three-point plane ensures repeatable measurements and can be applied to fragmented fossils.
238 Further work on other primate species would be of useful in illustrating whether the ratio of
239 brain and endocranial volume follows an identical relationship as in humans, helping elucidate
240 possible evolutionary and/or brain size-related variations. Such findings would be valuable in
241 adapting the equation for the oldest human species with smaller brains.

242 Endocast asymmetry, in terms of shape and lobe location, has been used as an indicator
243 of brain lateralisation (Balzeau et al., 2020; Melchionna et al., 2020; Neubauer et al., 2020).
244 However, it remained uncertain whether the level of endocast asymmetry corresponded to that
245 of the brain. This is why the final objective of this study was to investigate the correlation of the
246 level and direction of asymmetry between the brain and the endocast. Asymmetry was
247 significant for all analysed bilateral measurements (i.e. brain volume and the two endocast
248 parameters, Table 4). However, the Pearson correlation showed a non-significant relationship in
249 the level of two asymmetry indices (i.e. the %DA and %AA) between the brain and endocast
250 (Table 5). This suggests that endocast volume and surface area asymmetry levels are not reliable
251 indicators of the actual level of brain asymmetry. This is unsurprising given that the volume of
252 each hemisphere corresponds to differential variations in internal structures, in the brain with a
253 possible bilateral variation unrelated to the external extension of each hemisphere. On the other
254 hand, there was significant agreement in asymmetry direction (i.e. left or right-side bias)
255 between the endocast and brain (Table 6). This indicates that future research on fossils should
256 focus on the direction of endocast volume asymmetry, as it is a reliable indicator of brain
257 lateralisation.

258 This study used three-dimensional brain and endocast models reconstructed from MRI
259 data of the same participants obtained under the same conditions, minimising potential
260 technical error (Labra et al., 2024). The high ICC values (above 0.98) for each endocast
261 parameter demonstrate that the proposed method of dividing the endocast into left and right
262 hemispheres provides repeatable surface area and volume measurements. The lower ICC value
263 (0.68) for repeated calculations of the asymmetry index (i.e. the %AA) was primarily due to
264 multiplication of the measurement error of individual hemispheric values. Finally, the Pearson
265 correlation coefficients were stronger for the right side of the endocast than the left (Table 2). A
266 similar pattern was detected from the Monte Carlo simulation, where the equation using the
267 right side endocast volume exhibited greater regression accuracy than that of the left side (Table
268 3). This may be an effect of the general pattern of brain asymmetry in *Homo sapiens*, where the
269 right side of the endocast has a larger surface area and volume than the left (Balzeau et al.,
270 2012).

271 All correlation coefficients and regressions which analysed the relationship between
272 brain and endocast size were significant, which is important in reconstructing fragmented
273 fossils. Endocranial volume and/or surface area appear to reflect brain volume at the individual
274 and sample levels. This finding demonstrates a close correspondence between the endocast and
275 the brain, in terms of global shape (Dumoncel et al., 2021) and size. This study contributes to the
276 body of work demonstrating the suitability of the endocast as a proxy for studying the brain as
277 these results show that variations in endocranial volume are a suitable proxy for variations in
278 brain volume. This is important since the general and overall increase in endocranial size during
279 hominin evolution has been widely studied (Beals et al., 1984; Holloway et al., 2005), especially
280 considering the most recent works on the exceptions to this trend (De Caro, 2024; DeSilva et al.,
281 2023; Tattersall, 2023) and new information regarding a potential new group of large-brained
282 hominins (Wu et al., 2022).

283 Our findings related to bilateral variations are also interesting. The right/left laterality of
284 the endocast volume sufficiently reflects the direction observed in the brain, but not the
285 documented variations within the sample concerning hemispheric volumes. This is particularly
286 important as an increase in functional laterality of the primate brain is expected to be associated
287 with an increase in anatomical asymmetries (Friedrich et al., 2021). Comparative approaches to
288 bilateral endocranial variations provide information within a well-established comparative
289 framework (Gonzalez et al., 2022; Lin et al., 2022; Poza-Rey et al., 2017); however, it would be
290 preferable not to extrapolate interpretations of asymmetries in cerebral areas as quantified on
291 the surface of the endocast. Thus, speculative rather than functional interpretations can be made
292 using endocast surface data. To correctly estimate cerebral asymmetries, from endocast
293 asymmetry and, therefore, their potential functional implications, it may be preferable to focus
294 on specific areas of one hemisphere versus the other (Balzeau et al., 2012, 2014), rather than on
295 the overall surface area or volume measures quantified on the external surface of the endocast.
296 These considerations are important because many studies focus on bilateral variations which
297 are known to be involved in functional aspects (Bruner, 2025; Hurst et al., 2024; Ponce de León
298 et al., 2021). Finally, improving the ability to identify the cerebral sulci imprints on endocasts
299 accurately remains a challenge in this context (Labra et al., 2024) as debates on the structure of
300 the brain in fossil hominins (Zollikofer, 2022) derive from studies of the global shape of the
301 endocast or imprints whose relationships with the underlying brain sulci have not yet been
302 demonstrated.

303

304 Conclusions

305 Research on the evolution of the human brain must focus on the endocranium as a proxy
306 since soft tissues do not fossilise. A significant advantage of this approach is that comparisons
307 are made between individuals at the same stage of development, whereas the skull during
308 childhood has reached its adult size and does not significantly modify its general internal shape.
309 However, the brain changes throughout the life of the individual. Although the field of
310 paleoneurology has existed since the beginning of research on human evolution, our knowledge
311 of the validity of using the endocranium to describe various aspects of the size, shape and
312 structure of the brain still remains largely incomplete. For the first time, we propose a validation
313 of the link between the overall size of the brain and the endocast in a single sample of
314 volunteers. This study represents an undeniable contribution to the discussion of these aspects
315 during human evolution. Moreover, we also show that the asymmetry levels of endocast
316 parameters are not reliable indicators of the actual level of brain volume asymmetry, even if the
317 endocast volume sufficiently reflects the direction of bilateral variation observed in the brain.

318 Moreover, characterising the general relationship between the dimensions of the brain
319 and the endocast to the individual bowl is an essential preliminary step in order to one day
320 consider reconstructing, on a robust scientific basis, the shape of a brain of another species. The
321 only previous attempt involved distorting the current brain to fill the cranium of a Neandertal
322 specimen (Kochiyama et al., 2018). Using the unique database compiled here, our goal will be to
323 document the relationship between the position of the sulci in the brain and their expression in
324 the endocast at the individual level and among a sample. Thus, we will have all the data available
325 to truly appreciate the brain characteristics of other hominin species according to their
326 endocasts.

327
328 Acknowledgements

329 The authors would like to thank all volunteers who participated in this project and technicians
330 from the PaleoBRAIN project: Stéphanie Anastacio, Chahrazad Chenaf, Margaux Couppey, Mélanie
331 Didier, Maeva Donardim, Fatiha Heumez, Céline Homo, Frédéric Humbert, Christine Soeung. This
332 research was supported by the Agence National de la Recherche (ANR-20-CE27-0009). The
333 authors also wish to sincerely thank two reviewers (including Dr Vera Weisbecker from Flinders
334 University) and the editor P. Cox for valuable feedback on the first article version.

335
336 Author contributions
337 Designed research: Anna Maria Kubicka, Sylvain Prima, Victor Giolland, Antoine Balzeau
338 Contributed analytical tools: Anna Maria Kubicka, Sylvain Prima, Andréa Filippo, Victor Giolland,
339 Éric Bardinet, Mélanie Didier, Mathieu Santin, Antoine Balzeau

340 Collected samples: Sylvain Prima, Andréa Filippo, Victor Giolland, Éric Bardinet, Mélanie Didier,
341 Mathieu Santin

342 Collected data: Anna Maria Kubicka, Sylvain Prima

343 Analysed/interpreted data: Anna Maria Kubicka, Antoine Balzeau

344 Wrote/revised the article: Anna Maria Kubicka, Sylvain Prima, Andréa Filippo, Victor Giolland,
345 Éric Bardinet, Mélanie Didier, Mathieu Santin, Antoine Balzeau
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495
496 Tables

497 Table 1. Descriptive statistics of the brain and endocast parameters

<table><thead><tr><th>Measurement</th><th>Mean</th><th>Maximum</th><th>Minimum</th><th>Sd</th></tr></thead><tbody><tr><td>Brain volume [cm³]</td><td>1276.59</td><td>1528.55</td><td>1047.72</td><td>106.54</td></tr><tr><td>Left side</td><td>637.62</td><td>762.02</td><td>522.01</td><td>53.21</td></tr><tr><td>Right side</td><td>638.98</td><td>766.54</td><td>525.71</td><td>53.42</td></tr><tr><td>Endocast volume [cm³]</td><td>1462.85</td><td>1729.28</td><td>1233.79</td><td>121.53</td></tr><tr><td>Left side</td><td>727.75</td><td>896.42</td><td>622.80</td><td>60.14</td></tr><tr><td>Right side</td><td>735.11</td><td>879.73</td><td>610.99</td><td>64.62</td></tr><tr><td>Endocast surface [cm²]</td><td>755.68</td><td>874.42</td><td>659.35</td><td>46.93</td></tr><tr><td>Left side</td><td>375.73</td><td>431.93</td><td>327.43</td><td>23.59</td></tr><tr><td>Right side</td><td>379.95</td><td>442.85</td><td>331.48</td><td>24.47</td></tr></tbody></table>

498 Sd – standard deviation
<table><caption>499 Table 2. Pearson correlation between brain and endocast parameters, including sides of the body</caption><thead><tr><td>Correlation</td><td>Coefficient</td><td>P-value</td></tr></thead><tbody><tr><td>Endocast volume vs brain volume</td><td>0.931</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Left endocast volume vs left brain volume</td><td>0.894</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Right endocast volume vs right brain volume</td><td>0.920</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Left endocast volume vs brain volume</td><td>0.895</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Right endocast volume vs brain volume</td><td>0.918</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Endocast surface vs brain volume</td><td>0.829</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Left endocast surface vs left brain volume</td><td>0.783</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Right endocast surface vs right brain volume</td><td>0.834</td><td><strong>&lt;0.001</strong></td></tr></tbody></table>

500 Bold – significant at the level <0.05
<table><caption>Table 3. Monte Carlo Simulation for linear regression with 10000 permutations between the brain volume and volume of endocast and its hemispheres</caption><thead><tr><th>Variable</th><th>Estimate</th><th>Variable</th><th>Estimate</th><th>Variable</th><th>Estimate</th></tr></thead><tbody><tr><td>Intercept</td><td>83.07223</td><td>Intercept</td><td>122.888906</td><td>Intercept</td><td>163.660583</td></tr><tr><td>Endocast volume</td><td>0.8161542</td><td>Volume of the left endocast hemisphere</td><td>1.585306</td><td>Volume of the right endocast hemisphere</td><td>1.513953</td></tr><tr><td>R<sup>2</sup></td><td>0.87</td><td>R<sup>2</sup></td><td>0.80</td><td>R<sup>2</sup></td><td>0.84</td></tr></tbody></table>

