Stroke

BRIEF REPORT

White Matter Abnormalities in Spontaneous

Subarachnoid Hemorrhage
A Tract-Based Spatial Statistics Study
Sung Jun Lee, BS; Min Son Kim , MD; Sung Ho Jang , MD

BACKGROUND AND PURPOSE: We investigated white matter abnormalities in patients with spontaneous subarachnoid hemorrhage
following aneurysmal rupture, by using tract-based spatial statistics.

METHODS: Sixteen patients with spontaneous subarachnoid hemorrhage due to aneurysmal rupture and 18 age- and
sex-matched healthy control subjects were recruited. Voxel-wise statistical analysis of fractional anisotropy data was
performed by using tract-based spatial statistics as implemented in the Functional Magnetic Resonance Imaging of the
Brain Software Library. We calculated mean fractional anisotropy values across the tract skeleton and within 48 regions
of interest based on the intersections between the fractional anisotropy skeleton and the probabilistic Johns Hopkins
University white matter atlases.

RESULTS: Comparing the patient and control groups, the fractional anisotropy values of 44 regions of interest among the
48 regions of interest showed significant differences (P<0.05). However, significant differences were not observed in the
remaining 4 regions of interest (both retrolenticular parts of the internal capsule, the right superior longitudinal fasciculus,
and the right superior corona radiata; P>0.05).
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CONCLUSIONS: By undertaking tract-based spatial statistics analysis, we detected wide-ranging white matter abnormalities in
patients with spontaneous subarachnoid hemorrhage.

REGISTRATION: URL: http://www.e-irb.com/index.jsp. Unique identifier: 2019-06-032.

Key Words:  diffusion tensor imaging ◼ subarachnoid hemorrhage ◼ tract-based spatial statistics ◼ white matter

S
pontaneous subarachnoid hemorrhage (SAH) is the
extravasation of blood into the subarachnoid space
that occurs mainly after the rupture of an aneurysm
of the cerebral arteries.1,2 More than half of patients with
spontaneous SAH are reported to show various neuro-
logical symptoms suggestive of SAH-related brain inju-
ries.1,2 Regarding the pathophysiological mechanisms
of SAH-related brain injury, several mechanisms have
been suggested, including global vasogenic edema in
both white and deep gray matter, vasospasm and cere-
bral ischemia, mechanical injury (via increased intra-
cranial pressure by or direct mass effect of the SAH),
and chemical injury (a blood clot can cause neural injury
through the release of potentially damaging substances,
such as free iron, which may result in the generation of
free radicals or inflammatory cytokines).3–6 However, to
date, the pathophysiological mechanisms of SAH have
not been fully elucidated.
A few diffusion tensor imaging (DTI)-based studies
have suggested that axonal injury resulting from baro-
trauma following spontaneous SAH is a pathological
finding that is similar to traumatic brain injury (TBI), in
which axonal injury is a consistent feature.6–10 A distinct
advantage of DTI is its ability to identify microstructural

 
Correspondence to: Sung Ho Jang, MD, Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University 317-1, Daemyungdong,
Namku, Daegu, 705-717, Republic of Korea. Email strokerehab@hanmail.net
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.120.029996.
For Sources of Funding and Disclosures, see page e249
© 2020 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

e246   September 2020 Stroke. 2020;51:e246–e249. DOI: 10.1161/STROKEAHA.120.029996

