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Shape of the Central Sulcus and Disability After

Subcortical Stroke
A Motor Reserve Hypothesis
Eric Jouvent, MD, PhD; Zhong Yi Sun, PhD; Franois De Guio, PhD;
Edouard Duchesnay, PhD; Marco Duering, MD; Stefan Ropele, PhD; Martin Dichgans, MD;
Jean-Franois Mangin, PhD; Hugues Chabriat, MD, PhD

Background and PurposeBoth brain and cognitive reserves modulate the clinical impact of chronic brain diseases.
Whether a motor reserve also modulates the relationships between stroke and disability is unknown. We aimed to
determine whether the shape of the central sulcus, a marker of the development of underlying motor connections, is
independently associated with disability in patients with a positive history of small subcortical ischemic stroke.
MethodsShapes of central sulci were reconstructed from high-resolution magnetic resonance imaging and ordered without
supervision according to a validated algorithm in 166 patients with a positive history of small subcortical ischemic stroke
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caused by CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy),
a severe monogenic cerebral small vessel disease affecting young patients. Ordinal logistic regression modeling was used
to test the relationships between modified Rankin scale, a disability scale strongly weighted toward motor disability, and
sulcal shape.
ResultsModified Rankin scale was strongly associated with sulcal shape, independent of age, sex, and level of education
(proportional odds ratio =1.19, 95% confidence interval =1.061.35; P=0.002). Results remained significant after further
adjustment for brain atrophy, volume of lacunes, and volume of white matter hyperintensities of presumed vascular
origin.
ConclusionsThe severity of disability in patients with a positive history of small subcortical ischemic stroke caused
by a severe cerebral small vessel disease is related to the shape of the central sulcus, independently of the main
determinants of disability. These results support the concept of a motor reserve that could modulate the clinical severity
in patients with a positive history of small subcortical ischemic stroke.(Stroke. 2016;47:1023-1029. DOI: 10.1161/
STROKEAHA.115.012562.)
Key Words: CADASIL central sulcus cerebral cortex motor reserve stroke

I n chronic neurological disorders, both brain and cognitive


reserves modulate the relationships between brain pathol-
ogy and clinical symptomatology.1,2 After stroke, age, initial
central sulci among individuals without supervision.9 With
this approach, it was shown that the vertical position of the
hand motor area is the main source of variability regarding
clinical severity, treatment,3,4 and imaging characteristics of shapes of central sulci among healthy individuals, and that
the stroke lesion are associated with clinical outcomes,5 but when the hand area is shifted upwards, its size decreases.9
whether a motor reserve also modulates the relationships To determine whether disability after stroke is related to the
between stroke and the severity of disability is unknown. shape of the central sulcus, as a marker of the development
The shape of the central sulcus reflects the development of of underlying motor connections, we studied a large cohort of
underlying motor connections6,7 that might influence disabil- patients with a positive history of small subcortical ischemic stroke
ity in stroke patients. Particularly, the prominent development caused by Cerebral Autosomal Dominant Arteriopathy With
of the hand motor area shapes locally the central sulcus as an Subcortical Infarcts and Leukoencephalopathy (CADASIL),
inversed omega.8 Recent developments in magnetic resonance a severe monogenic cerebral small vessel disease character-
imaging (MRI) postprocessing allowed comparing shapes of ized, after normal brain development, by the early occurrence

Received December 23, 2015; final revision received February 1, 2016; accepted February 10, 2016.
From the Universit Paris Diderot, Sorbonne Paris Cit, UMR-S 1161 INSERM, F-75205 Paris, France and AP-HP, Lariboisire Hospital, Department
of Neurology, F-75475 Paris, France, and DHU NeuroVasc Sorbonne Paris Cit, Paris, France (E.J., F.D.G., H.C.); UNATI, Neurospin, I2BM, CEA,
Saclay, France (Z.Y.S., E.D., J.-F.M.); CATI Multicenter Neuroimaging Platform, cati-neuroimaging.com, France (Z.Y.S., E.D., J.-F.M.); Institute for
Stroke and Dementia Research, Klinikum der Universitt Mnchen, Ludwig-Maximilians-University, Munich, Germany (M. Duering, M. Dichgans);
Munich Cluster of Systems Neurology (SyNergy), Munich, Germany (M. Duering, M. Dichgans); and Department of Neurology, Medical University
of Graz, Austria (S.R.).
Correspondence to Hugues Chabriat, MD, PhD, Service de Neurologie, Hpital Lariboisire, 2 rue Ambroise Par, 75010 Paris, France. E-mail hugues.
chabriat@aphp.fr
2016 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.115.012562

