San Diego State University Neurodevelopment Discussion

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After reviewing the Read: Neocortical Morphometry in Huntington’s Disease: Indication of the Coexistence of Abnormal Neurodevelopmental and Neurodegenerative Processes item, prepare a thread that incorporates the following information:

Provide a brief overview of the main points and conclusions of the article. Only pertinent points should be stated – there is no need to include details of methods unless directly related to a main conclusion. Every result does not need to be included, if not pertinent to the thrust of your discussion.  However, there must be sufficient explanation to demonstrate an understanding of the paper. Simply summarizing the abstract is not acceptable.

What is the main novelty of this article?  Why are the results novel? What was previously known, and how do the results expand on previous knowledge? Why are these results an addition to the current field? Do they clarify something that was previously unknown? This section MUST incorporate outside research and not just recapitulate the authors’ discussion.

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NeuroImage: Clinical 26 (2020) 102211
Contents lists available at ScienceDirect
NeuroImage: Clinical
journal homepage: www.elsevier.com/locate/ynicl
Neocortical morphometry in Huntington’s disease: Indication of the
coexistence of abnormal neurodevelopmental and neurodegenerative
processes
T
Jean-Francois Mangina, Denis Rivièrea, Edouard Duchesnaya, Yann Cointepasa,
Véronique Gaurab, Christophe Vernyc, Philippe Damierd, Pierre Krystkowiake,
Anne-Catherine Bachoud-Lévif, Philippe Hantrayeg, Philippe Remyb, Gwenaëlle Douaudh,⁎
a
Université Paris-Saclay, CEA, CNRS, Baobab, Neurospin, Gif-sur-Yvette, France
Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d’Imagerie Biomédicale (I2BM), MIRCen,
France
c
Centre national de référence des maladies neurogénétiques, Service de neurologie, CHU, 49000 Angers, France, UMR CNRS 6214 – INSERM U1083, France
d
CHU Nantes, INSERM, CIC 0004, France
e
Neurologie, CHU Amiens-Picardie, France
f
AP-HP, Hôpital Henri Mondor, Centre de Référence-Maladie de Huntington, France
g
MIRCen, Institut d’Imagerie Biomédicale, Direction de la Recherche Fondamentale, Commissariat à l’Energie Atomique et aux Energies Alternatives, France
h
Functional Magnetic Resonance Imaging of the Brain (FMRIB) Centre, Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences,
University of Oxford, United Kingdom
b
ARTICLE INFO
ABSTRACT
Keywords:
Huntington’s disease
MRI
Cortical morphometry
Sylvian fissure
Neurodevelopment
Asymmetry
Huntington’s disease (HD) is an inherited, autosomal dominant disorder that is characteristically thought of as a
degenerative disorder. Despite cellular and molecular grounds suggesting HD could also impact normal development,
there has been scarce systems-level data obtained from in vivo human studies supporting this hypothesis. Sulcusspecific morphometry analysis may help disentangle the contribution of coexisting neurodegenerative and neurodevelopmental processes, but such an approach has never been used in HD. Here, we investigated cortical sulcal
depth, related to degenerative process, as well as cortical sulcal length, related to developmental process, in earlystage HD and age-matched healthy controls. This morphometric analysis revealed significant differences in the HD
participants compared with the healthy controls bilaterally in the central and intra-parietal sulcus, but also in the left
intermediate frontal sulcus and calcarine fissure. As the primary visual cortex is not connected to the striatum, the
latter result adds to the increasing in vivo evidence for primary cortical degeneration in HD. Those sulcal measures
that differed between HD and healthy populations were mainly atrophy-related, showing shallower sulci in HD.
Conversely, the sulcal morphometry also revealed a crucial difference in the imprint of the Sylvian fissure that could
not be related to loss of grey matter volume: an absence of asymmetry in the length of this fissure in HD. Strong
asymmetry in that cortical region is typically observed in healthy development. As the formation of the Sylvian
fissure appears early in utero, and marked asymmetry is specifically found in this area of the neocortex in newborns,
this novel finding likely indicates the foetal timing of a disease-specific, genetic interplay with neurodevelopment.
1. Introduction
gyrification allowing for the neocortical surface to increase and become
more complex in the last three months of development. These historical
observations prefigured a theory that poses the stability of these sulcal
“roots” across individuals, something which was further observed in vivo in
newborns (Regis et al., 2005; Dubois et al., 2008a; Dubois et al., 2008b).