 Jun Lee et al
Nonstandard Abbreviations and Acronyms
DTI diffusion tensor tractography
FA fractional anisotropy
ROI region of interest
SAH subarachnoid hemorrhage
TBI traumatic brain injury
white matter abnormalities that are not usually detect-
able through conventional brain magnetic resonance
imaging.5 Many studies have used DTI to demonstrate
SAH-related brain injury, and the majority of these stud-
ies have reported on injuries of neural tracts that are
located adjacent to the subarachnoid space.3,11,12 By con-
trast, little has been reported on the effect of SAH on the
whole white matter.8,12
In this study, by using tract-based spatial statistics, we
investigated the white matter abnormalities in patients
with spontaneous SAH following aneurysmal rupture
(Data Supplement).
METHODS
Subjects
The data that support the findings of this study are available
from the corresponding author upon reasonable request.
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Sixteen patients (6 men, 10 women; mean age 60.63±9.60
years; range, 46–79 years) with spontaneous SAH and 18
age- and sex-matched healthy control subjects (8 men, 10
women; mean age 55.56±10.88 years; range, 40–77 years)
with no history of neurological/psychiatric disease or head
trauma were recruited. The patients were recruited consecu-
tively according to the following inclusion criteria1: first-ever
stroke2; SAH due to aneurysmal rupture and confirmed by a
neuroradiologist3; and DTI data obtained during the chronic
SAH stage (>4 weeks after onset). Patients with intracere-
bral hemorrhage, intraventricular hemorrhage, hydrocephalus,
or a definite lesion in the brain parenchyma were excluded.
The demographic data for the patient and control groups are
summarized in Table I in the Data Supplement. No significant
difference in age or sex distribution was observed between
the patient and control groups (P>0.05). The written informed
consent was not obtained from the patients because this
study was performed retrospectively, and the study protocol
was approved by the institutional review board of our university
hospital (Methods in the Data Supplement and Figure).
RESULTS
The results of the voxel-wise comparison of the frac-
tional anisotropy (FA) values of the patient and control
groups are summarized as shown in Table II in the Data
Supplement. Among the 48 ROIs assessed, the FA val-
ues of 44 ROIs were significantly different between the
Stroke. 2020;51:e246–e249. DOI: 10.1161/STROKEAHA.120.029996
White Matter Abnormalities in SAH
patient and control groups (P<0.05; Figure). No signifi-
cant differences were detected among the 4 remaining
Brief Report
ROIs (both retrolenticular parts of the internal capsule,
the right superior longitudinal fasciculus, and the right
superior corona radiata; P>0.05).
The correlations between clinical scales and the FA
values of 44 ROIs (Data Supplement).
DISCUSSION
In this study, we investigated microstructural differences
in the subcortical white matter of SAH patient and nor-
mal control groups and determined that the FA values in
44 of the 48 ROIs examined were lower in the patient
group than in the control group. Among the various DTI
parameters, FA is the most commonly used diagnostic
parameter and is sensitive to microstructural changes in
white matter integrity by indicating the degree of direc-
tionality of water diffusion. Our results showing that the
FA values of 44 ROIs among the 48 ROIs assessed were
significantly lower in the patient group than in the control
group indicates the presence of decreased microstruc-
tural integrity in these neural structures in the patient
group. The results suggest that spontaneous SAH fol-
lowing aneurysmal rupture can induce abnormalities in
widespread areas of the brain’s white matter.
The correlations between clinical scales and the FA
values of 44 ROIs (Data Supplement).
A few studies using brain magnetic resonance imag-
ing have reported extensive changes in the brain of
patients with SAH.5,6,8 In 2007, Liu et al5 demonstrated
increments in the mean diffusivity value, which indicate
the magnitude of the water diffusion, of brain gray and
white matters (parietal, temporal, occipital lobes; cerebel-
lum; caudate nucleus; lentiform nucleus; thalamus; and
pons), except for the frontal lobe, on diffusion-weighted
images of 100 patients whose brain scans appeared
normal on T2-weighted and diffusion-weighted mag-
netic resonance imaging following aneurysmal SAH.5
Consequently, the authors suggested that SAH might
cause global mild vasogenic edema in the deep gray
and whiter matter areas. Subsequently, Reijmer et al12
reported that 49 patients with aneurysmal SAH had
higher mean diffusivity in the white matter than that of
22 patients with unruptured aneurysms at 2 weeks after
onset. As a result, the authors concluded that patients
with SAH have temporary white matter abnormalities
during the subacute stage following aneurysmal SAH.12
In 2016, Sener et al8 compared whole-brain DTI trac-
tography of 23 patients with aneurysmal SAH and 20
patients with severe TBI. Significant differences were
observed in FA values, the total number of tracts, and
the average tract lengths between survivors and non-
survivors of SAH and TBI; moreover, sensitivity analysis
revealed consistent results for various DTI measures
September 2020   e247
 Jun Lee et al White Matter Abnormalities in SAH
Brief Report
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Figure. Results of tract-based spatial statics analyses comparing fractional anisotropy (FA) values of the patient and control
groups, and the standard template of JHU diffusion tensor imaging-based white matter atlas.
A, The blue voxels represent areas of significantly higher mean FA values in the control group compared with the patient group. B, The 48 region
of interests (ROIs; Figure I in the Data Supplement). Among the 48 ROIs, the FA values of 44 ROIs are significantly different between the patient
and control groups except for the 4 ROIs (red rectangular boxes: both retrolenticular parts of the internal capsule [21 and 22], right superior
longitudinal fasciculus [41], and right superior corona radiata [25]).

between the SAH and TBI patients. Hence, the authors
concluded that similar patterns were present in both
SAH and TBI patients. Previously, Kummer et al6 had
demonstrated that the white matter abnormality in SAH
was an axonal injury, an observation that was confirmed
through histological, ultrastructural, and DTI studies in
animal (rodent) brain. As a result, the authors suggested
that acute SAH-induced brain injury may resemble
a form of endogenous TBI and that barotrauma from
pressure waves is a mechanism of SAH-related brain
injury. That conclusion was based on the Powers’ study
which suggested that intracerebral hemorrhage and TBI
share the presence of barotrauma arising from pressure
waves propagating through the intracranial content as
a common mechanism of brain injury.7 Taken together,
we suggest that the white matter abnormalities in the
patients with SAH in the present study might be reflec-
tive of axonal injuries induced by barotrauma following
spontaneous SAH. However, further studies to con-
firm the pathological findings of and the mechanisms
involved in spontaneous SAH should be undertaken.
To the best of our knowledge, we think this is the
first study to demonstrate white matter abnormality in
spontaneous SAH patients by using tract-based spa-
tial statistics. However, some limitations of this study
should be considered. First, the small number of sub-
jects enrolled is a limitation of the study. Second, we
could not provide relevant clinical data for the subjects
because this study was performed retrospectively.
Hence, further prospective studies that include larger
numbers of subjects and collect detailed clinical data
are warranted.

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 Jun Lee et al
In conclusion, by applying the tract-based spatial
statistics approach, we were able to detect widespread
white matter abnormalities in patients with SAH. We sug-
gest that our results could be helpful in the planning of
patient neurorehabilitation because precise estimation of
the extent and severity of neural injury is necessary for
establishing suitable therapeutic strategies and for pre-
dicting prognosis. Furthermore, we believe our results will
be useful in future studies into clarifying the pathophysi-
ology of brain injury in spontaneous SAH.
ARTICLE INFORMATION
Received March 17, 2020; final revision received April 28, 2020; accepted June
25, 2020.
Affiliation
Department of Physical Medicine and Rehabilitation, College of Medicine, Yeung-
nam University, Namku, Daegu, Republic of Korea.
Sources of Funding
This work was supported by the National Research Foundation of Korea (NRF)
grant funded by the Korean Government (MSIP; No. 2018R1A2B6000996).
Disclosures
None.
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