Estimate – components of the linear regression, Intercept - brain volume, R² – measure of the regression accuracy
<table><caption>Table 4. Asymmetry indices, paired T-test for differences between sides</caption><thead><tr><th>Measurement</th><th>Mean</th><th>Median</th><th>t</th><th>p</th></tr></thead><tbody><tr><td>Brain volume [cm³]</td><td></td><td></td><td></td><td></td></tr><tr><td>%DA</td><td>0.21</td><td>0.15</td><td></td><td></td></tr><tr><td>%AA</td><td>0.60</td><td>0.53</td><td>-2.53</td><td><strong>0.01</strong></td></tr><tr><td>Endocast volume [cm³]</td><td></td><td></td><td></td><td></td></tr><tr><td>%DA</td><td>0.96</td><td>0.54</td><td></td><td></td></tr><tr><td>%AA</td><td>3.08</td><td>2.62</td><td>-2.22</td><td><strong>0.03</strong></td></tr><tr><td>Endocast surface [cm²]</td><td></td><td></td><td></td><td></td></tr><tr><td>%DA</td><td>1.11</td><td>0.97</td><td></td><td></td></tr><tr><td>%AA</td><td>2.29</td><td>1.81</td><td>-3.49</td><td><strong>&lt;0.001</strong></td></tr></tbody></table>

506 %DA – directional asymmetry, %AA – absolute asymmetry, t – value of a paired t-test, p – p-value

507 of the paired t-test,

508 Bold – significant at the level <0.05
<table><caption>Table 5. Pearson correlation of %DA and %AA between the brain and endocast</caption><thead><tr><th rowspan="2">Correlation</th><th colspan="2">%DA</th><th colspan="2">%AA</th></tr><tr><th>Coefficient</th><th>P-value</th><th>Coefficient</th><th>P-value</th></tr></thead><tbody><tr><td>Endocast volume vs brain volume</td><td>0.143</td><td>0.220</td><td>0.082</td><td>0.483</td></tr><tr><td>Endocast surface vs brain volume</td><td>0.074</td><td>0.526</td><td>0.186</td><td>0.112</td></tr></tbody><tfoot><tr><td colspan="5">Bold – significant at the level &lt;0.05</td></tr></tfoot></table>

510
<table><caption>511 Table 6. Mc-Nemar's test of asymmetry directions between endocast and brain</caption><thead><tr><td>Direction of %DA</td><td>Chi²</td><td>P-value</td></tr></thead><tbody><tr><td>Endocast volume vs brain volume</td><td>0.516</td><td>0.473</td></tr><tr><td>Endocast surface vs brain volume</td><td>1.161</td><td>0.281</td></tr></tbody></table>

512
513 **Figure legends**

514 Fig. 1 Segmentation into hemispheres.

515 The brain with marked hemispheres using the volBrain platform. A: superior view of the brain
516 with marked the left (red) and right (green) hemispheres; B – posterior view of the brain with
517 marked the left (red) and right (green) hemispheres; C – lateral view of the brain with marked the
518 left (red) hemisphere

519 Three-point plane used for dividing endocast on the left and right sides.

520 D – anterior view of the endocast with the plane (blue) and points (red) between the frontal
521 convolutions and on the endobregma; E – right anterior view of the endocast with the plane (blue)
522 and points (red) between the frontal convolutions and on the endobregma; F – posterior view of
523 the endocast with the plane (blue) and a point (red) between the occipital poles; G – Anterior view
524 of the left side of the endocast cut along the three-point plane, H– right anterior view of the left
525 side of the endocast cut along the three-point plane, I – Posterior view of the left side of the
526 endocast cut along the three-point plane

527

528 Fig. 2 Plots of correlations between different parameters of endocast and brain

529

530 Fig. 3 Correlations between the volume of endocast and its hemispheres and the brain volume
531 with fitted regression lines from the Monte Carlo simulations
1 Brain vs endocast: does size differ? A unique experiment based on a cohort of 75 volunteers

2

3

4 Anna Maria Kubicka¹,²*, Sylvain Prima²,³, Andréa Filippo², Victor Giolland², Éric Bardinet⁴,

5 Mélanie Didier⁴, Mathieu Santin⁴, Antoine Balzeau²,⁵

6

7 ¹Department of Zoology, Poznań University of Life Sciences, Poznań, Poland

8 ²UMR 7194 Histoire Naturelle des Humanités Préhistoriques, CNRS, PaleoFED team, Département

9 Homme et Environnement, Muséum national d'Histoire naturelle, Paris, France

10 ³Inria, Rennes, France

11 ⁴Centre de NeuroImagerie de Recherche (CENIR), ICM - Institut du Cerveau, Hôpital

12 PitiéSalpêtrière, Paris, France

13 ⁵Department of African Zoology, Royal Museum for Central Africa, Tervuren, Belgium

14

15 *corresponding author: amkkubicka@gmail.com
16 Abstract

17 Research on brain evolution centres mainly on internal mouldings of the skull, known as
18 endocasts; however, the relationship between the size and asymmetry of the brain and endocasts
19 has been poorly investigated in humans. Therefore, the main objective of this study was to
20 investigate whether endocasts can be reliable indicators of brain size and asymmetry. Magnetic
21 Resonance Imaging (MRI) of 75 participants was used to calculate the volume and surface area of
22 the brain, the endocast, and their respective hemispheres. Two asymmetry indices (i.e. directional
23 and absolute asymmetry) were used to assess the differences in volume and surface area between
24 the sides of the brain and endocast. The Pearson correlation coefficient was calculated to assess
25 the relationships between the parameters, and a Monte Carlo simulation for linear regression was
26 performed to generate prediction equations for brain volume. The relationships between the level
27 and direction of asymmetry indices were investigated using the Pearson correlation and
28 McNemar's test, respectively. All correlations were statistically significant; however, correlation
29 coefficients between volumes were stronger (0.894-0.931) than between volumes and surface
30 areas (0.783-0.834). Brain volume can be predicted with high accuracy (ranging between 0.80 and
31 0.87) using the endocast total volume or the volume of one of the sides. The associations between
32 the levels of asymmetry indices of the brain and endocast were non-significant; however, the
33 McNemar's test indicated that endocasts show the same left- or right-biased asymmetry as the
34 brain. This was the first study conducted on a large sample of brain and endocast data from the
35 same individuals. The results demonstrated that brain volume can be accurately reconstructed
36 using the volume of the endocast or one of its sides. This finding is especially important in the
37 context of reconstructing fossil skulls, which are usually fragmented. Conversely, the asymmetry
38 levels of endocast parameters are not reliable indicators of the actual level of brain volume
39 asymmetry. Future research on fossils should focus on endocast asymmetry direction (left- or
40 right-biased) as this closely corresponds with brain lateralisation.

41
42 **Keywords:** MRI, 3D model, directional asymmetry, absolute asymmetry, prediction equation
43 **Introduction**

44 As the brain never fossilises, anatomical studies focus on the internal surface of the skull, that is,
45 the endocast (Holloway et al., 2005). However, despite that the endocast has been used for over
46 150 years to infer the volume, shape and proportion of the brain lobes during human evolution,
47 knowledge of the relationship between these two objects remains limited. According to
48 Dumoncel et al., (2021), the morphology and structure of the brain and endocast correspond.

49 Other studies on hominins have focused on brain-endocast shape by comparing the morphology
50 of convolutions and sulci (Dumoncel et al., 2021; Labra et al., 2024; Zollikofer & De León, 2013).

51 However, comparisons between the sulci of the brain and the imprints visible on endocasts are
52 far more complex than previously imagined (Dumoncel et al., 2021; Labra et al., 2024).

53 Nevertheless still, little is known about the level of brain-endocast correspondence in terms of
54 size and bilateral variation.

55 A few articles have analysed the brain-to-endocast ratio, using reptiles and birds as
56 models (Clement et al., 2021; Iwaniuk & Nelson, 2002; Jirak & Janacek, 2017; Keirnan et al.,
57 2025; Morhardt et al., 2017; Watanabe et al., 2019). Recent studies found a strong correlation in
58 size and shape between the endocast and brain in birds (Keirnan et al., 2025) and the American
59 alligator (Watanabe et al., 2019), although the brain mass to endocast volume ratio differed
60 between species and during ontogeny in crocodiles (Jirak & Janacek, 2017). For example, in
61 amphibians, the correspondence between the brain and endocast is weak, as the brain only
62 partially fills the endocranial cavity (Clement et al., 2021). In terms of hominins, only one study
63 developed a formula for calculating brain volume using cranial capacity (Holloway et al., 2005).
64 This association was investigated on 12 human brains using a water displacement technique.

65 Variations in overall brain dimensions influence brain areas that have important
66 functional implications, especially in hominins. The trajectory in hominins over the past 7
67 million years has involved a general and overall increase in endocranial size, with some
68 exceptions (DeSilva et al., 2023; Tattersall, 2023). This general increase in size is insufficient to
69 explain the emergence and diversity of human behaviour, as brain structure certainly played a
70 central role. Indeed, research has revealed variations between hominin species in anatomical
71 areas with strong functional implications; however, this complex picture of brain size and
72 structural variation is linked to major modifications in human capacity. In addition, the
73 emergence of anatomical asymmetries and their functional implications is a debated topic in
74 paleoneurology (Balzeau et al., 2012, 2014; Bruner, 2025; Neubauer et al., 2020). In this context,
75 it is important to improve our ability to characterize the relationship between the brain and the
76 endocast, our only available proxy for studying human brain evolution.
77

78 This is why reconstruction of brain volume using endocast parameters could expand
79 what is currently known about fossil hominins. With the development of virtual anthropology, it
80 is possible to investigate the strength of the correlation between brain and endocast size. In
81 addition, three-dimensional data enable analysis of the associations between the entire organ
82 and the endocast, and evaluation of the extent to which the endocast and brain hemispheres
correspond.
Until recently, the automatic segmentation of bone tissues using Magnetic Resonance

Imaging (MRI) was not sufficiently accurate (White et al., 2008); moreover, white and grey

matter show low contrast in computed tomography (CT) scans (Irimia et al., 2019). This is why

comparisons of the brain and endocast required two types of imaging for the same datasets:

MRI, used for brain segmentation; and CT, used for endocast reconstruction. Although these two

imaging techniques can be performed on non-human specimens without major restrictions,

collecting similar data on non-pathological living humans proves difficult. These technical

challenges were recently overcome through the use of a deep learning model for bone tissue

segmentation based on MRI input volume (Valabregue et al., 2025). Therefore, this study

focused on comparing brain and endocast parameters using only MRIs of 75 living individuals

and a semi-automatic skull segmentation tool.

This is the first study to analyse the direct size relationship between the brain and endocast in humans using a large sample of brain and endocast data from the same individuals.