Furthermore, it has been known since the beginning of the 19th century
that various developmental abnormalities leading to cortical sulci
Cortical sulcal analysis has for long solely relied on the empirical description of the cortical foldings investigated post mortem (Dareste, 1852;
Broca, 1878). At the antenatal stage, two fundamental steps, now thought
to be common to the higher order mammals, had been observed: first, the
operculisation of the insula at 6 months, followed by a progressive
⁎
Corresponding author.
E-mail address: gwenaelle.douaud@ndcn.ox.ac.uk (G. Douaud).
https://doi.org/10.1016/j.nicl.2020.102211
Received 6 June 2019; Received in revised form 5 February 2020; Accepted 12 February 2020
Available online 13 February 2020
2213-1582/ © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/BY/4.0/).
NeuroImage: Clinical 26 (2020) 102211
J.-F. Mangin, et al.
malformation are associated with sensorimotor, cognitive or behavioural
disorders (Bruce, 1889; Cameron, 1907). Investigating sulcal morphometry might thus capture abnormalities emerging during neocortical development, either chronologically coinciding to the formation of sulcal
roots, or later during cortical maturation process.
Huntington’s disease (HD) is a fatal autosomal dominant, neurodegenerative disorder resulting from an expansion of a CAG repeat within
the IT15 gene on chromosome 4. While the striatum is the most atrophied structure in HD, there is evidence that the cortical atrophy is
more widespread than previously thought based on post mortem observations, this loss of volume sometimes appearing even before the
onset of symptoms (Rosas et al., 2002; Thieben et al., 2002; Rosas et al.,
2005; Douaud et al., 2006; Rosas et al., 2008). Importantly, two recent
in vivo studies of global anthropometric measures in asymptomatic
subjects carrying the mutated gene also point at a developmental aspect
in HD (Nopoulos et al., 2011; Lee et al., 2012). These are, to our
knowledge, the only human studies showing results supporting the
thought-provoking idea that degeneration in some disorders of possible
genetic aetiology, including HD and Alzheimer’s disease, might be the
consequence of abnormal development, with certain populations of
neuronal cells made more vulnerable to late life stressors (Mehler and
Gokhan, 2000; Molero et al., 2009; Marder and Mehler, 2012).
Here, we carried out for the first time in HD a sulcal morphometry
analysis using a tool that automatically reconstructs and labels sulci
from T1-weighted images (Riviere et al., 2002; Mangin et al., 2004).
This approach has revealed for instance significant phylogenetic differences in a language-related sulcal area (Leroy et al., 2015), or alterations in sulcal shape in ageing (Kochunov et al., 2005) – with, for
instance, a reduced sulcal depth related to adjacent gyral atrophy – as
well as in mild cognitive impairment and Alzheimer’s disease
(Reiner et al., 2012; Hamelin et al., 2015). Furthermore, differences in
sulcal length have been recently consistently related to (abnormal)
developmental processes (Auzias et al., 2014; Cachia et al., 2014;
Muellner et al., 2015).
We thus expected that sulcal morphometry analysis might reveal
evidence for coexisting abnormal degenerative and developmental
processes, in line with the duality, observed for the mutant protein, of
both gain-of-function and loss-of-function (effects which are in turn
thought to play a distinct role in brain degeneration and abnormal
development respectively) (Marder and Mehler, 2012). As this exploratory, yet region-of-interest based approach provides information
on the shape of sulci complementary to information obtained with
voxelwise techniques, we anticipated that it should in particular detect
subtle abnormalities not identified using an approach such as VBM
(Mangin et al., 2004; Douaud et al., 2006) and that it might, crucially,
reveal novel abnormalities related to altered neurodevelopment in HD.
Table 1
Clinical variables for the HD participants.