1023
1024StrokeApril 2016

of stroke and the development of highly variable levels of dis- take into account differences in head size between patients, as previ-
ability in young patients.10 The study of a monogenic disorder ously detailed.16
Reconstruction and identification of cortical sulci were performed
responsible for small subcortical ischemic strokes in young using Brainvisa (http://brainvisa.info). Ordering of shapes of central
patients allows reducing the confounding effect of age and of sulci was performed using previously validated methodology.9 Right
potentially associated prodromal neurodegenerative disorders central sulci were first flipped relative to the interhemispheric plane to
in the elderly. Additionally, the cerebral cortex is macroscopi- allow comparison with left central sulci (Figure1). Hence, all analy-
ses included both left and right sulci of each patient. A pairwise shape
cally largely spared in this disorder, allowing fine analyzes of
similarity matrix was computed across the whole set of sulci.9 The
its morphology.11,12 similarity between 2 sulci was coded by the average quadratic dis-
tance between their 3-dimensional representations after alignment.
Methods This pairwise registration was achieved using the iterative closest
point algorithm, which aligns one sulcus relative to the other through
Patients successive rotations and translations. The shape similarity matrix was
One hundred and ninety patients (123 from Paris and 67 from built from all the pairwise comparisons, and manifold learning (using
Munich) with CADASIL (proven genetically) were included in the the Isomap algorithm) was used to capture a 1-dimensional approxi-
present study between 2003 and 2009 and were evaluated every 18 mation of the high dimensional space spanned by central sulci.9 This
months. At each visit, both clinical, biological, and MRI evaluations 1-dimensional approximation provided a numeric index of sulcal
were performed using harmonized protocols. The present analyses shape (I) for each sulcus relative to all the others (hence each subject
are based on the initial assessment of MRI and clinical data. All had an index for his right central sulcus IR and one for his left central
patients had a positive history of small subcortical ischemic stroke sulcus IL). For analyses, an index IRL was calculated for each patient
as the average of this numeric index on both sides (Figure1).
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caused by CADASIL and were aged >18 years. Small subcortical


