Stroke
TOPICAL REVIEW
Artificial Intelligence Applications in Stroke
Kim Mouridsen , PhD; Patrick Thurner, MD; Greg Zaharchuk, MD, PhD
M anagement of stroke highly depends on informa-tion
from imaging studies. Noncontrast computed tomography
(CT) and magnetic resonance imag-ing (MRI) can both be
used to distinguish between isch-
emic and hemorrhagic stroke, which is difficult based on
clinical features. Hypodensity on CT and DWI hyper-
intensity on MRI identifies irreversibly damaged tissue,
although the sensitivity of MRI is higher in the acute set-
ting. Angiographic and perfusion imaging sequences can
identify a large vessel occlusion and, along with perfu-sion
imaging, can select patients for endovascular ther-apy.
The FLAIR-DWI mismatch yields information about
patients with unknown time of onset (including wake-up
strokes). Stroke imaging also gives insight into progno-sis,
with current methods aiming to give a picture of the short-
term consequences of successful reperfusion or continued
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large vessel occlusion. One important caveat about stroke
imaging is that it must be done quickly, as faster treatment
leads to better outcomes.1 However, most steps in the
stroke imaging triage pathway require the presence of
human radiologists and neurologists, and this is often the
time-limiting step. The expertise required for these tasks
may not be available at all sites or at all times. Therefore,
there is interest in automated methods for stroke imaging
evaluation.
Artificial intelligence (AI) is a broad term reflecting the
use of computers to perform tasks that humans may find
difficult, often in ways that are hard to pinpoint. For
example, although humans find high-level computa-tion
difficult, calculator technology is not considered AI
because we know how to break this down into discrete
steps and feel we understand it. However, facial recogni-
tion is a task that humans perform well, but an algorithm to
identify faces is usually considered AI since we cannot
articulate precisely how this is done. Machine learning
(ML) is a subset of AI in which algorithms learn from
Key Words: artificial intelligence
Correspondence to: Kim Mouridsen, PhD, CFIN, Aarhus University Hospital, Bldg 1A, 1st Floor, Nørrebrogade 44, DK-8000 Aarhus C, Denmark. Email kim@cfin.au.dk
For Sources of Funding and Disclosures, see page 2578.
© 2020 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str
Stroke. 2020;51:2573–2579. DOI: 10.1161/STROKEAHA.119.027479
the data itself without explicit programming. ML methods
reflect a broad range of statistical techniques ranging from
linear regression to more complex methods such as
support vector machines and decision trees. ML meth-ods
can be further broken into supervised and unsuper-vised
learning, which differ from one another in that the former
requires access to gold standard labels although the latter
attempts to find the answers implicitly in the data itself.
While ML methods have grown more popular over recent
years, the advent of a specific supervised ML method
based on architectures resembling human neu-ral
networks over the past decade has led to a quantum leap
in performance.2 This method, called deep learning (DL)
because of many multiple internal layers, can be
considered a transformative technology. Compared with
previous methods that required humans to identify image
features, a deep neural network trained on a dataset with
known outputs can learn the best features for organiz-ing
the data. In this review, we will discuss ML methods
applied to stroke imaging with an emphasis on DL appli-
cations. We refer to Figure for a graphical overview of the
applications discussed in this review.
FROM LINEAR THRESHOLDS TO
DEEP LEARNING
Early approaches to image analysis relied on apply-ing
fixed threshold values to quantitative maps to pre-dict
information of interest, such as the amount of infarcted
tissue on follow-up or the location of hemor-rhagic
transformation. While simple to implement, apply-ing
threshold values can fail due to patient cohort and scan
heterogeneity as well as post-processing variations.
More fundamentally, the underlying assumptions are
usually physiologically too simplistic as tissue outcome
deep learning hemorrhage ischemia machine learning
August 2020  2573
 Mouridsen et al
Nonstandard Abbreviations and Acronyms
Topical Review
AUC area-under-the-curve
CNN convolutional neural network
CT computed tomography
DL deep learning
ML machine learning
MRI magnetic resonance imaging
depends on many factors, such as location, tissue type,
and collaterals, which may be reflected on other imaging
sequences or modalities. Due to this complexity, there is a
need to flexibly combine different kinds of imaging and
clinical characteristics to best represent overall treat-ment
potential and guide management.