The first objective of this study was to analyse the strength of the correlation between the actual

volume of an individual's brain, and the volume and surface area of its endocast, including

hemispheric volumes, thus quantifying whether endocranial volume reflects brain volume at the

individual and sample levels. Regression equations were generated for reconstructing brain

volume based on endocast total and hemispheric volumes. The final objective was to evaluate

the correlation of the level and direction of asymmetry between the brain and endocast. These

results, in determining whether endocast volume and surface area are good indicators of brain

morphology, and may be useful in future research on fossils.
104 **Materials and methods**

105 A total of 75 patients (36 females, 39 males, age range: 18-75 years) were recruited during the
106 PaleoBRAIN project for complementary biological and behavioural experiments. MRI
107 acquisitions occurred at the Center for Neuroimaging Research, Brain Institute, Pitié-Salpêtrière
108 Hospital, Paris, France, in 2022 and 2023. The 'Comité de Protection des Personnes Sud-
109 Méditerranée II' approved the research protocol for the imaging centre used for this study
110 (comity reference 221 B38, identification number 2021-A02404-37). All volunteers underwent,
111 in particular, T1 and ultrashort time-to-echo (UTE) sequences.

112 The brains of the 75 participants were segmented into subcortical and cortical structures
113 using the volBrain open-access platform, which allows for automatic and rapid processing of
114 high-resolution T1-weighted MR images. The AssemblyNet pipeline (Coupé et al., 2020) was
115 used to provide grey and white matter volumes for the different lobes of the left and right
116 hemispheres. Brain structures were defined according to the Neuromorphometrics protocol
117 (http://www.neuromorphometrics.com/), which provides a consensus between the standard
118 practice in several research centres and different neuroanatomical atlases. The final brain
119 volume included separate hemispherical parameters for the cerebrum and cerebellum
120 separately for the sides, allowing for the calculation of asymmetry indices.

121 The endocast of each participant was reconstructed using the image obtained from a UTE
122 MRI sequence following a previously published protocol (Labra et al., 2024). A total of 49
123 endocasts were automatically obtained using a specifically adapted pipeline in Morphologist
124 (Fischer et al., 2012). This method was less successful with the 26 other specimens, which were
125 manually segmented using Avizo software (ver. 5.4.5).

126 Two parameters were calculated for the endocast and hemispheres: volume and surface
127 area. These measurements were performed using Avizo software (ver. 5.4.5). The left and right
128 sides of the endocasts were determined based on a plane located at three points: between the
129 frontal poles (at the most anterior protruding points of both frontal poles); on the endobregma;
130 and between the occipital poles (at the most posterior protruding points of both occipital poles,
131 Figure 1). This was carried out using GomInspect software (ver. 2.0.1). The plane's location and
132 endocast parameters were calculated twice for each participant by the same researcher (AMK),
133 and intra-observer error determined using the Intraclass correlation coefficient (ICC).

134 *Statistical analysis*

135 All brain and endocast parameters were checked for normality of distribution and
136 homogeneity of variance using the Shapiro-Wilk and Bartlett's tests, respectively. This analysis
137 was carried out separately for body side parameters. All measurements of the endocast and
138 brain followed a normal distribution and homogeneity of variance; therefore, further analyses
139 were carried out using parametric tests. Descriptive statistics such as the mean, maximum,
140 minimum, and standard deviation were calculated for all parameters.

141 The Pearson correlation coefficient was used to evaluate the association between brain
142 and endocast volume and surface area. In assessing the volume and surface area association, the
143 cube root of the volume was compared with the square root of the surface area. The associations
144 between the hemispherical parameters of the brain and endocast were also calculated. A Monte
Carlo simulation for linear regression was performed on the entire dataset (i.e. 75 individuals) to generate a regression equation for reconstructing brain volume using endocast parameters.

For this purpose, three simulations were performed: between the brain and endocast volumes, and between the brain volume and the volume of each endocast side. All three analyses were performed with 10,000 permutations. The accuracy of each regression equation was estimated using the R², which is the proportion of variance accounted for by the regression.

Two asymmetry indices were calculated for the brain and endocast parameters. The directional asymmetry index (%DA) was calculated using the equation:

$$ \%DA = (\text{right} - \text{left})/(\text{average of left and right}) \times 100. $$
Positive %DA values indicate right-side asymmetry, with negative values indicating left-side asymmetry. The second index was an absolute asymmetry index (%AA) calculated using the equation:

$$ \%AA = (\text{maximum} - \text{minimum})/(\text{average of maximum and minimum}) \times 100 $$
(Auerbach & Ruff, 2006). A paired samples t-test was performed to test the significance of differences in brain volume and endocast parameters between body sides.

The concluding part of the analysis focused on the asymmetry and correlations between values and directions of the asymmetry indices. The association of %DA and %AA values between the brain and endocast was calculated using the Pearson correlation. The final analysis focused on the %DA directions, using McNemar's test for paired dichotomous variables. This assessed whether the endocasts exhibited the same left- or right-biased asymmetry as brains. All statistical analyses were carried out using R software and the following packages: dplyr (Wickham et al., 2014), ggpubr (Kassambara, 2023), psych (Revelle, 2025), MASS (Ripley & Venables, 2025), with p-values at a significance level of <0.05. The R script and measurements of the endocasts and brains are in the supplementary material. The 3D models of endocasts and brains are available in the repository of the Histoire Naturelle des Humanités Préhistoriques (Balzeau, 2025).
## 170 Results

171 The ICC (intra-class correlation coefficient) values for each endocast parameter (i.e. the volume
172 and surface area of the endocasts and sides) were greater than 0.98, indicating excellent
173 repeatability of the plane's location and endocast measurements. The ICC value of the %AA
174 (absolute asymmetry index) was 0.68, considered moderate; however, this value includes the
175 cumulated measurement errors of the metrical traits. This illustrates that measurement errors
176 in bilateral data do not impede the ability to distinguish anatomical variations between
177 hemispheres. Further statistical analysis was performed on the average of the two
178 measurements. No outliers were detected for any of the parameters.

179 Table 1 outlines brain and endocast descriptive statistics. All correlations were
180 statistically significant, with high coefficient values (Table 2, Figure 2); however, coefficient
181 values were stronger for the associations between volumes than between volumes and surface
182 areas. These findings were similar when comparing cube root values for the volumes and square
183 root values for the surface areas. The strongest correlation coefficient obtained was between
184 brain volume and endocranial volume. Correlation values were weaker, but still significant,
185 when brain volume was compared with endocranial surface area. The correlations between the
186 brain and endocast hemispheres were also significant and at high levels.

187 Table 3 shows the constant and regression coefficients of the three linear regressions
188 calculated using the Monte Carlo simulation from which the prediction equations were
189 generated. Fitted regression lines from the Monte Carlo simulations with 10,000 permutations
190 are illustrated in Figure 3. Brain volume can be predicted using the following equations:

1. Predicted brain volume = Endocast volume × 0.82 + 83.07

192 2. Predicted brain volume = Volume of the left endocast hemisphere × 1.59 + 122.89

193 3. Predicted brain volume = Volume of the right endocast hemisphere × 1.51 + 163.66

194 The accuracy of these regressions ranged between 0.80 and 0.87 (R² values reported in
195 Table 3). The largest part of the variation was explained by the prediction equation, which
196 included the entire endocast volume (i.e. R² = 0.87).

197 Table 4 shows %DA (directional asymmetry index) and %AA values, and paired t-test
198 results. The differences in all analysed measurements were statistically significant between
199 hemispheres. The Pearson correlations of %DA and %AA between brain volume and both
200 endocast parameters (volume and surface area) were non-significant (Table 5). Regarding the
201 %DA direction (left- or right-biased asymmetry), the McNemar's test showed no significant
202 differences between both endocast parameters and the brain (Table 6). This indicates that
203 endocasts show the same left- or right-biased asymmetry as the brain.

204
## Discussion

The results of the current study, obtained from a large dataset (i.e. 75 participants), confirm a previous study (Holloway et al., 2005) that endocranial volume reflects brain volume at the individual level. Moreover, this study demonstrates that endocranial surface area is also a good indicator of brain size; despite that the correlation coefficient values were weaker than with volumes, they were significant and positive nonetheless (Table 2).

Owing to advancements in imaging techniques and virtual anthropology methods, it was also possible to evaluate the strength of the relationship between endocast and brain hemispheres. This approach is important in the context of reconstructing fossil skulls, which are usually fragmented (Gunz et al., 2009; Ogihara et al., 2015; Senck et al., 2015). The relationship between endocast sides and brain hemispheres was significant; however, the coefficient values for the volume were stronger than for the surface area (Table 2). This suggests that, as much as investigating lobe surface area could inform on their contribution to hemispherical anatomy (Balzeau et al., 2012), research on brain evolution should ideally focus on endocast volume, as this provides more direct information on brain size.

Considering the strong correlation between the parameters (Table 2), this study calculated regression equations allowing for the reconstruction of brain volume based on the volume of the entire endocast and its hemispheres. The Monte Carlo simulations with 10,000 permutations produced three equations (Table 3). The highest accuracy was obtained for a regression which used the endocast volume parameter to predict the brain volume of an individual. As this analysis was performed on a larger dataset than the cranial capacity and brain volume study previously discussed (Holloway et al., 2005), and utilised the volBrain open-access platform which accurately measures grey and white matter volumes (Coupé et al., 2020), in our opinion, the revised equation may be applicable in future fossil research.

A high regression accuracy was also observed for the equations in which the volume of the left or right endocast side was a predictor of brain volume (Table 3). This is interesting from the perspective of analysing partial endocasts and attempting to estimate volume. Due to the fragmentation of many cranial remains, endocasts of other individuals are used as models to reconstruct the missing parts of some fossils (Falk et al., 2000; Kochiyama et al., 2018; Ogihara et al., 2018). In our opinion, the equations proposed in this study will allow the reconstruction of the brain volume in the case of fragmented endocasts, with a high degree of accuracy. This is especially the case as the approach of dividing the endocasts into left and right sides using a three-point plane ensures repeatable measurements and can be applied to fragmented fossils. Further work on other primate species would be of useful in illustrating whether the ratio of brain and endocranial volume follows an identical relationship as in humans, helping elucidate possible evolutionary and/or brain size-related variations. Such findings would be valuable in adapting the equation for the oldest human species with smaller brains.

Endocast asymmetry, in terms of shape and lobe location, has been used as an indicator of brain lateralisation (Balzeau et al., 2020; Melchionna et al., 2020; Neubauer et al., 2020). However, it remained uncertain whether the level of endocast asymmetry corresponded to that of the brain. This is why the final objective of this study was to investigate the correlation of the
246 level and direction of asymmetry between the brain and the endocast. Asymmetry was
247 significant for all analysed bilateral measurements (i.e. brain volume and the two endocast
248 parameters, Table 4). However, the Pearson correlation showed a non-significant relationship in
249 the level of two asymmetry indices (i.e. the %DA and %AA) between the brain and endocast
250 (Table 5). This suggests that endocast volume and surface area asymmetry levels are not reliable
251 indicators of the actual level of brain asymmetry. This is unsurprising given that the volume of
252 each hemisphere corresponds to differential variations in internal structures, in the brain with a
253 possible bilateral variation unrelated to the external extension of each hemisphere. On the other
254 hand, there was significant agreement in asymmetry direction (i.e. left or right-side bias)
255 between the endocast and brain (Table 6). This indicates that future research on fossils should
256 focus on the direction of endocast volume asymmetry, as it is a reliable indicator of brain
257 lateralisation.