Clinical Variable
Mean±std
Range
CAG repeat
Total Functional Capacity
Disease Burden
Motor UHDRS
Behavioural UHDRS
Functional Assessment
Independence Scale
Verbal Fluency (P, R, V) – 1min
Verbal Fluency (P, R, V) – 2min
Digit Symbol
Stroop (Words)
Stroop (Colour)
Stroop (Interference)
46±4
11±1
409±73
35±14
12±10
27±2
88±9
27±10
37±13
26±9
63±21
46±15
26±9
40–57
8–13
239–538
16–61
0–36
25–31
70–100
7–43
14–62
14–48
29–103
24–76
10–43
8–13). 18 healthy controls (HC, 14 males, 4 females, 2 left-handed)
matched for age (41 ± 8 years) to the HD patients underwent the same
imaging protocol. Each HD patient was examined using the Unified
Huntington’s Disease Rating Scale (UHDRS, 1996) in each hospital and
the scores for each subscale (motor, behavioural, functional and neuropsychological) were collected (Table 1).
2.2. Data acquisition
Whole-brain anatomical MRI was acquired in all 41 participants
with a 1.5 T Signa imager (General Electric Healthcare, Milwaukee, WI)
with a standard 3D T1-weighted inversion recovery fast spoiled gradient recalled (IR-FSPGR) sequence with the following parameters:
axial orientation, matrix 256 × 256, 124 slice locations,
0.9375 × 0.9375 mm2 in-plane resolution, slice thickness 1.2 mm, TI/
TE/TR (inversion/echo/repetition time) 600/2/10.2 ms, flip angle (α)
10°, read bandwidth (RBW) 12.5 kHz.
2.3. Image processing
Here is a brief description of the main steps implemented in
BrainVISA for the reconstruction of the sulci http://brainvisa.info
(Mangin et al., 2004).
First, T1-weighted images were corrected for inhomogeneities and a
brain mask (grey matter GM and white matter WM) was created for
each image, based on the analysis of the histogram and a morphological
opening, before being segmented into left and right hemispheres, as
well as cerebellum. Next, the complement of the white matter, defined
as the space between the brain envelope (identified using a morphological closing) and the GM/WM boundary (identified from the intensities of the two tissues), was skeletonised to create a 3D print of
each sulcus. We thus obtained the 3D reconstruction of sulci for each of
the 23 HD patients and 18 healthy controls.
Various sulcal features can then be analysed, but here we focused on
two that are easily interpretable: depth and length of the sulcus.
Decrease of depth of sulci has been consistently reported in case of
neurodegeneration (with healthy ageing and Alzheimer’s disease), as
the sulci become more shallow as adjacent gyri degenerate
(Kochunov et al., 2005; Reiner et al., 2012; Hamelin et al., 2015). In
contrast, differences in length of the sulci are thought to relate to abnormal developmental processes (Auzias et al., 2014; Cachia et al.,
2014; Muellner et al., 2015).
As there is a substantial inter-subject variability in the shape and
location of the sulci, making a non-linear warping to standard space
approach not appropriate, the strategy here was to use the automatic
recognition of the sulci based on supervised learning from a database
created by neurosurgeons and using neural networks (Riviere et al.,
2002). This process relies on energy minimisation and in this specific
case three successive annealings, where we selected the one which
2. Methods
This study was part of the MIG-HD project (Multicentric
Intracerebral Grafting in Huntington’s Disease) and was approved by
the ethics committee of Henri Mondor Hospital in Créteil. All subjects
gave written informed consent.
2.1. Participants
Twenty-three HD patients (14 males, 9 females, 2 left-handed, aged
42 ± 8 years, range 25–54) were included from four different hospitals
(Nantes, Angers, Lille and Créteil). All were scanned using the same
scanner, in the same imaging centre in Orsay. To meet inclusion criteria, all had genetically proven HD, with an abnormal number of CAG
repeats ranging from 40 to 57 (46 ± 4). None had juvenile HD. They all
had clinical symptoms for at least 1 year and 15 were at stage I of the
disease according to their total functional capacity score (TFC ≥ 11)
(Shoulson and Fahn, 1979), i.e., they were autonomous and could
function fully both at work and at home (on average 10.9 ± 1.4, range
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NeuroImage: Clinical 26 (2020) 102211
J.-F. Mangin, et al.
minimised best the system’s energy.