The natural progression from thresholds of individual
image features is to combine them, a technique known as
linear or logistic regression. To predict a continuous
variable, such as size of infarct, linear regression is used.
If the objective is classification into binary outcomes such
as good clinical outcome (ie, modified Rankin Scale score
≤2), logistic regression can be used. This is where one of
the most important questions arises: which pre-dictors
should be included? This has been the domain expertise
of countless generations of scientists and is often (but not
always) based on theories of underlying biological
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principles. A particular challenge with voxel-level
prediction is that the characteristics of surround-ing tissue
likely also have an influence. Differences in image-based
algorithm performance are due to both the imaging feature
choices and the methods on how to combine information
about their spatial relationship. More recently, other ML
methods have been proposed that go beyond the limits of
regression, particularly those imposed by linear models.
These include support vector machines, classification
trees, random forests, and dis-criminant analysis that can
combine features in nonlinear
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Artificial Intelligence Applications in Stroke
ways, via kernels or nonlinear transformations to
obtain more flexible decision boundaries.
The truly transformative aspect of DL methods is that
they do not require a priori assumptions of what image
features are important. Instead, the network learns to
identify them implicitly. With DL, features are automati-
cally identified and encoded in the network of hidden
layers. For this reason, the time to implement these
methods is drastically reduced. In this review. we will
review AI applications in stroke imaging showing that
these methods can be used in many settings, including
classification, segmentation, and image synthesis. One
important point about DL methods is that they continue to
improve with access to very large amounts of data,
whereas classical ML methods tend to plateau at lower
performance levels despite access to the same data. The
specific choice of ML method is still more an art than a
science, though typically DL works well with large amounts
of data while classical ML methods have advan-tages for
smaller datasets. It is important to realize that DL is still in
its early days, and its performance does not always
exceed that of more classical approaches involv-ing hand-
selected features.
AI TO IMPROVE IMAGE QUALITY
AND SPEED
Stroke imaging is central to patient triage but concerns
have been raised about time delays associated with brain
scanning. For this reason, arguments have been made
against the use of advanced imaging such as CT perfu-
sion or MRI, which tend to take longer to acquire and
process than noncontrast CT and CT angiography. Most
MRI stroke protocols require <10 minutes of scan time,
although MRI does require more detailed screening and
patient transfer time than CT. Thus, reducing scan time
with MRI continues to be important and is desirable given
the high tissue contrast of DWI and its specificity for tissue
highly likely to be irreversibly damaged.
Figure. Graphical overview of the
main applications of artificial
intelligence (AI) in acute ischemic
stroke.
During the acute phase, the main interest is
in supporting detection of key imaging
characteristics such as presence of large
vessel occlusion, presence of hemorrhage,
and volume of irreversibly damaged and
potentially salvageable tissue. AI can
be used to predict short-term imaging
outcome or can be applied to aid image
reading at this time. Similarly, AI can be
used to predict long-term functional
outcome based on acute imaging.
Stroke. 2020;51:2573–2579. DOI:
 Mouridsen et al
AI-inspired methods can improve the quality of medi-cal
images, allowing them to be acquired faster or at lower
dose. In particular, reconstruction algorithms based on
deep convolutional neural networks (CNNs) are well-
suited to this task. One example with relevance to acute
stroke imaging is the ability to use a CNN to de-noise MR
brain perfusion images using arterial spin labeling,
allowing diagnostic images to be created with shorter
scans.3 This approach has been applied to other MR
sequences as well, including quantitative susceptibility
mapping, which can detect brain hemorrhage and calci-
fication.4 Given concerns regarding gadolinium deposi-tion
following MR contrast administration, an AI method that
can significantly reduce the amount of gadolinium required
for diagnostic imaging may find application for bolus
perfusion-weighted imagin.5 While it is difficult to
significantly shorten acquisition times given the speed of
modern multidetector CT scanners, CNNs can be used to
reduce radiation dose.6 This may be helpful to allay
radiation concerns related to CT perfusion imaging, a
relatively high-dose procedure.7
Another approach is to use DL to predict gold stan-dard
imaging biomarkers in situations where they are infeasible
to obtain. One example is that of cerebral blood flow
imaging, where the reference standard is 15O-water
positron emission tomography. Given the 2-minute half-life
of 15O, this requires an on-site cyclo-tron and 24-7
synthesis capability, which limits its use for acute diseases
such as stroke. However, it is pos-sible to train a deep
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CNN to predict 15O-water CBF using only MR images in
more stable patients, includ-ing subacute and chronic
ischemia.8 Then, this trained model can be applied in the
acute setting using only MR images to estimate the true
perfusion in patients with stroke. Such a paradigm could
be used more broadly, for example, to predict CTP results
from CT and CTA images, or to predict Tmax lesions from
noncontrast MR scans. Thus, the complex relationship
between the desired imaging biomarkers and those that
are feasible to obtain in the acute setting can be learned in
advance, and then applied on the fly in patients with
stroke. This area is largely unexplored but offers the
potential to optimize imaging in a wide range of settings.
