Stroke

BRIEF REPORT

White Matter Integrity and Chronic Poststroke

Upper Limb Function: An ENIGMA Stroke
Recovery Analysis
Martin Domin , PhD; Brenton Hordacre , PhD; Pavel Hok , PhD, MD; Lara A. Boyd , PhD; Adriana B. Conforto , PhD, MD;
Justin W. Andrushko , PhD; Michael R. Borich , PhD, DPT; Richard C. Craddock , PhD; Miranda R. Donnelly , MSc;
Adrienne N. Dula , PhD; Steven J. Warach , MD; Steven A. Kautz , PhD; Bethany P. Lo , BSc; Christian Schranz , PhD;
Na Jin Seo , PhD; Shraddha Srivastava , PhD; Kristin A. Wong , MD; Artemis Zavaliangos-Petropulu , PhD;
Paul M. Thompson, PhD; Sook-Lei Liew , PhD, OTR/L; Martin Lotze , PhD, MD

BACKGROUND: Integrity of the corticospinal tract (CST) is an important biomarker for upper limb motor function following
stroke. However, when structurally compromised, other tracts may become relevant for compensation or recovery of function.

METHODS: We used the ENIGMA Stroke Recovery data set, a multicenter, retrospective, and cross-sectional collection of patients
with upper limb impairment during the chronic phase of stroke to test the relevance of tracts in individuals with less and more
severe (laterality index of CST fractional anisotropy ≥0.25) CST damage in an observational study design. White matter integrity
was quantified using fractional anisotropy for the CST, the superior longitudinal fascicle, and the callosal fibers interconnecting the
primary motor cortices between hemispheres. Optic radiations served as a control tract as they have no a priori relevance for the
motor system. Pearson correlation was used for testing correlation with upper limb motor function (Fugl-Meyer upper extremity).
Downloaded from http://ahajournals.org by on September 6, 2023

RESULTS: From 1235 available data sets, 166 were selected (by imaging, Fugl-Meyer upper extremity, covariates, stroke
location, and stage) for analyses. Only individuals with severe CST damage showed a positive association of fractional
anisotropy in both callosal fibers interconnecting the primary motor cortices (r[21]=0.49; P=0.025) and superior longitudinal
fascicle (r[21]=0.51; P=0.018) with Fugl-Meyer upper extremity.

CONCLUSIONS: Our data support the notion that individuals with more severe damage of the CST depend on residual pathways
for achieving better upper limb outcome than those with less affected CST.

GRAPHIC ABSTRACT: A graphic abstract is available for this article.

Key Words: diffusion tensor imaging ◼ corticospinal tract ◼ neuroimaging ◼ stroke ◼ upper extremity ◼ white matter

T
he importance of corticospinal tract (CST) integrity
passing the posterior limb of the internal capsule
following stroke is well-documented in upper limb
motor recovery (chronic stage1,2; acute stage3). However,
for individuals with severe CST damage, other tracts may
become more important to regain upper limb function.
Several studies have reported that the integrity of other
structural pathways might help facilitate recovery of the
upper limb. These tracts are the superior longitudinal
fascicle (SLF3,4) and the callosal fibers interconnecting
the primary motor cortices (CC_M15–8). In a multicenter
approach, we assessed the relevance of SLF and CC_M1
integrity for motor outcome after severe CST damage.
METHODS
Data from the ENIGMA Stroke Recovery Working Group were
collected from multiple sites and cohorts, comprising 1235

Correspondence to: Martin Lotze, PhD, MD, Center for Diagnostic Radiology and Neuroradiology, University of Greifswald. Email martin.lotze@uni-greifswald.de
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.123.043713.
For Sources of Funding and Disclosures, see page 2440–2441.
© 2023 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