To create an additional variable, we manually delineated the striatal
regions on each axial plane of each individual T1-weighted scan, after
all the images were rigidly reoriented so that the anterior and posterior
commissures were located in the same axial plane (Douaud et al.,
2006). The accuracy of delineation was further checked in both sagittal
and coronal planes, and each striatal region was reconstructed in 3D to
control for the shape of each volume created. We then calculated the
asymmetry index of the striatal regions to further correlate with possible results showing a marked unilateral effect.
statistical model, as well as after normalising for intracranial volume
3.1. Results consistent with voxel-based findings of cortical atrophy
In line with the literature and our previous voxel-based results
based on the same HD population (18 out of 23 HD participants in
common) (Douaud et al., 2006), we found the strongest difference in
the left central sulcus, with a significant reduction of depth of more
than 8.8% in the HD patients (see Table 2, Figs. 1 and 2). The right
central sulcus depth was also found significantly reduced in HD
(−6.6%). The other sulcus significantly different bilaterally in the patients compared with the healthy controls was the intra-parietal sulcus,
which was shallower on the left by 8.3%, and on the right by 8.7%
(Table 2, Figs. 1 and 2).
2.4. Statistical analysis
We carried out an ANCOVA to compare sulci between the two populations, with diagnosis, age, and age by diagnosis interaction as
covariates to make the results easily comparable with a previous voxelbased study in this population (18 out of 23 HD patients in common)
(Douaud et al., 2006). Results were considered significant for P < 0.05 (two-tailed), corrected for false discovery rate (FDR) across all sulci (n = 57). We additionally checked that our sulcal results held when: 1. adding sex and handedness as additional covariates, 2. normalising for intracranial volume by calculating the residuals for depth and length after the linear contribution of the intracranial volume to the power 1/3 was removed (Sanfilipo et al., 2004). We further ensured that our results showing differences in the length of the sulci – presumably of developmental nature – were in fact not associated with disease burden ((nCAG-35.5) × age) or disease stage (TFC). To this effect, we calculated the correlation coefficient within the HD group between these two clinical measures and our imaging measures of length showing significant group differences. In addition, we investigated within the HD group whether any of our significant findings might be correlated a posteriori with their behavioural and clinical scores (Table 1) using Pearson correlation (with and without age added as a covariate of no interest), as well as with their striatal volumetric asymmetry for asymmetric finding. To account for multicollinearity of these scores, we reduced the set of clinical scores to those that did not share more than 50% of explained variance. Normality of the data was tested in R for every statistical analysis (using the Datamind software of BrainVISA) (Duchesnay et al., 2007). 3.2. Further cortical atrophy findings This individual measure approach further revealed significantly shallower left intermediate frontal sulcus, decreased by 12.9% in the patients, in line with the consistent cortical post mortem observation of dorso-lateral prefrontal cortex atrophy (Table 2, Figs. 1 and 3). The depth of right subparietal sulcus (in the precuneus) and left superior temporal sulcus were also found significantly decreased in the patients (Table 2). Remarkably, we also found a strong decrease in depth of the left calcarine fissure of 20.6% in the HD patients, despite this cortical area not projecting onto the basal ganglia (Table 2, Figs. 1 and 3). 3.3. Evidence for abnormality of neurodevelopment in HD Beyond these consistent findings of reduced sulcal depth pointing at cortical degeneration, the sulcal analysis also revealed a strong difference in the length of the posterior Sylvian fissure, with a length increased by 18.9% for the HD participants compared with healthy controls (Table 2, Figs. 1 and 4). This measure of the sulcal length, on the contrary to that of sulcal depth which is a probably marker of colocalised atrophy, is more likely the hallmark of an altered developmental process during the formation of the sulcal roots (Auzias et al., 2014; Cachia et al., 2014; Muellner et al., 2015). Investigating further the measure of length in the Sylvian fissure, it is clear that, in healthy controls, this fissure is in fact considerably shorter in the left hemisphere than the right (Fig. 5). Rather than simply seeing the finding in the left Sylvian fissure as a mere longer sulcus in the patients, it can thus be interpreted more appropriately as an almost complete absence of asymmetry for this sulcus in HD, asymmetry that is normally found in healthy participants (Fig. 5). The left Sylvian fissure is indeed shorter than the right by 18.8% in the healthy participants, compared with only 5.5% in HD. This absence of asymmetry is further maintained at the single-subject level, as the asymmetry index between left and right Sylvian fissure length, AI=(R-L)/0.5*(R + L), is significantly decreased (towards 0) in the HD group (P = 0.02, n = 41). 