ischemic strokes were defined as neurological deficits lasting more
that 24H linked to a recent small subcortical infarct identified on Statistical Analyses
imaging (computed tomographic scan or MRI). They participated Statistical analyses were performed using the R software (http://
in a prospective cohort study of CADASIL at Lariboisire (Paris) www.r-project.org/). To determine whether mRS is independently
or Ludwig-Maximilians-Universitt (Munich). Details of the proto- related to IRL, we used ordinal logistic regression analyses to deter-
col have been previously reported.12 Age, sex, and level of education mine the regression coefficients on the log scale that were further
were collected among a large set of clinical and epidemiological data. exponentiated to obtain proportional odds ratios (ORP) together with
Disability was assessed using the modified Rankin scale (mRS), a their 95% confidence interval (95% CI). In model 1, univariate analy-
widely used scale heavily weighted toward motor disability, rang- sis was tested, with mRS as the dependent variable and IRL as the
ing from 0 (no symptom) to 5 (bedridden).13 An ethics committee independent variable. In model 2, IRL, age, sex, and level of education
approved the study in both centers. were included as covariates. In model 3, IRL, age, sex, level of educa-
tion, brain parenchymal fraction, volume of lacunes, volume of white
matter hyperintensities, and number of microbleeds were included as
MRI Acquisition covariates, those imaging variables being associated with disability in
MRI scans were obtained on 1.5-T systems (Siemens Magnetom cerebral small vessel disease in general and in CADASIL in particu-
Vision [Munich] or General Electric Medical Systems Signa [Paris lar.13 In model 4 (full model), the same covariates as model 3 were
and Munich]). 3DT1 sequences (Munich: repetition time/echo time included, but volume of lacunes, volume of white matter hyperinten-
(TR/TE) =11.4/4.4 ms, slice thickness =1.2 mm, no interslice gap, sities, and number of microbleeds were evaluated separately within
in-plane resolution =0.90.9 mm; Paris: TR/TE=9.1/2 ms, slice and outside pyramidal tracts and considered as different covariates.
thickness =0.8 mm, no gap, in-plane resolution =1.021.02 mm), The different models were compared by analysis of variance.
fluid-attenuated inversion recovery (Munich: repetition time/echo
time/inversion time (TR/TE/TI) =4284/110/1428 ms, slice thickness
=5 mm, no gap, in-plane resolution =0.980.98 mm; Paris: TR/TE/ Results
TI =8402/161/2002 ms, slice thickness =5.5 mm, no gap, in-plane Among 190 CADASIL patients with a positive history of
resolution =0.940.94 mm), and T2*-weighted gradient echo imag- small subcortical ischemic stroke caused by CADASIL who
ing (Munich: TR/TE=1056/22 ms, slice thickness =5 mm, no gap, were recruited in the 2 centers, 6 were excluded from analyses
in-plane resolution =0.980.98 mm; Paris: TR/TE=500/15 ms, slice
thickness =5.5 mm, no gap, in-plane resolution =0.980.98 mm)
because they also had a large cortical infarct on MRI. Seven
were performed. had incomplete MRI data or MRI data of insufficient qual-
ity for image processing. For 11 patients, the reconstruction
Image Processing of one or the other central sulcus failed for various technical
White matter hyperintensities and lacunes of presumed vascular ori- reasons, leaving 166 patients for analyses. Characteristics of
gin as well as microbleeds were extracted using validated methods those 166 patients are given in Table1. Fifty-three percent
detailed elsewhere from high-resolution fluid-attenuated inversion of patients experienced 2 small subcortical ischemic strokes,
recovery, 3DT1, and T2* MRI sequences, respectively,12 in agree- whereas 28% had 3.
ment with the STRIVE (Standards for Reporting Vascular Changes We observed that the first source of variability regarding the
on Neuroimaging) criteria.14 Volume of white matter hyperintensities,
shape of central sulci among CADASIL patients was the verti-
volume of lacunes, and number of microbleeds were measured as pre-
viously reported.12 In a second step, those variables were measured cal position of the hand knob along the central sulcus together
specifically within pyramidal tracts after registration within the Johns with a decrease of its size when shifted upward (Figure1).
Hopkins University probabilistic atlas of major white matter tracts A scatterplot of the rough relationships between sulcal shape
in the Montreal Neurological Institute template.15 Given the skewed (IRL) and mRS is presented Figure2.
distributions of the volumes of white matter hyperintensities both
In univariate ordinal logistic regression analysis, mRS was
globally, within and without pyramidal tracts, these variables were
log-transformed to obtain close to normal distributions. Brain paren- significantly associated with IRL (ORP=1.20, 95% CI =1.07
chymal fraction, a recognized measure of brain atrophy, was defined 1.35; P=0.002). In other words, for a 1-unit increase in IRL, the
as the ratio of brain tissue volume to the intracranial cavity volume to odds to move from a low or intermediate mRS to a larger mRS
Jouvent et al Motor Reserve in Subcortical Stroke 1025
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Figure 1. Methodology. A, Native magnetic resonance imaging (MRI) axial slices illustrating the variability of shapes of central sulci
among 5 CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy) patients with a posi-
tive history of subcortical ischemic stroke, particularly respective to the position and size of hand knobs (white stars). B, Central sulci
were reconstructed using BrainVisa (http://brainvisa.info). The right sulci were transformed by symmetry through the interhemispheric
plane to compare them to left sulci. Sulcal shapes are represented overlaid on meshes of underlying white matter. C, The whole sample
of central sulci of patients included in the present study is shown according to the ordering determined without supervision by the Iso-
map algorithm. Ten meshes representing the average shape of similar sulci are represented overlaid over the whole sample to highlight
the main source of variability. Importantly, this first and most important source of variability was the vertical position and size of the hand
knob, as reported previously in healthy subjects.9 An index was determined for each central sulcus respective to the whole sample of
central sulci. The IRL index for a subject was obtained by averaging right and left indexes.