2438   September 2023 Stroke. 2023;54:2438–2441. DOI: 10.1161/STROKEAHA.123.043713

 Domin et al
patients with stroke (data are available on request from the
corresponding author; see Table S1). The group’s methods
and data repository have been described elsewhere.9 For the
current study, data was frozen on November 22, 2022 and
selected for participants with chronic upper limb motor impair-
ment that had T1-weighted and diffusion-weighted MRI (at
least 30 directions), the Fugl-Meyer upper extremity (FMUE)10
assessment, age, and sex covariates. MRIs used in this study
were performed in the chronic phase of stroke (equal or greater
than 180 days poststroke onset), at the same time as the
behavioral assessments.
Structural integrity of the tracts (ipsilesional: CST and SLF,
interhemispheric: CC_M1; Supplemental Material) was quanti-
fied by fractional anisotropy (FA) from DWI scans and a lateral-
ity index (LI) was calculated for CST, where LI ≥0.25 indicated
severe FA asymmetry within CST.11
The optic radiation was used as a reference tract as we
expected no relevant effect when associated with FMUE. We
performed Pearson correlation analyses between FA within each
tract and FMUE for all individuals with LI<0.25 (n=145), and
LI≥0.25 (n=21) separately. To compare our results (with respect
to CC) with those reported by Hayward et al8 and extend them
to the SLF, we also performed separate associations with FA
in CC_M1 and SLF for each impairment severity group (severe:
FMUE≤30; nonsevere: FMUE>30). Differences between individ-
uals with severe or less severe CST damage, with regard to their
association of tract integrity with FMUE, were calculated using
Fisher Z tests. Details of the methods and data are described
in the Supplemental Material. FA was defined as the predic-
tor for the outcome parameter FMUE. This study was reported
according to the STROBE (Strengthening the Reporting of
Downloaded from http://ahajournals.org by on September 6, 2023
Observational Studies in Epidemiology) guidelines.12
Written informed consent was obtained from all subjects,
and data were collected in compliance with each institu-
tion’s local ethical review boards and in accordance with the
Declaration of Helsinki.
RESULTS
From 1235 stroke patients, 166 were eligible for analy-
sis (age: 60.9±13.0 years; 66 female; years poststroke:
4.45±4.56; FMUE score: 39.22±16.35, 80 showed
left, 70 right, 5 bilateral, 4 cerebellar/multiple lesions,
and 3 brainstem lesions). See the Supplemental Mate-
rial for details comparing patient groups. Overall, FA
differed by tracts and hemispheres (F[2165]=33.29;
P≤0.001). There were more individuals showing severe
asymmetry for the anterior compartments of the CST
(ventral and dorsal premotor cortex: 39/38 of 166 par-
ticipants) than for the posterior ones (superior parietal
lobe/primary somatosensory cortex [S1]/M1: 23/28/33
of 166 individuals; Figure [A]). LI was more symmetrical
for SLF (LI=0.07±0.13) than for CST (LI=0.10±0.15;
t[165]=2.04; P=0.043). As expected, integrity of the
complete CST and its subparts was positively asso-
ciated with FMUE (CST: r[166]=0.45, P≤0.001;
CSTdorsalpremotorcortex: r[166]=0.35, P≤0.001; CSTventral­premotorcortex:
r[166]=0.39, P≤0.001; CSTM1: r[166]=0.50, P≤0.001;
CSTsomatosensory cortex: r[166]=0.43, P≤0.001; CSTsuperior parietal lobe:
Stroke. 2023;54:2438–2441. DOI: 10.1161/STROKEAHA.123.043713
Poststroke Motor Function—White Matter Integrity
r[166]=0.37, P≤0.001). There was no detectable associa-
tion between FMUE score and LI of the reference tract
(optic radiation, r[166]=−0.12; P=0.124).
Brief Report
Individuals with severe CST damage (LI≥0.25) exhib-
ited lower FMUE (24.42±11.35) than those with less
asymmetry (41.58±15.84; t[164]=4.71; P≤0.001).
FMUE positively correlated with FA of the SLF and
CC_M1 in individuals with severe damage, but not less
severe damage (Figure [B]). This difference was sig-
nificant (SLF: Z=1.90; Pone-sided=0.029; CC_M1: Z=1.65;
Pone-sided=0.049).
When differentiating impairment severity (severe:
n=59; nonsevere: n=107), we found comparable results
for the CC_M1 to those reported by Hayward et al8
(severe: r=0.277; Pone-sided=0.017; nonsevere: r=0.142;
Pone-sided=0.072).
DISCUSSION
With increasing damage in the posterior limb of the
internal capsule, the residual integrity of the SLF in the
affected hemisphere in combination with the M1_CC
becomes important for upper limb motor outcome in the
chronic stage following stroke. These findings support
previous reports suggesting that SLF and CC integrity
are critical for upper limb motor recovery in individuals
with more severe CST damage.3,4,8 Our data support find-
ings from another multicenter study showing that callosal
motor fiber integrity is related to upper limb motor per-
formance only for individuals with severe CST damage.8
One explanation for the importance of SLF in individu-
als with severe CST damage might relate to the role of
the ipsilesional dorsal premotor cortex and ventral pre-
motor cortex for stroke recovery.13,14 The SLF contributes
to connections between the frontoparietal motor areas
to support grasp movements.15 Interactions between
the premotor cortex and the parietal lobe might play an
increasingly important role after CST damage following
stroke.4 Another possibility might be that SLF integrity
is compensatory as it contributes to cognitive integrity
following stroke.16 This should be tested in future studies
combining cognitive and motor testing in these patients.
In addition, age differed between CST damage groups
(Table S2). However, the younger group showed more
severe CST damage which is most probably an effect
of patient recruitment. Limitations of this study include
potential bias as the selected cohorts may not represent
the full population of individuals with stroke, as well as
the small sample size of the severely impaired group,
which is generally limited in research studies due to addi-
tional barriers to participation.
Overall, multicenter studies of stroke samples can
demonstrate small effect sizes associating white matter
damage with functional outcomes. Our findings empha-
size the importance of differentiating subgroups for upper
limb impairment severity when investigating the role of
September 2023   2439
 Domin et al Poststroke Motor Function—White Matter Integrity
Brief Report