3. Results Several sulci were significantly abnormal in the HD patients (Table 2, Fig. 1, FDR-corrected). While most of the measures that differed between the two populations were atrophy-related, showing shallower sulci in HD (8 out of 9 of the significant findings), one measure could not be related to loss of grey matter volume seen in this neurodegenerative disorder: the length of the left posterior Sylvian fissure. These results held when adding sex and handedness to the Table 2 All significant (FDR-corrected) sulcal differences between HD (n = 23) and healthy controls (HC, n = 18). Sulci Side Feature HC Mean±std HD Mean±std P-value P-value*(Sex+Handedness) P-value⁎⁎(ICV) Central Sulcus L R L R L L R L L Depth Depth Depth Depth Depth Depth Depth Depth Length 22.6 ± 1.3 23.0 ± 1.2 25.1 ± 1.5 24.4 ± 1.8 17.1 ± 2.1 31.4 ± 5.9 14.3 ± 2.9 24.7 ± 2.4 282.7 ± 42.3 21.2 ± 1.1 21.0 ± 1.3 23.0 ± 1.8 22.2 ± 1.5 14.9 ± 1.5 24.9 ± 6.4 11.4 ± 2.8 22.7 ± 4.0 335.9 ± 58.1 4.0 × 10−4 4.6 × 10−6 2.9 × 10−5 3.0 × 10−4 3.5 × 10−5 1.5 × 10−4 2.0 × 10−4 7.3 × 10−4 3.2 × 10−4 1.9 × 10−3 3.0 × 10−5 1.3 × 10−4 4.4 × 10−4 2.6 × 10−2 1.1 × 10−3 5.6 × 10−3 1.6 × 10−3 8.9 × 10−4 1.8 × 10−2 2.1 × 10−3 5.2 × 10−4 2.1 × 10−3 3.2 × 10−2 1.2 × 10−2 5.5 × 10−3 2.6 × 10−2 1.4 × 10−3 Intra-parietal sulcus Intermediate frontal sulcus Calcarine fissure Subparietal sulcus Superior temporal sulcus Sylvian (lateral) fissure ⁎ ⁎⁎ Same analyses carried out adding sex and handedness as two additional covariates of no interest. Same analyses carried out on the residuals obtained after partialling out the effect of intracranial volume (ICV). 3 NeuroImage: Clinical 26 (2020) 102211 J.-F. Mangin, et al. Fig. 1. Visual representation of some of the sulci found the most different between healthy and HD participants (5 of 7). We show the sulci in the left hemisphere of one randomly selected healthy control: left, opaque cortex; right, partially transparent cortex to visualise the 3D conformation of the sulci, and those on the medial surface. The central sulcus appears in red, the intra-parietal sulcus in green, the posterior lateral fissure in dark blue, the intermediate frontal sulcus in light blue, and by transparency, the calcarine fissure in brown. While the results in the central sulcus and intra-parietal sulcus were bilateral, differences in the posterior lateral fissure, intermediate frontal sulcus and calcarine fissure were left-lateralised. Fig. 2. Bilateral results consistent with cortical atrophy in HD: shallower central and intra-parietal sulcus in HD. Top: Central Sulcus. Left, 3D rendering of the left central sulcus in one healthy subject. Middle and Right, maximal depth of the right and left central sulcus in the healthy controls (HC, n = 18, in blue circles, average in dark blue), and in the HD participants (n = 23, in magenta triangles, average in dark magenta) (a.u.). Bottom: Intra-Parietal Sulcus. Same representation as above. As the length of the left posterior Sylvian fissure seemed to be a hallmark of abnormal asymmetry in HD, we further investigated within this group if it was associated with their striatal volumetric asymmetry, as measured using careful manual segmentation of the subcortical structures (Douaud et al., 2006). We found that it was significantly correlated with such subcortical asymmetry (r23 = 0.49, 24% of variance explained, P = 0.017, Supplementary Figure 1). Finally, we established that the abnormal length of the Sylvian fissure in HD was not correlated with either disease burden (r21 = 0.08, P = 0.38) or TFC (r20 = 0.19, P = 0.21). 3.4. Post-hoc correlations with clinical scores We first reduced the set of scores to those that did not share more than 50% of explained variance (r > 0.70). This allowed us to assess
correlations between the significant sulcal findings of depth and length
with the Motor UHDRS, Behavioural UHDRS, Stroop Interference
(highly correlated with Stroop Word and Colour, and Digit Symbol),
Functional Assessment (highly correlated with Independence Scale),
TFC and Sum Fluency (where we summed the two runs, and which was
highly correlated with the MATTIS). Associations are summarised in
4
NeuroImage: Clinical 26 (2020) 102211
J.-F. Mangin, et al.