258 This study used three-dimensional brain and endocast models reconstructed from MRI
259 data of the same participants obtained under the same conditions, minimising potential
260 technical error (Labra et al., 2024). The high ICC values (above 0.98) for each endocast
261 parameter demonstrate that the proposed method of dividing the endocast into left and right
262 hemispheres provides repeatable surface area and volume measurements. The lower ICC value
263 (0.68) for repeated calculations of the asymmetry index (i.e. the %AA) was primarily due to
264 multiplication of the measurement error of individual hemispheric values. Finally, the Pearson
265 correlation coefficients were stronger for the right side of the endocast than the left (Table 2). A
266 similar pattern was detected from the Monte Carlo simulation, where the equation using the
267 right side endocast volume exhibited greater regression accuracy than that of the left side (Table
268 3). This may be an effect of the general pattern of brain asymmetry in *Homo sapiens*, where the
269 right side of the endocast has a larger surface area and volume than the left (Balzeau et al.,
270 2012).

271 All correlation coefficients and regressions which analysed the relationship between
272 brain and endocast size were significant, which is important in reconstructing fragmented
273 fossils. Endocranial volume and/or surface area appear to reflect brain volume at the individual
274 and sample levels. This finding demonstrates a close correspondence between the endocast and
275 the brain, in terms of global shape (Dumoncel et al., 2021) and size. This study contributes to the
276 body of work demonstrating the suitability of the endocast as a proxy for studying the brain as
277 these results show that variations in endocranial volume are a suitable proxy for variations in
278 brain volume. This is important since the general and overall increase in endocranial size during
279 hominin evolution has been widely studied (Beals et al., 1984; Holloway et al., 2005), especially
280 considering the most recent works on the exceptions to this trend (De Caro, 2024; DeSilva et al.,
281 2023; Tattersall, 2023) and new information regarding a potential new group of large-brained
282 hominins (Wu et al., 2022).

283 Our findings related to bilateral variations are also interesting. The right/left laterality of
284 the endocast volume sufficiently reflects the direction observed in the brain, but not the
285 documented variations within the sample concerning hemispheric volumes. This is particularly
286 important as an increase in functional laterality of the primate brain is expected to be associated
287 with an increase in anatomical asymmetries (Friedrich et al., 2021). Comparative approaches to bilateral endocranial variations provide information within a well-established comparative framework (Gonzalez et al., 2022; Lin et al., 2022; Poza-Rey et al., 2017); however, it would be preferable not to extrapolate interpretations of asymmetries in cerebral areas as quantified on the surface of the endocast. Thus, speculative rather than functional interpretations can be made using endocast surface data. To correctly estimate cerebral asymmetries, from endocast asymmetry and, therefore, their potential functional implications, it may be preferable to focus on specific areas of one hemisphere versus the other (Balzeau et al., 2012, 2014), rather than on the overall surface area or volume measures quantified on the external surface of the endocast. These considerations are important because many studies focus on bilateral variations which are known to be involved in functional aspects (Bruner, 2025; Hurst et al., 2024; Ponce de León et al., 2021). Finally, improving the ability to identify the cerebral sulci imprints on endocasts accurately remains a challenge in this context (Labra et al., 2024) as debates on the structure of the brain in fossil hominins (Zollikofer, 2022) derive from studies of the global shape of the endocast or imprints whose relationships with the underlying brain sulci have not yet been demonstrated.

303

## Conclusions

304 Research on the evolution of the human brain must focus on the endocranium as a proxy since soft tissues do not fossilise. A significant advantage of this approach is that comparisons are made between individuals at the same stage of development, whereas the skull during childhood has reached its adult size and does not significantly modify its general internal shape. However, the brain changes throughout the life of the individual. Although the field of paleoneurology has existed since the beginning of research on human evolution, our knowledge of the validity of using the endocranium to describe various aspects of the size, shape and structure of the brain still remains largely incomplete. For the first time, we propose a validation of the link between the overall size of the brain and the endocast in a single sample of volunteers. This study represents an undeniable contribution to the discussion of these aspects during human evolution. Moreover, we also show that the asymmetry levels of endocast parameters are not reliable indicators of the actual level of brain volume asymmetry, even if the endocast volume sufficiently reflects the direction of bilateral variation observed in the brain.

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327
328 Acknowledgements

329 The authors would like to thank all volunteers who participated in this project and technicians
330 from the PaleoBRAIN project: Stéphanie Anastacio, Chahrazad Chenaf, Margaux Couppey, Mélanie
331 Didier, Maeva Donardim, Fatiha Heumez, Céline Homo, Frédéric Humbert, Christine Soeung. This
332 research was supported by the Agence National de la Recherche (ANR-20-CE27-0009). The
333 authors also wish to sincerely thank two reviewers (including Dr Vera Weisbecker from Flinders
334 University) and the editor P. Cox for valuable feedback on the first article version.

335
336 Author contributions
337 Designed research: Anna Maria Kubicka, Sylvain Prima, Victor Giolland, Antoine Balzeau
338 Contributed analytical tools: Anna Maria Kubicka, Sylvain Prima, Andréa Filippo, Victor Giolland,
339 Éric Bardinet, Mélanie Didier, Mathieu Santin, Antoine Balzeau
340 Collected samples: Sylvain Prima, Andréa Filippo, Victor Giolland, Éric Bardinet, Mélanie Didier,
341 Mathieu Santin
342 Collected data: Anna Maria Kubicka, Sylvain Prima
343 Analysed/interpreted data: Anna Maria Kubicka, Antoine Balzeau
344 Wrote/revised the article: Anna Maria Kubicka, Sylvain Prima, Andréa Filippo, Victor Giolland,
345 Éric Bardinet, Mélanie Didier, Mathieu Santin, Antoine Balzeau
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495
496 Tables

497 Table 1. Descriptive statistics of the brain and endocast parameters

<table><thead><tr><th>Measurement</th><th>Mean</th><th>Maximum</th><th>Minimum</th><th>Sd</th></tr></thead><tbody><tr><td>Brain volume [cm³]</td><td>1276.59</td><td>1528.55</td><td>1047.72</td><td>106.54</td></tr><tr><td>Left side</td><td>637.62</td><td>762.02</td><td>522.01</td><td>53.21</td></tr><tr><td>Right side</td><td>638.98</td><td>766.54</td><td>525.71</td><td>53.42</td></tr><tr><td>Endocast volume [cm³]</td><td>1462.85</td><td>1729.28</td><td>1233.79</td><td>121.53</td></tr><tr><td>Left side</td><td>727.75</td><td>896.42</td><td>622.80</td><td>60.14</td></tr><tr><td>Right side</td><td>735.11</td><td>879.73</td><td>610.99</td><td>64.62</td></tr><tr><td>Endocast surface [cm²]</td><td>755.68</td><td>874.42</td><td>659.35</td><td>46.93</td></tr><tr><td>Left side</td><td>375.73</td><td>431.93</td><td>327.43</td><td>23.59</td></tr><tr><td>Right side</td><td>379.95</td><td>442.85</td><td>331.48</td><td>24.47</td></tr></tbody></table>

498 Sd – standard deviation
<table><caption>Table 2. Pearson correlation between brain and endocast parameters, including sides of the body</caption><thead><tr><td>Correlation</td><td>Coefficient</td><td>P-value</td></tr></thead><tbody><tr><td>Endocast volume vs brain volume</td><td>0.931</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Left endocast volume vs left brain volume</td><td>0.894</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Right endocast volume vs right brain volume</td><td>0.920</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Left endocast volume vs brain volume</td><td>0.895</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Right endocast volume vs brain volume</td><td>0.918</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Endocast surface vs brain volume</td><td>0.829</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Left endocast surface vs left brain volume</td><td>0.783</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Right endocast surface vs right brain volume</td><td>0.834</td><td><strong>&lt;0.001</strong></td></tr></tbody></table>

500 Bold – significant at the level <0.05
<table><caption>Table 3. Monte Carlo Simulation for linear regression with 10000 permutations between the brain volume and volume of endocast and its hemispheres</caption><thead><tr><th>Variable</th><th>Estimate</th><th>Variable</th><th>Estimate</th><th>Variable</th><th>Estimate</th></tr></thead><tbody><tr><td>Intercept</td><td>83.07223</td><td>Intercept</td><td>122.888906</td><td>Intercept</td><td>163.660583</td></tr><tr><td>Endocast volume</td><td>0.8161542</td><td>Volume of the left endocast hemisphere</td><td>1.585306</td><td>Volume of the right endocast hemisphere</td><td>1.513953</td></tr><tr><td>R<sup>2</sup></td><td>0.87</td><td>R<sup>2</sup></td><td>0.80</td><td>R<sup>2</sup></td><td>0.84</td></tr></tbody></table>

Estimate – components of the linear regression, Intercept - brain volume, R² – measure of the regression accuracy
<table><caption>Table 4. Asymmetry indices, paired T-test for differences between sides</caption><thead><tr><th>Measurement</th><th>Mean</th><th>Median</th><th>t</th><th>p</th></tr></thead><tbody><tr><td>Brain volume [cm³]</td><td></td><td></td><td></td><td></td></tr><tr><td>%DA</td><td>0.21</td><td>0.15</td><td></td><td></td></tr><tr><td>%AA</td><td>0.60</td><td>0.53</td><td>-2.53</td><td><strong>0.01</strong></td></tr><tr><td>Endocast volume [cm³]</td><td></td><td></td><td></td><td></td></tr><tr><td>%DA</td><td>0.96</td><td>0.54</td><td></td><td></td></tr><tr><td>%AA</td><td>3.08</td><td>2.62</td><td>-2.22</td><td><strong>0.03</strong></td></tr><tr><td>Endocast surface [cm²]</td><td></td><td></td><td></td><td></td></tr><tr><td>%DA</td><td>1.11</td><td>0.97</td><td></td><td></td></tr><tr><td>%AA</td><td>2.29</td><td>1.81</td><td>-3.49</td><td><strong>&lt;0.001</strong></td></tr></tbody></table>

506 %DA – directional asymmetry, %AA – absolute asymmetry, t – value of a paired t-test, p – p-value

507 of the paired t-test,

508 Bold – significant at the level <0.05
<table><caption>Table 5. Pearson correlation of %DA and %AA between the brain and endocast</caption><thead><tr><th rowspan="2">Correlation</th><th colspan="2">%DA</th><th colspan="2">%AA</th></tr><tr><th>Coefficient</th><th>P-value</th><th>Coefficient</th><th>P-value</th></tr></thead><tbody><tr><td>Endocast volume vs brain volume</td><td>0.143</td><td>0.220</td><td>0.082</td><td>0.483</td></tr><tr><td>Endocast surface vs brain volume</td><td>0.074</td><td>0.526</td><td>0.186</td><td>0.112</td></tr></tbody><tfoot><tr><td colspan="5">Bold – significant at the level &lt;0.05</td></tr></tfoot></table>
<table><caption>511 Table 6. Mc-Nemar's test of asymmetry directions between endocast and brain</caption><thead><tr><td>Direction of %DA</td><td>Chi²</td><td>P-value</td></tr></thead><tbody><tr><td>Endocast volume vs brain volume</td><td>0.516</td><td>0.473</td></tr><tr><td>Endocast surface vs brain volume</td><td>1.161</td><td>0.281</td></tr></tbody></table>