Figure. Diffusion weighted imaging characteristics and associations with motor outcome.
A, Seed-to-target parcellation of the posterior limb of the internal capsule (PLIC). The corticospinal tract (CST) consisted of compartments based on
Downloaded from http://ahajournals.org by on September 6, 2023

seeds in the ventral and dorsal premotor cortex (vPMC, dPMC), primary motor (M1), and somatosensory (S1) cortex, and superior parietal lobe (SPL).
For each parcel, lateralization index (LI) of fractional anisotropy (FA) was calculated as a measure of CST damage. A threshold of LI≥0.25 (single parcel
or entire PLIC) resulted in different group sizes, reflecting damage severity. In general, the more anterior the more affected were the CST compartments
(upper right). B, left, Superior lateral fasciculus (SLF) integrity (tract visualization coded in green). The SLF of the affected hemisphere is relevant for
Fugl-Meyer upper extremity (FMUE) outcome only for those with severely damaged corticospinal tract (LI≥0.25; red dots, r[21]=0.51; P=0.018; Fisher
Z=1.90; Pone-sided=0.029). Correlation between FMUE and FA was absent for those with nonsevere CST damage (blue dots, r[145]=0.089; P=0.29).
Right, The M1-part of the corpus callosum (callosal fibers interconnecting the primary motor cortices [CC_M1]) is shown in red in a rendered glass brain.
Correlation between FMUE and FA was absent for those with nonsevere CST damage (blue dots; r[145]=0.12; P=0.15) but present for those with more
severe CST damage (red dots; r[21]=0.49; P=0.025; Fisher Z=1.65; Pone-sided=0.049). A indicates anterior; L, left; P, posterior; and R, right.

biomarkers and treatment approaches. We conclude that,
especially for those individuals with severe CST damage,
the integrity of SLF and CC_M1 tracts should be con-
sidered for more profound upper limb motor outcome
prognosis.
ARTICLE INFORMATION
Informatics Institute, Keck School of Medicine (P.M.T.), University of Southern
California, Los Angeles. Department of Neurology, Dell Medical School at The
University of Texas Austin (A.N.D., S.J.W.). Department of Health Sciences &
Research (S.A.K., N.J.S., S.S.) and Department of Rehabilitation Sciences (C.S.,
N.J.S.), Medical University of South Carolina, Charleston. Ralph H. Johnson VA
Health Care System, Charleston, SC (S.A.K., N.J.S.). Brain Mapping Center, De-
partment of Neurology, Geffen School of Medicine, University of California, Los
Angeles (A.Z.-P.). Mark and Mary Stevens Neuroimaging and Informatics Insti-
tute, Keck School of Medicine, University of Southern California, Los Angeles,
CA (S.-L.L.).

Received April 28, 2023; final revision received June 23, 2023; accepted June
26, 2023.
Affiliations
Functional Imaging Unit, Diagnostic and Neuroradiology, University Hospital
Greifswald, Germany (M.D., P.H., M.L.). IIMPACT in Health, University of South
Australia, Adelaide (B.H.). Department of Physical Therapy, University of British
Columbia, Vancouver, Canada (L.A.B., J.W.A.). Hospital das Clínicas, São Paulo
University, Brazil (A.B.C.). Hospital Israelita Albert Einstein, São Paulo, Brazil
(A.B.C.). Department of Rehabilitation Medicine, Emory School of Medicine, At-
lanta, GA (M.R.B.). Department of Diagnostic Medicine (R.C.C.) and Department
of Physical Medicine & Rehabilitation (K.A.W.), The University of Texas at Austin.
Chan Division of Occupational Science and Occupational Therapy (M.R.D., B.P.L.,
S.-L.L.) and Imaging Genetics Center, Mark & Mary Stevens Neuroimaging &
Sources of Funding
This study did receive funding for gathering data sets in each center (Dr Lo-
tze: Deutsche Forschungsgemeinschaft [DFG]: LO 795/7-1; Dr Boyd: Canadi-
an Institutes of Health Research; Dr Liew: National Institutes of Health (NIH)
R01NS115845, Dr Seo: NIH/National Institute of General Medical Sciences
P20 GM109040, NIH/National Institute of Child Health and Human Develop-
ment/National Center for Medical Rehabilitation Research R01 HD075813).
Disclosures
Dr Hordacre has a clinical partnership with Fourier Intelligence. Dr Conforto is a
consultant for Boehringer Ingelheim. Dr Kautz reports grants from US Depart-
ment of Veterans Affairs and grants from National Institute of General Medical
Sciences. Dr Thompson has received research grant support from Biogen, Inc, for

2440   September 2023 Stroke. 2023;54:2438–2441. DOI: 10.1161/STROKEAHA.123.043713

 Domin et al
research unrelated to this article. Dr Warach is a consultant for Genentech and
BrainsGate. The other authors report no conflicts.
Supplemental Material
Supplemental Methods
Tables S1–S2
References 17–19
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