Fig. 3. Additional left-lateralised results consistent with cortical atrophy in HD: shallower intermediate frontal sulcus and calcarine fissure.Top:
Intermediate Frontal Sulcus. Left, 3D rendering of the left intermediate frontal sulcus in one healthy subject. Right, maximal depth of the left intermediate frontal
sulcus in the healthy controls (HC), and in the HD patients (a.u.). Bottom: Calcarine Fissure. Same representation as above.
Supplementary Table 1, but briefly: these showed an association between Stroop Interference and depth of the right intra-parietal sulcus
(r20 = 0.40, 16% of variance explained, P = 0.04), Functional
Assessment and depth of the left intermediate frontal sulcus
(r20 = −0.46, 21% of variance explained, P = 0.02), and Behavioural
UHDRS and depth of the left calcarine fissure (r20 = −0.52, 28% of
variance explained, P = 0.009). After regressing age out, we also found
an association between the sum of the fluency scores and the depth of
the left intermediate frontal sulcus (Supplementary Table 1).
Rosas et al., 2005). A previous global morphological study found a global
decrease of sulcal depth in HD (Nopoulos et al., 2007). Here, our results
might explain this global effect by showing a clear, localised decrease in
depth of the central and intra-parietal sulcus in both hemispheres, right
sub-parietal sulcus, and left intermediate frontal sulcus, calcarine fissure
and superior temporal sulcus. Second, as this sulcal morphometry approach may be able to differentiate underlying degenerative and developmental processes, it was further motivated by two recent in vivo studies
in gene carriers showing the first signs of abnormal development using
anthropometric measurements (Nopoulos et al., 2011; Lee et al., 2012).
Remarkably, our sulcal analysis revealed a substantial difference in the
imprint of the posterior Sylvian fissure, namely an absence of asymmetry
in the HD population between left and right hemispheres, suggesting a
very early insult to the developing neocortex.
A shallower central sulcus in our HD participants can be easily related
to the most consistent loss of cortical grey matter in the precentral and
postcentral gyri observed in a meta-analysis in HD (Dogan et al., 2013),
4. Discussion
This is the first study of sulcal morphology carried out in HD. The
motivation for this study was two-fold. First, it was prompted by a string of
published evidence that has established early cortical degeneration in HD,
whether in the same early HD population (18 out of 23 in common):
(Douaud et al., 2006), or even in premanifest HD: (Thieben et al., 2002;
5
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J.-F. Mangin, et al.
Fig. 4. Evidence for abnormality of neurodevelopment in HD: longer left posterior Sylvian (lateral) fissure in HD. Left, 3D rendering of the left posterior
Sylvian fissure in one healthy subject. Right, length of the left posterior Sylvian fissure in the healthy controls (HC, n = 18, turquoise circles), and in the HD
participants (n = 23, mauve triangles) (a.u.).
not least in the same patients (Douaud et al., 2006). The depth of the
intraparietal sulcus was also significantly decreased bilaterally in the HD
participants, particularly so in the left hemisphere (Fig. 3). The left intraparietal sulcus is, together with the premotor and primary sensorimotor
cortex, the cortical region found to also discriminate best between premanifest and manifest HD in a meta-analysis (Dogan et al., 2013). In addition, the right intraparietal sulcus depth correlated in the patients with
the Stroop Interference (r20==0.40, Supplementary Table 1), a measure
of selective attention whose functional network is centred on the intraparietal sulcus (Hedden et al., 2012). When we also investigated, as an
additional analysis, the surface measure of the sulci, we found that the
strongest differences were found bilaterally in the intraparietal sulcus
(Supplementary Table 2). While mainly redundant (and less sensitive)
than the measure of sulcal depth, the surface of sulci solely revealed a
significant difference in the left olfactory sulcus, which might be linked to
the smell deficits consistently observed in HD (Paulsen et al., 2017).