512
513 **Figure legends**

514 Fig. 1 Segmentation into hemispheres.

515 The brain with marked hemispheres using the volBrain platform. A: superior view of the brain
516 with marked the left (red) and right (green) hemispheres; B – posterior view of the brain with
517 marked the left (red) and right (green) hemispheres; C – lateral view of the brain with marked the
518 left (red) hemisphere

519 Three-point plane used for dividing endocast on the left and right sides.

520 D – anterior view of the endocast with the plane (blue) and points (red) between the frontal
521 convolutions and on the endobregma; E – right anterior view of the endocast with the plane (blue)
522 and points (red) between the frontal convolutions and on the endobregma; F – posterior view of
523 the endocast with the plane (blue) and a point (red) between the occipital poles; G – Anterior view
524 of the left side of the endocast cut along the three-point plane, H– right anterior view of the left
525 side of the endocast cut along the three-point plane, I – Posterior view of the left side of the
526 endocast cut along the three-point plane

527

528 Fig. 2 Plots of correlations between different parameters of endocast and brain

529

530 Fig. 3 Correlations between the volume of endocast and its hemispheres and the brain volume
531 with fitted regression lines from the Monte Carlo simulations
<figure><img src="image_2.png" /></figure>

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>
A

<figure><img src="image_9.png" /></figure>

B

<figure><img src="image_10.png" /></figure>

C

<figure><img src="image_11.png" /></figure>

D

<figure><img src="image_12.png" /></figure>

E

<figure><img src="image_13.png" /></figure>

F

<figure><img src="image_14.png" /></figure>

G

<figure><img src="image_15.png" /></figure>

H

<figure><img src="image_16.png" /></figure>
<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /></figure>