increase by 20% (multiplied by a factor of 1.2), with upper P=0.01), the number of microbleeds measured outside pyra-
and smaller hand knobs being associated with larger mRS. midal tracts (ORP=1.11, 95% CI =1.021.22; P=0.009), brain
In model 2, including age, sex, and level of education parenchymal fraction (ORP=0.86, 95% CI =0.790.94; P<104),
as covariates, mRS was significantly associated with IRL and level of education (ORP=0.74, 95% CI =0.550.98;
(ORP=1.19, 95% CI =1.061.35; P=0.004), age (ORP=1.08, P=0.03). The full model performed statistically significantly
95% CI =1.041.12; P<104), and level of education better than model 3 (P=0.003). The inclusion of center as a
(ORP=0.69, 95% CI =0.520.90; P=0.006), but not sex fixed effect in the 4 different models did not alter the results.
(Table2). Model 2 performed statistically significantly better
than model 1 (P<104). Discussion
In model 3, further including as covariates brain paren- The results of the present study show that, in a large cohort
chymal fraction, volume of lacunes, volume of white mat- of young patients all affected by the same severe monogenic
ter hyperintensities, and number of microbleeds, mRS was cerebral small vessel disease responsible for small subcortical
significantly related to IRL (ORP=1.19, 95% CI =1.051.35; ischemic strokes,17 the severity of disability is independently
P=0.005), brain parenchymal fraction (ORP=0.88, 95% CI associated with the shape of the central sulcus, mostly driven
=0.810.96; P<104), and level of education (ORP=0.73, 95% by the vertical position and the size of the hand knob as in
CI =0.550.97; P=0.03), but not to age, sex, volume of lacu- healthy subjects. Our results suggest that the position of the
nes, or of white matter hyperintensities or number of micro- hand knob, a cortical marker that can be easily determined on
bleeds. Model 3 performed statistically significantly better brain MRI before stroke, might predict the patients ability to
than model 2 (P=0.0009). recover after stroke, providing an alternative explanation for
In the full model (model 4) including volume of lacunes, the various levels of disability observed in patients with simi-
volume of white matter hyperintensities, and number of micro- lar subcortical ischemic lesions at the same age.
bleeds evaluated separately outside and within pyramidal Our findings are in line with the widely recognized con-
tracts, mRS was significantly associated with IRL (ORP=1.23, cepts of cognitive reserve (mostly related to the amount and
95% CI =1.091.41; P=0.002), the volume of lacunes mea- efficiency of brain networks, development of which would
sured within pyramidal tracts (ORP=1.01, 95% CI =1.001.01; take place during childhood18) and with that of brain reserve
1026StrokeApril 2016