Findings of a left-lateralised degeneration around the intermediate
frontal sulcus concur with the wealth of post mortem evidence on the
injury to the dorso-lateral prefrontal cortex e.g., (Hedreen et al., 1991;
Halliday et al., 1998). As it was not detected using VBM (Douaud et al.,
2006), this suggests that the method used here might be sensitive to
detect very early signs of prefrontal degeneration, which are typically
seen at later stages of HD (Rosas et al., 2008). For instance, total
functional capacity score (TFC) ranging from 1 to 13 was found to
correlate with left prefrontal areas (Rosas et al., 2008). In our predominantly stage I HD population, where TFC range was more limited,
Fig. 5. Evidence for abnormality of neurodevelopment in HD: absence of asymmetry in the posterior Sylvian fissure in HD. A. There is a natural asymmetry
between left and right length of the posterior Sylvian fissure in healthy controls (HC) (a.u.). In HC, the left fissure is shorter on average by almost 20%. By contrast,
there is almost no difference on average in the HD patients. For the patients, the left Sylvian fissure is only shorter by less than 6% on average. B.This absence of
asymmetry is also found at the single-subject level: the asymmetry index of the Sylvian fissure length is close to 0 in the HD patients.
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J.-F. Mangin, et al.
we found similar associations specifically between the depth of the
intermediate frontal sulcus and the UHDRS measures o Functional Assessment (r20 = −0.46), and at a trend level with TFC (r20 = 0.31)
(Supplementary Table 1).
Decrease in depth of the left calcarine fissure could seem surprising at
first, as this part of the brain is not connected to the striatum. But it is in
fact a result consistent with in vivo surface-based studies of HD, where
degeneration was found in the occipital lobe and in particular around the
left calcarine fissure (Rosas et al., 2002; Rosas et al., 2008), as well as with
post mortem studies (Halliday et al., 1998). Indeed, while cortical degeneration in HD had been initially thought to be a secondary event due to the
striatal degeneration, it is more likely that both primary and secondary
degenerative processes co-exist in the cortex (Rub et al., 2015). This is
further supported by histopathological findings showing damage to layer
VI of the cortex that does not project to the striatum (Hedreen et al.,
1991). Of note, the decrease in depth in the calcarine fissure is the
strongest in terms of effect size (more than 20%) compared with all other
sulci found shallower in HD. Intriguingly, the depth of the left calcarine
fissure was correlated with the behavioural UHDRS score (r20 = −0.52,
Supplementary Table 1). This association might perhaps be related to the
association observed between behavioural symptoms – visual hallucinations and depression – and this specific region of the brain also seen in
Parkinson’s disease (Matsui et al., 2006; Hu et al., 2015).
Interestingly, this sulcal analysis also revealed an increase of nearly
20% in the length of the left posterior Sylvian fissure in HD compared with
the healthy participants. The consistent decrease of depth found in various
sulci are consistent with a neurodegenerative process, and thus mainly
consistent with volume-based and surface-based findings. A significant
difference in the length of one sulcus, on the contrary, is more difficult to
be interpreted, especially in light of the absence of colocalised atrophy,
and the lack of association with disease stage or burden, and age. As such,
it is more likely related to an altered development. This left peri‑Sylvian
region is for instance well known to be associated with functional language lateralisation and specialisation, although it did not correlate with
verbal fluency (Table 1), the only language-related measure available in
our HD population. Morphological anomalies in this brain region have
been found in population with neurodevelopmental disorders, such as
stuttering and in children with dyslexia (Foundas et al., 2004; Kibby et al.,
2004; Cykowski et al., 2008). It is also connected by white matter tracts
that are the only fibre bundles showing the effect of genetic associations
with handedness (Wiberg et al., 2019). However, as shown in the Results
section, healthy development typically leads to a strong asymmetry between the two hemispheres – in fact the strongest asymmetry found across
the entire cortex, as demonstrated for instance in preterm newborns
(Dubois et al., 2010). Our result in the posterior Sylvian fissure therefore
demonstrates an absence of asymmetry in HD, compared with normal development. Interestingly, differences in sulcal asymmetry have recently
demonstrated to be key in understanding differences in developmental
processes (Kloppel et al., 2010; Cachia et al., 2014; Leroy et al., 2015).