Volume of the right endocast hemisphere [cm3]
<table><thead><tr><th>ID</th><th>LEFT_END Ended</th><th>RIGHT_END Ended</th><th>DA End</th><th>AA End</th><th>ALL_END Ended</th><th>LEFT_END End</th><th>RIGHT_END End</th><th>DA End</th><th>AA End</th><th>ALL_END End</th><th>LEFT BRAIN</th><th>RIGHT BRAIN</th><th>DA End</th><th>AA End</th><th>ALL BRAIN</th></tr></thead><tbody><tr><td>1</td><td>379.91</td><td>375.911</td><td>-1.058187058</td><td>1.058187058</td><td>755.821</td><td>763.923</td><td>739.715</td><td>-3.219923944</td><td>3.219923944</td><td>1503.638</td><td>661.13</td><td>668.67</td><td>1.134005114</td><td>1.134005114</td><td>1329.8</td></tr><tr><td>2</td><td>327.428</td><td>331.919</td><td>1.3622569</td><td>1.3622569</td><td>659.347</td><td>627.507</td><td>630.118</td><td>0.415227115</td><td>0.415227115</td><td>1257.625</td><td>551.87</td><td>547.86</td><td>-0.729269912</td><td>0.729269912</td><td>1099.73</td></tr><tr><td>3</td><td>336.667</td><td>331.483</td><td>-1.551747362</td><td>1.551747362</td><td>668.15</td><td>622.8</td><td>610.985</td><td>-1.915244552</td><td>1.915244552</td><td>1233.785</td><td>536.495</td><td>537.385</td><td>0.165754088</td><td>0.165754088</td><td>1073.88</td></tr><tr><td>4</td><td>333.143</td><td>340.066</td><td>2.056716413</td><td>2.056716413</td><td>673.209</td><td>623.568</td><td>632.227</td><td>1.379046739</td><td>1.379046739</td><td>1255.795</td><td>543.89</td><td>544.37</td><td>0.088214214</td><td>0.088214214</td><td>1088.26</td></tr><tr><td>5</td><td>342.618</td><td>337.848</td><td>-1.401980408</td><td>1.401980408</td><td>680.466</td><td>624.497</td><td>621.862</td><td>-0.422831624</td><td>0.422831624</td><td>1246.359</td><td>522.01</td><td>525.71</td><td>0.706295575</td><td>0.706295575</td><td>1047.72</td></tr><tr><td>6</td><td>343.082</td><td>337.791</td><td>-1.554181176</td><td>1.554181176</td><td>680.873</td><td>639.689</td><td>622.09</td><td>-2.78955348</td><td>2.78955348</td><td>1261.779</td><td>551.155</td><td>550.755</td><td>-0.072601211</td><td>0.072601211</td><td>1101.91</td></tr><tr><td>7</td><td>339.095</td><td>343.938</td><td>1.418086681</td><td>1.418086681</td><td>683.033</td><td>625.244</td><td>617.868</td><td>-1.186699187</td><td>1.186699187</td><td>1243.112</td><td>565.015</td><td>564.095</td><td>-0.162960208</td><td>0.162960208</td><td>1129.11</td></tr><tr><td>8</td><td>341.114</td><td>348.948</td><td>2.27052062</td><td>2.27052062</td><td>690.062</td><td>646.376</td><td>661.351</td><td>2.290233359</td><td>2.290233359</td><td>1307.727</td><td>571.2</td><td>570.03</td><td>-0.205041928</td><td>0.205041928</td><td>1141.23</td></tr><tr><td>9</td><td>338.938</td><td>351.533</td><td>3.648234321</td><td>3.648234321</td><td>690.471</td><td>647.114</td><td>672.799</td><td>3.89192318</td><td>3.89192318</td><td>1319.913</td><td>606.09</td><td>599.94</td><td>-1.019875127</td><td>1.019875127</td><td>1206.03</td></tr><tr><td>10</td><td>356.018</td><td>345.892</td><td>-2.885270191</td><td>2.885270191</td><td>701.91</td><td>711.194</td><td>672.248</td><td>-5.630304704</td><td>5.630304704</td><td>1383.442</td><td>604.105</td><td>604.245</td><td>0.023172094</td><td>0.023172094</td><td>1208.35</td></tr><tr><td>11</td><td>355.253</td><td>349.831</td><td>-1.537972781</td><td>1.537972781</td><td>705.084</td><td>661.105</td><td>652.311</td><td>-1.339103529</td><td>1.339103529</td><td>1313.416</td><td>607.005</td><td>605.865</td><td>-0.187983873</td><td>0.187983873</td><td>1212.87</td></tr><tr><td>12</td><td>349.592</td><td>355.981</td><td>1.811010342</td><td>1.811010342</td><td>705.573</td><td>679.209</td><td>690.449</td><td>1.641285635</td><td>1.641285635</td><td>1369.658</td><td>577.37</td><td>569.95</td><td>-1.293449081</td><td>1.293449081</td><td>1147.32</td></tr><tr><td>13</td><td>350.149</td><td>356.199</td><td>1.713036634</td><td>1.713036634</td><td>706.348</td><td>641.159</td><td>633.296</td><td>-1.233939213</td><td>1.233939213</td><td>1274.455</td><td>543.225</td><td>552.945</td><td>1.773447549</td><td>1.773447549</td><td>1096.17</td></tr><tr><td>14</td><td>351.302</td><td>355.343</td><td>1.143714312</td><td>1.143714312</td><td>706.645</td><td>654.199</td><td>663.226</td><td>1.370400592</td><td>1.370400592</td><td>1317.425</td><td>583.48</td><td>593.8</td><td>1.753193803</td><td>1.753193803</td><td>1177.28</td></tr><tr><td>15</td><td>340.533</td><td>368.842</td><td>7.98139207</td><td>7.98139207</td><td>709.375</td><td>653.773</td><td>684.712</td><td>4.62298793</td><td>4.62298793</td><td>1338.485</td><td>597.205</td><td>596.355</td><td>-0.142431047</td><td>0.142431047</td><td>1193.56</td></tr><tr><td>16</td><td>349.823</td><td>362.114</td><td>3.452833607</td><td>3.452833607</td><td>711.937</td><td>659.67</td><td>693.736</td><td>5.034113932</td><td>5.034113932</td><td>1353.406</td><td>577.4</td><td>577.94</td><td>0.093478976</td><td>0.093478976</td><td>1155.34</td></tr><tr><td>17</td><td>354.665</td><td>357.462</td><td>0.785534041</td><td>0.785534041</td><td>712.127</td><td>666.839</td><td>696.536</td><td>4.356394976</td><td>4.356394976</td><td>1363.375</td><td>581.645</td><td>589.305</td><td>1.308339383</td><td>1.308339383</td><td>1170.95</td></tr><tr><td>18</td><td>351.403</td><td>370.825</td><td>5.378356973</td><td>5.378356973</td><td>722.228</td><td>674.213</td><td>721.762</td><td>6.812299647</td><td>6.812299647</td><td>1395.975</td><td>621.545</td><td>622.515</td><td>0.155941032</td><td>0.155941032</td><td>1244.06</td></tr><tr><td>19</td><td>354.783</td><td>370.572</td><td>4.353454515</td><td>4.353454515</td><td>725.355</td><td>681.256</td><td>706.77</td><td>3.676300012</td><td>3.676300012</td><td>1388.026</td><td>630.97</td><td>629.17</td><td>-0.285682543</td><td>0.285682543</td><td>1260.14</td></tr><tr><td>20</td><td>361.67</td><td>365.211</td><td>0.974299782</td><td>0.974299782</td><td>726.881</td><td>732.577</td><td>729.446</td><td>-0.428310635</td><td>0.428310635</td><td>1462.023</td><td>623.9</td><td>623.32</td><td>-0.093006847</td><td>0.093006847</td><td>1247.22</td></tr><tr><td>21</td><td>359.789</td><td>367.283</td><td>2.061418952</td><td>2.061418952</td><td>727.072</td><td>727.773</td><td>747.09</td><td>2.61949754</td><td>2.61949754</td><td>1474.863</td><td>652.935</td><td>655.445</td><td>0.383680582</td><td>0.383680582</td><td>1308.38</td></tr><tr><td>22</td><td>367.282</td><td>363.245</td><td>-1.105229512</td><td>1.105229512</td><td>730.527</td><td>684.227</td><td>675.753</td><td>-1.246194797</td><td>1.246194797</td><td>1359.98</td><td>593.675</td><td>586.745</td><td>-1.17415835</td><td>1.17415835</td><td>1180.42</td></tr><tr><td>23</td><td>362.949</td><td>369.581</td><td>1.810710824</td><td>1.810710824</td><td>732.53</td><td>721.678</td><td>725.873</td><td>0.579599613</td><td>0.579599613</td><td>1447.551</td><td>640.38</td><td>642.11</td><td>0.269787679</td><td>0.269787679</td><td>1282.49</td></tr><tr><td>24</td><td>370.767</td><td>363.709</td><td>-1.921914399</td><td>1.921914399</td><td>734.476</td><td>697.38</td><td>681.585</td><td>-2.290848571</td><td>2.290848571</td><td>1378.965</td><td>613.875</td><td>618.425</td><td>0.738456545</td><td>0.738456545</td><td>1232.3</td></tr><tr><td>25</td><td>366.996</td><td>367.815</td><td>0.222914464</td><td>0.222914464</td><td>734.811</td><td>727.116</td><td>717.779</td><td>-1.292412251</td><td>1.292412251</td><td>1444.895</td><td>646.105</td><td>650.845</td><td>0.73094568</td><td>0.73094568</td><td>1296.95</td></tr><tr><td>26</td><td>361.214</td><td>374.617</td><td>3.642956059</td><td>3.642956059</td><td>735.831</td><td>689.585</td><td>725.34</td><td>5.053978126</td><td>5.053978126</td><td>1414.925</td><td>601.765</td><td>610.725</td><td>1.477950334</td><td>1.477950334</td><td>1212.49</td></tr><tr><td>27</td><td>366.675</td><td>369.879</td><td>0.869997312</td><td>0.869997312</td><td>736.554</td><td>726.236</td><td>697.888</td><td>-3.981114004</td><td>3.981114004</td><td>1424.124</td><td>616.76</td><td>620.09</td><td>0.538464648</td><td>0.538464648</td><td>1236.85</td></tr><tr><td>28</td><td>366.433</td><td>370.43</td><td>1.084869236</td><td>1.084869236</td><td>736.863</td><td>700.504</td><td>720.746</td><td>2.848478452</td><td>2.848478452</td><td>1421.25</td><td>613.735</td><td>614.635</td><td>0.146535653</td><td>0.146535653</td><td>1228.37</td></tr><tr><td>29</td><td>368.335</td><td>369.785</td><td>0.392890045</td><td>0.392890045</td><td>738.12</td><td>724.54</td><td>711.332</td><td>-1.839718304</td><td>1.839718304</td><td>1435.872</td><td>626.79</td><td>631.45</td><td>0.740717192</td><td>0.740717192</td><td>1258.24</td></tr><tr><td>30</td><td>370.554</td><td>368.921</td><td>-0.441664695</td><td>0.441664695</td><td>739.475</td><td>721.254</td><td>700.736</td><td>-2.885814949</td><td>2.885814949</td><td>1421.99</td><td>609.995</td><td>605.975</td><td>-0.661200523</td><td>0.661200523</td><td>1215.97</td></tr><tr><td>31</td><td>366.005</td><td>375.346</td><td>2.519993903</td><td>2.519993903</td><td>741.351</td><td>693.289</td><td>694.231</td><td>0.135781827</td><td>0.135781827</td><td>1387.52</td><td>622.715</td><td>620.845</td><td>-0.300749461</td><td>0.300749461</td><td>1243.56</td></tr><tr><td>32</td><td>370.38</td><td>371.246</td><td>0.233540895</td><td>0.233540895</td><td>741.626</td><td>682.406</td><td>672.594</td><td>-1.448265683</td><td>1.448265683</td><td>1355</td><td>596.255</td><td>596.645</td><td>0.065386872</td><td>0.065386872</td><td>1192.9</td></tr><tr><td>33</td><td>367.066</td><td>375.048</td><td>2.151151979</td><td>2.151151979</td><td>742.114</td><td>718.052</td><td>738.275</td><td>2.777260876</td><td>2.777260876</td><td>1456.327</td><td>637.685</td><td>641.435</td><td>0.586340609</td><td>0.586340609</td><td>1279.12</td></tr><tr><td>34</td><td>365.442</td><td>377.184</td><td>3.162291652</td><td>3.162291652</td><td>742.626</td><td>687.461</td><td>739.741</td><td>7.326222917</td><td>7.326222917</td><td>1427.202</td><td>647.37</td><td>650.04</td><td>0.411589243</td><td>0.411589243</td><td>1297.41</td></tr><tr><td>35</td><td>379.989</td><td>363.889</td><td>-4.328666798</td><td>4.328666798</td><td>743.878</td><td>765.39</td><td>722.748</td><td>-5.730920116</td><td>5.730920116</td><td>1488.138</td><td>625.04</td><td>623.48</td><td>-0.249895877</td><td>0.249895877</td><td>1248.52</td></tr><tr><td>36</td><td>370.41</td><td>374.561</td><td>1.114405796</td><td>1.114405796</td><td>744.971</td><td>732.059</td><td>751.516</td><td>2.62298839</td><td>2.62298839</td><td>1483.575</td><td>655.35</td><td>656.83</td><td>0.225578808</td><td>0.225578808</td><td>1312.18</td></tr><tr><td>37</td><td>371.397</td><td>376.749</td><td>1.430736781</td><td>1.430736781</td><td>748.146</td><td>725.546</td><td>719.113</td><td>-0.89059079</td><td>0.89059079</td><td>1444.659</td><td>636.495</td><td>635.335</td><td>-0.182414316</td><td>0.182414316</td><td>1271.83</td></tr><tr><td>38</td><td>381.539</td><td>368.736</td><td>-3.412881943</td><td>3.412881943</td><td>750.275</td><td>701.38</td><td>707.111</td><td>0.813778718</td><td>0.813778718</td><td>1408.491</td><td>595.08</td><td>602.89</td><td>1.303872384</td><td>1.303872384</td><td>1197.97</td></tr><tr><td>39</td><td>381.545</td><td>369.124</td><td>-3.309314758</td><td>3.309314758</td><td>750.669</td><td>760.793</td><td>729.029</td><td>-4.264133568</td><td>4.264133568</td><td>1489.822</td><td>654.135</td><td>651.405</td><td>-0.418217749</td><td>0.418217749</td><td>1305.54</td></tr><tr><td>40</td><td>368.255</td><td>383.249</td><td>3.990397922</td><td>3.990397922</td><td>751.504</td><td>727.685</td><td>748.902</td><td>2.873789353</td><td>2.873789353</td><td>1476.587</td><td>667.275</td><td>664.415</td><td>-0.429529395</td><td>0.429529395</td><td>1331.69</td></tr><tr><td>41</td><td>374.712</td><td>377.999</td><td>0.873376369</td><td>0.873376369</td><td>752.711</td><td>721.521</td><td>710.863</td><td>-1.488148429</td><td>1.488148429</td><td>1432.384</td><td>602.72</td><td>600.42</td><td>-0.382332896</td><td>0.382332896</td><td>1203.14</td></tr><tr><td>42</td><td>378.42</td><td>376.58</td><td>-0.487417219</td><td>0.487417219</td><td>755</td><td>781.099</td><td>775.212</td><td>-0.756532595</td><td>0.756532595</td><td>1556.311</td><td>686.63</td><td>683.01</td><td>-0.528606057</td><td>0.528606057</td><td>1369.64</td></tr><tr><td>43</td><td>382.183</td><td>375.159</td><td>-1.854908351</td><td>1.854908351</td><td>757.342</td><td>742.978</td><td>702.639</td><td>-5.580869622</td><td>5.580869622</td><td>1445.617</td><td>578.615</td><td>584.165</td><td>0.954608782</td><td>0.954608782</td><td>1162.78</td></tr><tr><td>44</td><td>379.698</td><td>378.753</td><td>-0.249192103</td><td>0.249192103</td><td>758.451</td><td>774.754</td><td>753.738</td><td>-2.749899901</td><td>2.749899901</td><td>1528.492</td><td>683.3</td><td>685.69</td><td>0.349162521</td><td>0.349162521</td><td>1368.99</td></tr><tr><td>45</td><td>378.771</td><td>382.669</td><td>1.023849548</td><td>1.023849548</td><td>761.44</td><td>718.67</td><td>736.919</td><td>2.50743857</td><td>2.50743857</td><td>1455.589</td><td>606.965</td><td>610.165</td><td>0.525827151</td><td>0.525827151</td><td>1217.13</td></tr><tr><td>46</td><td>381.842</td><td>382.718</td><td>0.229151407</td><td>0.229151407</td><td>764.56</td><td>747.793</td><td>758.843</td><td>1.466844015</td><td>1.466844015</td><td>1506.636</td><td>669.5</td><td>674.92</td><td>0.806295652</td><td>0.806295652</td><td>1344.42</td></tr></tbody></table>
<table><tr><td>47</td><td>372.624</td><td>394.957</td><td>5.819060138</td><td>5.819060138</td><td>767.581</td><td>729.632</td><td>799.818</td><td>9.177939782</td><td>9.177939782</td><td>1529.45</td><td>663.005</td><td>671.465</td><td>1.267919099</td><td>1.267919099</td><td>1334.47</td></tr><tr><td>48</td><td>375.658</td><td>392.005</td><td>4.258900064</td><td>4.258900064</td><td>767.663</td><td>722.655</td><td>762.381</td><td>5.350173329</td><td>5.350173329</td><td>1485.036</td><td>657.93</td><td>664.39</td><td>0.977070603</td><td>0.977070603</td><td>1322.32</td></tr><tr><td>49</td><td>383.243</td><td>385.074</td><td>0.476626184</td><td>0.476626184</td><td>768.317</td><td>736.875</td><td>750.323</td><td>1.808501625</td><td>1.808501625</td><td>1487.198</td><td>670.49</td><td>673.28</td><td>0.415249633</td><td>0.415249633</td><td>1343.77</td></tr><tr><td>50</td><td>384.724</td><td>387.774</td><td>0.789646057</td><td>0.789646057</td><td>772.498</td><td>742.694</td><td>735.365</td><td>-0.991706014</td><td>0.991706014</td><td>1478.059</td><td>657.325</td><td>655.825</td><td>-0.228458287</td><td>0.228458287</td><td>1313.15</td></tr><tr><td>51</td><td>385.42</td><td>390.93</td><td>1.419462871</td><td>1.419462871</td><td>776.35</td><td>735.831</td><td>714.254</td><td>-2.975963478</td><td>2.975963478</td><td>1450.085</td><td>625.2</td><td>629.37</td><td>0.664769602</td><td>0.664769602</td><td>1254.57</td></tr><tr><td>52</td><td>392.674</td><td>387.36</td><td>-1.362504711</td><td>1.362504711</td><td>780.034</td><td>757.951</td><td>767.243</td><td>1.218467946</td><td>1.218467946</td><td>1525.194</td><td>701.53</td><td>711.46</td><td>1.405530117</td><td>1.405530117</td><td>1412.99</td></tr><tr><td>53</td><td>391.836</td><td>390.428</td><td>-0.359980774</td><td>0.359980774</td><td>782.264</td><td>823.198</td><td>822.917</td><td>-0.034140993</td><td>0.034140993</td><td>1646.115</td><td>704.15</td><td>700.38</td><td>-0.536834386</td><td>0.536834386</td><td>1404.53</td></tr><tr><td>54</td><td>393.449</td><td>390.132</td><td>-0.846625939</td><td>0.846625939</td><td>783.581</td><td>787.307</td><td>766.058</td><td>-2.735866973</td><td>2.735866973</td><td>1553.365</td><td>660.355</td><td>664.285</td><td>0.593368764</td><td>0.593368764</td><td>1324.64</td></tr><tr><td>55</td><td>384.969</td><td>401.456</td><td>4.192898242</td><td>4.192898242</td><td>786.425</td><td>759.514</td><td>818.546</td><td>7.481591321</td><td>7.481591321</td><td>1578.06</td><td>688.92</td><td>684.45</td><td>-0.650953494</td><td>0.650953494</td><td>1373.37</td></tr><tr><td>56</td><td>399.162</td><td>388.373</td><td>-2.739941717</td><td>2.739941717</td><td>787.535</td><td>742.314</td><td>715.855</td><td>-3.629071802</td><td>3.629071802</td><td>1458.169</td><td>647.395</td><td>647.525</td><td>0.02007846</td><td>0.02007846</td><td>1294.92</td></tr><tr><td>57</td><td>390.164</td><td>397.941</td><td>1.973594889</td><td>1.973594889</td><td>788.105</td><td>737.973</td><td>775.236</td><td>4.925030184</td><td>4.925030184</td><td>1513.209</td><td>654.535</td><td>650.115</td><td>-0.677576361</td><td>0.677576361</td><td>1304.65</td></tr><tr><td>58</td><td>388.033</td><td>405.019</td><td>4.283703969</td><td>4.283703969</td><td>793.052</td><td>765.977</td><td>820.197</td><td>6.836576567</td><td>6.836576567</td><td>1586.174</td><td>666.69</td><td>670.63</td><td>0.589238178</td><td>0.589238178</td><td>1337.32</td></tr><tr><td>59</td><td>386.201</td><td>407.083</td><td>5.264697132</td><td>5.264697132</td><td>793.284</td><td>756.531</td><td>798.923</td><td>5.450755856</td><td>5.450755856</td><td>1555.454</td><td>640.95</td><td>648.29</td><td>1.138655332</td><td>1.138655332</td><td>1289.24</td></tr><tr><td>60</td><td>388.027</td><td>406.847</td><td>4.735341702</td><td>4.735341702</td><td>794.874</td><td>817.66</td><td>852.857</td><td>4.213905037</td><td>4.213905037</td><td>1670.517</td><td>724.85</td><td>730.99</td><td>0.843499286</td><td>0.843499286</td><td>1455.84</td></tr><tr><td>61</td><td>396.144</td><td>399.093</td><td>0.741665692</td><td>0.741665692</td><td>795.237</td><td>729.183</td><td>788.615</td><td>7.831345146</td><td>7.831345146</td><td>1517.798</td><td>712.475</td><td>712.695</td><td>0.03087351</td><td>0.03087351</td><td>1425.17</td></tr><tr><td>62</td><td>398.488</td><td>400.029</td><td>0.385965484</td><td>0.385965484</td><td>798.517</td><td>749.719</td><td>745.12</td><td>-0.615317101</td><td>0.615317101</td><td>1494.839</td><td>673.275</td><td>672.885</td><td>-0.057942592</td><td>0.057942592</td><td>1346.16</td></tr><tr><td>63</td><td>404.643</td><td>395.272</td><td>-2.342998944</td><td>2.342998944</td><td>799.915</td><td>758.946</td><td>749.24</td><td>-1.28710915</td><td>1.28710915</td><td>1508.186</td><td>700.305</td><td>697.795</td><td>-0.359058723</td><td>0.359058723</td><td>1398.1</td></tr><tr><td>64</td><td>399.885</td><td>402</td><td>0.527507061</td><td>0.527507061</td><td>801.885</td><td>684.882</td><td>712.51</td><td>3.954223296</td><td>3.954223296</td><td>1397.392</td><td>572.305</td><td>570.675</td><td>-0.285219339</td><td>0.285219339</td><td>1142.98</td></tr><tr><td>65</td><td>402.29</td><td>415.544</td><td>3.241244556</td><td>3.241244556</td><td>817.834</td><td>797.412</td><td>823.33</td><td>3.198288191</td><td>3.198288191</td><td>1620.742</td><td>696.62</td><td>697.8</td><td>0.169245995</td><td>0.169245995</td><td>1394.42</td></tr><tr><td>66</td><td>415.2</td><td>404.54</td><td>-2.600824652</td><td>2.600824652</td><td>819.74</td><td>782.808</td><td>779.93</td><td>-0.368327896</td><td>0.368327896</td><td>1562.738</td><td>678.31</td><td>671.58</td><td>-0.997118284</td><td>0.997118284</td><td>1349.89</td></tr><tr><td>67</td><td>416.18</td><td>404.096</td><td>-2.946325383</td><td>2.946325383</td><td>820.276</td><td>791.982</td><td>773.414</td><td>-2.372307071</td><td>2.372307071</td><td>1565.396</td><td>650.395</td><td>646.825</td><td>-0.550407795</td><td>0.550407795</td><td>1297.22</td></tr><tr><td>68</td><td>410.419</td><td>411.263</td><td>0.205432272</td><td>0.205432272</td><td>821.682</td><td>750.05</td><td>740.647</td><td>-1.261557513</td><td>1.261557513</td><td>1490.697</td><td>640.805</td><td>647.745</td><td>1.077179776</td><td>1.077179776</td><td>1288.55</td></tr><tr><td>69</td><td>407.614</td><td>414.648</td><td>1.710890203</td><td>1.710890203</td><td>822.262</td><td>825.236</td><td>843.932</td><td>2.240157971</td><td>2.240157971</td><td>1669.168</td><td>710.52</td><td>709</td><td>-0.214156898</td><td>0.214156898</td><td>1419.52</td></tr><tr><td>70</td><td>397.682</td><td>429.203</td><td>7.624034781</td><td>7.624034781</td><td>826.885</td><td>854.246</td><td>858.88</td><td>0.540999319</td><td>0.540999319</td><td>1713.126</td><td>759.33</td><td>749.94</td><td>-1.244310163</td><td>1.244310163</td><td>1509.27</td></tr><tr><td>71</td><td>397.682</td><td>429.203</td><td>7.624034781</td><td>7.624034781</td><td>826.885</td><td>794.814</td><td>879.728</td><td>10.14175816</td><td>10.14175816</td><td>1674.542</td><td>714.725</td><td>729.205</td><td>2.005637392</td><td>2.005637392</td><td>1443.93</td></tr><tr><td>72</td><td>408.204</td><td>425.049</td><td>4.043189763</td><td>4.043189763</td><td>833.253</td><td>800.484</td><td>872.318</td><td>8.588464146</td><td>8.588464146</td><td>1672.802</td><td>731.69</td><td>733.12</td><td>0.195247165</td><td>0.195247165</td><td>1464.81</td></tr><tr><td>73</td><td>429.44</td><td>411.885</td><td>-4.173179211</td><td>4.173179211</td><td>841.325</td><td>896.423</td><td>832.852</td><td>-7.352329734</td><td>7.352329734</td><td>1729.275</td><td>762.015</td><td>766.535</td><td>0.59141016</td><td>0.59141016</td><td>1528.55</td></tr><tr><td>74</td><td>431.931</td><td>434.494</td><td>0.591626511</td><td>0.591626511</td><td>866.425</td><td>859.046</td><td>848.473</td><td>-1.238404961</td><td>1.238404961</td><td>1707.519</td><td>686.915</td><td>692.225</td><td>0.770045101</td><td>0.770045101</td><td>1379.14</td></tr><tr><td>75</td><td>431.575</td><td>442.847</td><td>2.578160202</td><td>2.578160202</td><td>874.422</td><td>852.51</td><td>865.086</td><td>1.464372297</td><td>1.464372297</td><td>1717.596</td><td>730.06</td><td>730.74</td><td>0.093099671</td><td>0.093099671</td><td>1460.8</td></tr></table>
<table><thead><tr><td>VARIABLE</td><td>MEANING</td></tr></thead><tbody><tr><td>LEFT_ENDoku</td><td>surface of the left side of the endocast (in cm2)</td></tr><tr><td>RIGHT_END_SURF</td><td>surface of the right side of the endocast (in cm2)</td></tr><tr><td>DA End_SURF</td><td>directional asymmetry index of the endocast surface</td></tr><tr><td>AA End_SURF</td><td>absolute asymmetry index of the endocast surface</td></tr><tr><td>ALL_END_SURF</td><td>surface of the left and right side of the endocast (in cm2)</td></tr><tr><td>LEFT_END_VOL</td><td>volume of the left side of the endocast (in cm3)</td></tr><tr><td>RIGHT_END_VOL</td><td>volume of the right side of the endocast (in cm3)</td></tr><tr><td>DA_VOL_END</td><td>directional asymmetry index of the endocast volume</td></tr><tr><td>AA_VOL_END</td><td>absolute asymmetry index of the endocast volume</td></tr><tr><td>ALL_END_VOL</td><td>volume of the left and right side of the endocast (in cm3)</td></tr><tr><td>LEFT_BRAIN</td><td>volume of the left side of the brain (in cm3)</td></tr><tr><td>RIGHT_BRAIN</td><td>volume of the right side of the brain (in cm3)</td></tr><tr><td>DA_VOL_BR</td><td>directional asymmetry index of the brain volume</td></tr><tr><td>AA_VOL_BR</td><td>absolute asymmetry index of the brain volume</td></tr><tr><td>ALL_BRAIN</td><td>volume of the left and right side of the brain (in cm3)</td></tr></tbody></table>
June, 2025