Table 1. Clinical and MRI Data of the 166 Patients motor cortex volume, offering higher probabilities to detect
intersubject differences.
Clinical Data
Others and we have previously shown that the cortical
Age, meanSD (range) 52.29.7 (31.477.5) mantle can be altered secondary to subcortical lesions in
Male sex, count (%) 84/166 (51%) cerebral small vessel diseases.19,20 In the present study, we
Level of education, count (%) Basic: 24 (14%)
cannot formally exclude that the observed cortex shape varia-
tions between patients are in fact the remote cortical conse-
Secondary: 109 (66%)
quences of subcortical strokes and lacunes on connected fiber
University: 27 (16%) bundles.19 However, it is important to note that the pattern of
Number of subcortical ischemic strokes, 1: 79 (47%) variations of shapes of central sulci detected by our unsuper-
count (%) vised algorithm was very similar to that of healthy individuals.
2: 41 (25%)
This strongly argues against the hypothesis that the variations
3: 46 (28%) observed in patients results from remote effects of subcorti-
Modified Rankin scale, median, 1, 2, 05 cal lesions, but rather support the hypothesis that they actu-
interquartile range, range ally represent a developmental marker independent of the
Time elapsed in days between first stroke 1203, 1675, 176655 effects of the disease.9 In addition, by contrast to other MRI
and current study, median, interquartile measures, the shape of the central sulcus seems highly stable
range, range during lifespan, also rendering less likely the possibility of
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Time elapsed in days between last stroke 471, 993, 176258 secondary alterations. In our cohort, >30 patients are being
and current study, median, interquartile followed using MRI acquisitions every 18 months since >12
range, range years, and the shape of the central sulcus is largely unaltered
Imaging data as illustrated by a typical case even when they develop dis-
ability (Figure3).
Brain parenchymal fraction, %, meanSD 84.26.1 (65.396.1)
After stroke, motor recovery seems highly variable among
(range)
individuals.21 Both structural and functional reorganization
Volume of lacunes, mm3, meanSD 478671 (03864) occur not only locally but also remotely to the stroke lesion.22
(range)
Bilateral modulations of sensorimotor activations have been
Volume of white matter hyperintensities of 11314068273 (3796 consistently observed and may predict motor recovery after
presumed vascular origin, mm3, meanSD 414400) stroke.23 The integrity of pyramidal tracts measured using vari-
(range) ous quantitative measures of diffusion and electrophysiological
Number of microbleeds, meanSD (range) 3.712.7 (0123)
MRI indicates magnetic resonance imaging.

(mostly related to available tissue resources and components)


that can modulate the clinical expression of brain patholo-
gies both in young and older populations.1 Whether our find-
ings are specific to CADASIL or can be generalized to other
types of cerebral small vessel diseases or to other stroke
populations will of course require further investigations. In
particular, although all the patients included in the present
study experienced at least one small subcortical ischemic
stroke, 53% of them experienced 2 small subcortical isch-
emic strokes. Moreover, in these patients, the whole burden
of lacunes, a large proportion of which did not lead to stroke,
is a major determinant of disability compared with other eti-
ologies of stroke.13
Other metrics such as the volume of gyri or of primary
motor cortex might have also been of interest to evaluate the
motor aspects of the cerebral cortex. However, the analysis
of sulcal shape offers several advantages. First, the volume Figure 2. Relationships between sulcal shape and modified
of cortex structures, such as the primary motor area, is dif- Rankin scale. Scatter plot representing the rough relationships
ficult to determine on a simple morphological MR scan, between the index of sulcal shape and modified Rankin scale.
The line of best fit obtained with ordinary least square regression
and more elaborate acquisitions would be required to delin- is shown with its 95% confidence interval. The suggested link
eate its limits. Another major advantage is that shape is was confirmed by ordinal regression analyses (see the results
invariant with respect to head size, whereas all other volu- section). Please note that a small amount of random noise was
metric measures would need statistical adjustment for this added on the horizontal axis to allow a better visualization, par-
ticularly regarding scores 0 and 1 of modified Rankin scale for
confounding effect. Finally, the variability of sulcal shape which several points would have been otherwise overlaid onto
among healthy subjects is far larger than that of primary each other.
Jouvent et al Motor Reserve in Subcortical Stroke 1027