This altogether suggests that the abnormal length of the left posterior
Sylvian fissure in HD might bear the hallmark of an early, altered developmental process. As the formation of the Sylvian fissure appears early in
utero, and marked asymmetry is specifically found in this region in preterm newborns (Dubois et al., 2010), this likely indicates the foetal timing
of a disease-related genetic interplay with neurodevelopment. In our HD
population, the length of the left posterior Sylvian fissure was further
significantly associated with the striatal volumetric asymmetry, as measured using careful manual segmentation of the subcortical structures
(r23 = 0.49, 24% of variance explained, P = 0.017, Supplementary
Figure 1) (Douaud et al., 2006). Such striatal asymmetry in turn explains a
substantial part of the variance in two fundamental UHDRS measures in
our cohort: TFC (r20 = −0.49, 24% of variance explained, P = 0.027) and
Independence Scale (r19 = −0.59, 35% of variance explained,
P = 0.0075). It could thus be that the subcortical volume asymmetry seen
in the striatum of HD patients is both a combination of developmental and
degenerative processes.
Compared with a technique such as VBM, this specific sulcal approach cannot show precisely where some of the abnormalities might
be localised along a sulcus (e.g., dorsal vs. ventral part of the central
sulcus). Newest developments might be able to resolve these limitations
(Coulon et al., 2015). In any case, it revealed in the same HD population
(18 out of 23 in common), and using the same statistical model, significant differences in areas where the VBM analysis had failed to detect
a loss of volume or morphology: the right precuneus, as well as the left
dorso-lateral prefrontal cortex, primary visual cortex, superior temporal
cortex and peri‑Sylvian region (Douaud et al., 2006). Other VBM studies, possibly because of larger sample size or more advanced HD population, have in some cases demonstrated voxelwise differences in
those cortical regions where only our sulcal approach revealed abnormalities (Muhlau et al., 2007; Scahill et al., 2013; Minkova et al.,
2018). The sample size of this study is also limited, but we made sure to
only present in the main manuscript sulcal group differences surviving
correction for multiple comparisons (as an indication, top 20 results in
Supplementary Table 3). This relatively small sample size also meant
large effect sizes for our significant results, such as a difference of 19%
in length of the Sylvian fissure, or of 21% in the depth of the calcarine
fissure. Finally, another clear limitation is that our participants were
already symptomatic. Especially for the findings in the Sylvian fissure, a
study on (ideally young) gene carriers far from the onset of symptoms such as done in Lee et al. (2012) – should confirm the pre-existing
nature of this sulcal abnormality, and in particular of its distinctive
asymmetry in HD.
In summary, we used for the first time a detailed analysis of sulcal
morphology in HD. This approach, which precisely targets cortical
features, offers complementary sources of information, not only to
conventional voxel- and vertex-wise approaches, but also in how they
relate to different underlying physiopathological processes, and could
help detect subtle neurodevelopmental abnormalities that would
otherwise go unnoticed in other degenerative disorders with a genetic
susceptibility. It revealed in HD abnormalities consistent with a neurodegenerative process, but also importantly with an altered neurodevelopment. While the atrophy found in the left visual cortex adds to the
increasing wealth of data indicative of a primary cortical degeneration
in HD, this study provides, to the best of our knowledge, the first in vivo
indication of an interplay between disease and neocortical development.
CRediT authorship contribution statement
Jean-Francois Mangin: Conceptualization, Formal analysis,
Software, Writing – original draft. Denis Rivière: Formal analysis,
Software, Writing – original draft. Edouard Duchesnay: Formal analysis, Software. Yann Cointepas: Software. Véronique Gaura:
Resources. Christophe Verny: Resources. Philippe Damier:
Resources. Pierre Krystkowiak: Resources. Anne-Catherine
Bachoud-Lévi: Resources, Funding acquisition. Philippe Hantraye:
Supervision, Funding acquisition. Philippe Remy: Supervision,
Resources,
Funding
acquisition.
Gwenaëlle
Douaud:
Conceptualization, Resources, Investigation, Formal analysis, Funding
acquisition, Writing – original draft, Writing – review & editing.
Declaration of Competing Interest
The authors declare no competing financial interests.
Acknowledgements and Funding
G.D. is supported by the UK Medical Research Council (MR/
K006673/1). This study was part of the MIG-HD trial coordinated by A.C.B.-L. (Principal investigator) and granted through PHRCs AOM00139
and AOM 04021 from the DRCD (Assistance Publique- Hôpitaux de
Paris). We would like to thank the patients and their families.
7
NeuroImage: Clinical 26 (2020) 102211
J.-F. Mangin, et al.
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