Editorial Board Member

Journal of Anatomy

**Manuscript ID:** JANAT-2025-0144

**Manuscript title:** Brain vs endocast: does size differ? A unique experiment based on a cohort of 75 volunteers

**Authors:** Anna Maria Kubicka, Sylvain Prima, Andréa Filippo, Victor Giolland, Éric Bardinet, Mélanie Didier, Mathieu Santin, Antoine Balzeau

Dear Dr Philip Cox,

Thank you for your message. Below, we present answers to all the comments of the first and second reviewers. All changes made according to the reviewers' suggestions are highlighted in blue in the manuscript.

Following changes:

**Reviewer 1:** Thank you for the opportunity to review the manuscript entitled "Brain vs endocast: does size differ? A unique experiment based on a cohort of 75 volunteers."

The concept underlying this study is innovative and easily captured my interest, especially as I frequently work with endocasts, particularly in relation to brain lateralization throughout human evolution. The primary aim of the manuscript is to assess whether endocasts serve as reliable proxies for brain size and asymmetry. From what I can observe, the methodology adopted is straightforward and rigorous, although somewhat limited in scope.

One of the most compelling findings is that endocast volume and surface area asymmetries are not dependable indicators of true cerebral asymmetry. This is a valuable insight for researchers investigating the evolution of endocast morphology. I was reassured to see that the limitations identified concern volume and surface area measurements rather than shape analysis. However, it would have been relevant (and informative) to see how these limitations accrue to shape data, as they come with Geometric Morphometrics (GM), since GM relies on the use of landmarks and semilandmarks, grounded in both anatomical and geometrical homology. Its primary focus lies in the relative positioning among landmarks, rather than the extent of surface features. This approach aligns well with the authors' statement at lines 269-271:

"To correctly estimate cerebral asymmetries from endocast asymmetries, it may be preferable to focus on specific areas of one hemisphere versus the other."