Table 2. Results of Ordinal Logistic Regression Models Testing the Associations Between
Modified Rankin Scale and Sulcal Shape According to Various Covariate Configurations
Proportional Odds Ratios Model 1 Model 2 Model 3 Model 4
IRL 1.20 [1.071.35]* 1.19 [1.061.35]* 1.19 [1.051.35]* 1.23 [1.091.41]*
Age 1.08 [1.041.12] 1.02 [0.971.07] 1.04 [0.991.09]
Sex 0.65 [0.341.32] 1.17 [0.542.54] 1.46 [0.643.37]
Level of education 0.69 [0.520.90]* 0.73 [0.550.97] 0.74 [0.550.98]
BPF 0.88 [0.810.96] 0.86 [0.790.94]
Volume of lacunes 1.00 [0.991.00] 1.00 [1.001.00]
Volume of WHM 1.77 [0.983.41] 2.58 [0.878.09]
Number of MB 1.01 [0.961.07] 1.11 [1.021.22]*
Volume of lacunes in PT 1.01 [1.001.01]*
Volume of WMH in PT 0.60 [0.261.45]
Number of MB in PT 1.01 [0.911.11]
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Proportional odds ratios are provided with 95% confidence intervals. BPF indicates brain parenchymal fraction; IRL, index
of sulcal shape; MB, microbleeds; PT, pyramidal tracts; and WMH, white matter hyperintensities.
*Level of significance: <0.01.
Level of significance: <0.001.
Level of significance: <0.05.
Measured outside pyramidal tracts in model 4.

parameters was found promising to help predict motor recov- Our study has several limitations. We studied patients
ery,24,25 although the yield of these techniques compared with with CADASIL, a rare monogenic disorder, thus question-
clinical data alone remains undetermined.26 Analysis of sulcal ing the generalizability of our results to other stroke popula-
morphology is independent from all these methods and may tions. Also, we used mRS to assess disability while it is not
provide additional information to better determine the patients a direct measure of motor function but a general measure of
who will more likely benefit of neurorehabilitation.26 Whether disability. Although in the present cohort we did not plan
sulcal shape can help in predicting long-term disability in to measure scores of motor function, pyramidal involve-
patients having initially the same level of motor impairment ment was tested at each visit. We tested, using a logistic
will require further investigations. regression model, whether pyramidal involvement was

Figure 3. Stability of sulcal shape over long periods of time. Example of a 46-year-old female CADASIL (Cerebral Autosomal Dominant
Arteriopathy With Subcortical Infarcts and Leukoencephalopathy) patient, representative of our sample. After a 12-year-long follow-up period,
significant whole brain atrophy has developed, with major enlargement of ventricles (lateral, 3rd, 4th), whereas cortical sulci are wider and
less deep. By contrast, the global shape of the central sulcus appears stable both on magnetic resonance imaging (MRI) axial slices and on
3-dimensional reconstruction when overlaid on surfaces meshes (please note that MRI slices are conventionally flipped, but meshes are repre-
sented through a top-down view, with right hemisphere on right side). Meanwhile, significant disability has developed (mRS score from 0 to 2).
1028StrokeApril 2016

associated with IRL. Results were significant both in univari- Sources of Funding
ate analyses and after adjustment for potential confounders. This work was supported by grants from the French Ministry
Furthermore, adding pyramidal involvement as a covariate of Health (Regional and National PHRC AOR 02-001), an FP7
in the different regression models led to lower and less sig- ERA-NET NEURON grant (01EW1207), and grants from the
Vascular Dementia Research Foundation and the Fondation Leducq
nificant effect of IRL as a predictor of mRS (data not shown).
(Transatlantic Network of Excellence on the Pathogenesis of Small
Altogether, these additional results strongly support that the Vessel Disease of the Brain) (http://fondationleducq.org).
link between IRL and mRS is actually mostly mediated by
motor involvement. Moreover, given the few values allowed
Disclosures
by this score (05), sampling variations may promote the None.
detection of significant results because of chance alone.
However, we found similar results with the Barthel Index,
another measure of disability largely independent from the
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Downloaded from http://stroke.ahajournals.org/ by guest on March 19, 2017
Shape of the Central Sulcus and Disability After Subcortical Stroke: A Motor Reserve
Hypothesis
Eric Jouvent, Zhong Yi Sun, Franois De Guio, Edouard Duchesnay, Marco Duering, Stefan
Ropele, Martin Dichgans, Jean-Franois Mangin and Hugues Chabriat
Downloaded from http://stroke.ahajournals.org/ by guest on March 19, 2017

Stroke. 2016;47:1023-1029; originally published online March 3, 2016;


doi: 10.1161/STROKEAHA.115.012562
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