This recommendation reflects the core principle of GM, which allows for targeted, region-specific asymmetry assessment. It is clear, however, that a proper application of GM, particularly in the context of asymmetry studies, requires a thorough understanding of the anatomical features that can be recognized on the surface of an endocast as compared to those of the brain itself, as the authors have also rightly emphasized in the manuscript.

**Action:** Thank you very much for this comment. We obviously agree with the substance. On the one hand, it is a deliberate choice to limit oneself to the global comparison between the volume of the brain and the endocast. This is a fundamental aspect that has never been addressed. On the other hand, the analysis of the details of the correspondence between the shapes of the two objects is obviously a vast subject of interest. In another work for
which we are finalizing an article (titled: The Rosetta Stone of Paleoneurology: A detailed study of the link between the brain and the endocast on 75 volunteers), we have chosen to conduct a detailed analysis of the link between cerebral sulci and visible marks on the endocast. The results show that this is a very complex subject. Thus, proposing a comparison by GM of brains and endocasts would have involved either having to simplify (fill and smooth the sulci) the models of the brains, or considering the depressions on the brains and endocasts as homologous, whereas we know that it is more complex. We have therefore chosen to focus on what is covered in this article and leave the rest for later within our PaleoBRAIN project. It would have been too early to use GM in our analysis, but we have this in the plans.

**Reviewer 1:** As side note, I am not entirely convinced by the statement (line 63): "The brain's dimensions reflect its functional importance, especially in hominins. This is why reconstruction of brain volume using endocast parameters could expand what is currently known about fossil hominins."

While brain, and consequently endocast, size can provide useful insights, it represents just a single aspect to consider when examining human brain evolution. It is well established that brain size increased significantly across the hominin lineage, though this progression was not consistent over time. The case of *Homo floresiensis*, for instance, demonstrates that reduced brain volume does not necessarily equate to diminished cognitive function. Moreover, *Homo sapiens* possesses a smaller brain than *Homo neanderthalensis*, which suggests that brain size alone is not enough to explain the emergence of modern human cognitive traits. Instead, the uniqueness of the human brain might lie in other features, such as substantial structural reorganization, particularly in cortical association areas related to higher cognitive processes (Ponce de León et al., 2024), and the development of an integrated, juvenilized brain (Sansalone et al., 2023).

**Action:** Thank you for this comment. We agree and have modified this section.

**Reviewer 1:** As a general recommendation, I would suggest expanding the reference section to include a broader range of studies, particularly those focusing on specific brain regions associated with asymmetry, which are often more informative than generalized approaches. I also note that the current reference list mostly includes works authored or co-authored by the present authors. Additionally, if possible, I would recommend including an image that clearly shows the hemispheric division and segmentation not only for the endocast but also for the brain.

Ponce de León, M. S., Bienvenu, T., Marom, A., Engel, S., Tafforeau, P., Alatorre Warren, J. L., ... & Zollikofer, C. P. (2021). The primitive brain of early *Homo*. *Science*, *372*(6538), 165-171.
Sansalone, G., Profico, A., Wroe, S., Allen, K., Ledogar, J., Ledogar, S., ... & Raia, P. (2023).
*Homo sapiens* and *Neanderthals* share high cerebral cortex integration into adulthood.
*Nature Ecology & Evolution*, *7*(1), 42-50.

**Action:** Thank you for this suggestion. In our first version, we had thought to stay focused on the brain/endocast volume link. But in fact, it is important to better contextualize this and to detail recent work in paleoanthropology because it sheds light on our approach. So this is
done in this new version. The figure 1 has been amended, it also shows segmentation of the brain.

**Reviewer 2:** This study used a sophisticated automated segmentation workflow to generate endocast and brain anatomy data from 75 human volunteers, asking whether the bony endocast and the actual brain correspond in living humans. This is an important ground-truthing step because even right after death, mammalian brains expand and then shrink (depending on treatment) so that it has been nearly impossible to determine how well the endocast of a fossil mammal (including humans) represents the actual brain dimensions without these previously unobtainable live data.

I really like this paper and jealous of the automated pipeline! I definitely would like to see it published. It is rare to have such clear data and this will make it widely cited.

**Action:** Thank you very much for this comment, we appreciate all suggestions on how to improve the manuscript. Please see below our answers.

**Reviewer 2:** I have one major issue – neither the data nor the code to do the analyses is available, and therefore the research cannot be replicated. There should be a supplement of the raw data at least. I understand that there might be issues related to human ethics, but surely it is possible to publish de-identified data?

**Action:** The raw data and R script have been prepared and submitted as a supplement. Moreover, we also uploaded 3D models of endocasts and brains to an external repository that will be available to everyone. The link to the repository has been added to the text and will be activated after the manuscript is accepted for publication. However, we would like to share a private link with both reviewers, which already works ([https://data.indores.fr:443/privateurl.xhtml?token=4a028ab3-1d4e-4f64-9ea5-dc6394f96aed](https://data.indores.fr:443/privateurl.xhtml?token=4a028ab3-1d4e-4f64-9ea5-dc6394f96aed)). This link allows downloading the data.

**Reviewer 2:** A less important issue is the relatively narrow focus of the manuscript. It is lovely and short, but the broader context is not well developed. There are a lot of influential studies in palaeoanthropology and beyond that are using brains and endocasts, and have commented on their uses and limitations. So I believe that a much broader discussion of the relevance to the discipline and implications to the discipline would make the paper much more impactful.

**Action:** Thank you for your comment. We have amended the introduction accordingly, including a new paragraph to address your comment and another from the first reviewer.

**Reviewer 2:** The introduction is a little jumbled and would benefit from streamlining. I would put the paragraph starting in line 63 first, and give a better connection to the first two paragraphs so it is more obvious what the problem is, what has been done and what the shortcomings are (not just a summary of what has been done – this is not informative enough), and why a better approach is necessary. I would also keep in mind that this paper is relevant not just for anthropology, but mammals in general, and this is a brilliant first step. I would expand a bit more on what kind of information can be taken from endocasts. There is a small paragraph on this starting in line 63, but the aspects investigated here (size,
asymmetry, surface area).

**Action:** The introduction has been improved.

**Reviewer 2:** The methods are sophisticated and efficient. Just check your references, for example the Morphologist toolbox is not from Labra et al. 2024 – they only used it and the authors should be Perrot, Cointepas, Fischer.

**Action:** Thank you, the citation has been corrected.

**Reviewer 2:** What software and (if relevant) packages were used for the analyses? Make sure you cite them all. The figures used suggest you used R code, so you should ideally publish the code to replicate the analyses.

**Action:** The packages have been added to the text.

**Reviewer 2:** Homogeneity of Variance is conducted to assess differences in variance between groups to be compared, and this only seems relevant to the side comparisons. So either place there or explain what groups were compared. Cube root of volume vs. square root of surface area is good (although instead you could also leave the values unchanged and test for a predicted slope that reflects the different scaling of surface area vs volume, which we did in our bird paper cited below). But perhaps add an explanation of why the transformation was done.

**Action:** Homogeneity of variance was calculated as we checked whether differences between sides were significant using a paired sample t-test. This is a typical approach in studies on asymmetry. The fragment has been changed. We decided to include cube root and square root variables, as in our opinion, this is the correct way to analyse the relationship between volume and surface.

**Reviewer 2:** Please repeat all the abbreviations once again to help with readability.

**Action:** The abbreviations have been explained in the results section once again.

**Reviewer 2:** The figures should be improved by changing the font sizes in R, relatively easily changed with the help of StackOverflow (or ChatGPT, if permissible!). If you want the polygon to be behind the data points in the last figure, just add another line to plot the green points again – not elegant, but it works !

**Action:** All the figures have been improved.

**Reviewer 2:** The discussion is good a discussing al the results in order and articulating what they basically mean, but I find it a bit thin on connecting it to previous research. Like the introduction, it would benefit from a little more literature research and interpretation.

There is a lot of information that was either already given in the introduction or methods, or should have been in the introduction (e.g. the lateralisation discussion). There does not need to be a separate introduction to each part of the study, particularly not with new literature cited. I would instead recommend focusing more on how these results add to previous studies and how they can help us understand the efficiency and limits of using endocasts.

For example, do the results validate some important previous insights? In which situation
would you say that the approach is not detailed enough? The latter consideration of limitations should generally be developed a bit more.

**Action:** The discussion has been improved.

**Reviewer 2:** As a potential expansion with the literature: in paragraph 2, it might be worth contrasting your results with the other studies on mammals and non-mammals mentioned in the introduction. For example, we found much tighter relationships in bird brains (see Keirnan et al. paper link below; our Rsquareds were above 0.95 for endocast surface area vs. brain volume!). This is not the core purpose of the paper but is a nice additional informative fact on how humans, and mammals in general, just have a much more loosely-housed brain compared to the birds where it is tightly squeezed into the cranial cavity.

**Action:** We have added a few new citations and reworded the second paragraph of the introduction.

**Reviewer 2:** It would also be useful to give some more information on why the brain might not match the endocast by listing the main anatomical features that prevent a good match (meninges, sinuses etc.), either here or in the intro.

**Action:** Thank you for this comment, we have added this fragment to the introduction. We also prepared an article which investigated this topic: based on the same material, we assessed sulci on endocasts and checked their presence on the brain using a tailored MRI imaging methodology. The article titled: *The "Rosetta Stone" of Paleoneurology: A detailed study of the link between the brain and the endocast on 75 volunteers*" will be submitted soon.

**Reviewer 2:** The first few paragraph of the discussion is not really needed, it is a bit jumbled and could go into the introduction. It would be fine to start with the 2nd paragraph or to have a short summary of the results and their implications as the first few sentences.

**Action:** Thank you for this comment. The first paragraph has been removed from the discussion. Also, some minor changes to the discussion have been made.

**Reviewer 2:** Line 54: A large-scale study on birds, probably the most diverse sample of vertebrates yet was just published, and includes correlations between surface area and endocast volume also mentioned here (admittedly from my lab, but I hope signing my name makes this ok!): https://royalsocietypublishing.org/doi/abs/10.1098/rsbl.2024.0596,

**Action:** Thank you for this suggestion. More articles on non-human animals have been added to the discussion and introduction (for example, study of Clement et al., 2021; Keirnan et al., 2025, Morhardt et al., 2017).

**Reviewer 2:** L. 61, I suggest first developing the problem fully and only mentioning what the intention of this study is towards the end. Otherwise it gets too confusing.

**Action:** The introduction has been partially reworded.

**Reviewer 2:** First sentence of intro: not just palaeoanthropological studies – this would be
underselling the importance of the paper.

**Action:** The word has been changed.

**Reviewer 2:** l. 237 – non-significant, not insignificant

**Action:** The word has been corrected here and throughout the manuscript.

**Reviewer 2:** Vera Weisbecker (Happy to have my name published and happy to help if needed)

**Action:** Thank you very much for this valuable review, we tried to improve the text according to all comments. We also added the name and surname of the second reviewer to the acknowledgements to appreciate the contribution to improving the text.