One can also bypass traditional computation of stan-
dard biomarkers, such as the computation of cerebral
blood flow and volume from source CT or MR perfu-sion
images. This is an error-prone process with many steps,
including identification of an arterial input func-tion and a
noise-sensitive computational step where tracer-kinetic
markers are extracted based on dynamic tissue
enhancement and the arterial supply. The resulting
perfusion maps are used to predict the infarcted (core)
and at-risk tissue. However, with AI, this prediction could
also be made directly from the source perfusion images
themselves. This option has been explored9 in a study with
44 patients where a CNN performed better than a
Stroke. 2020;51:2573–2579. DOI: 10.1161/STROKEAHA.119.027479
Artificial Intelligence Applications in Stroke
linear combination of perfusion markers including
cere-bral blood flow, blood volume, and Tmax.
Topical Review
PREDICTING CONTEMPORANEOUS
INFORMATION
Time From Onset
The mismatch between DWI and FLAIR lesions has been
suggested as radiological indicator of whether a stroke is
more than 3 to 4 hours old. 10 If a lesion is visible on DWI but
not on FLAIR, the stroke is believed to have occurred more
recently. In practice, detecting the presence of a DWI-FLAIR
mismatch visually can be challenging. Alter-natively, time from
onset can be directly estimated with machine learning as
described in a study using a combina-tion of neural networks
and classical ML techniques.11 In a first step, features from
the MR source perfusion images were identified using a
neural network–based technique known as an auto-encoder.
In the second step, these fea-tures were combined with DWI
and FLAIR images using a different supervised learning
algorithm (support vector machines and stepwise regression).
In a population of 105 patients with stroke, the authors report
an area-under-the-curve (AUC) of up to 0.68 to classify
patients into before/ after 4.5 hours from symptom onset.
Another group used a similar approach including multimodal
MRI for classifying patients into before/after 6 hours using
logistic regression showed equivalent performance.12
Automating ASPECTS Scoring
The Alberta Stroke Program Early CT Score is a 10-
point scale for middle cerebral artery stroke used to
triage patients for therapy and inclusion in clinical
trials.13 This is a challenging methodology to
standardize and sev-eral studies have reported
automated results using ML software, some of which is
available commercially. A software package called
eASPECTS has been shown to be noninferior to
human experts14 with a noninferi-ority requirement set
at 10%. In one follow-up study, 15 which included also
patients with stroke with preexist-ing pathology
including leukoencephalopathic changes, infarcts, and
atypical parenchymal defects, the auto-mated method
demonstrated lower performance, with an accuracy of
0.67, compared with manual evaluation (0.77–0.80).
Identificating LVOs
Using hand crafted features, several studies using auto-
mated pipelines have shown success in identifying LVOs
of the anterior circulation from CTA images; for exam-
ple,16 who showed 95% sensitivity and 79% specificity.
Although to our knowledge, little has been published in
this area, it has been reported that a CNN may be
August 2020   2575
 Mouridsen et al
used for detection of intracranial large vessel occlusion.
Results17 indicate a 82% sensitivity and 94% specificity
Topical Review
in a 650 person study. In practice, this has been shown
to offer the possibility of early alerting of a senior physi-
cian and aid with task prioritization.
Short-Term Tissue Segmentation:
Identification of Core/At-Risk Tissue
Considerable work has been reported on automated
identification of acute ischemic lesions (this section) and
lesion evolution (the following section). Two important
types of tissue worth identifying on acute stroke stud-ies
are (1) irreversibly damaged tissue (core lesion) and
(2) the ischemic penumbra (at-risk tissue). As these
lesions have a physiological rather than imaging defini-
tion, establishing a reference against which to train and
validate automated methods is challenging. In practice, 2
approaches are used: manual delineation on acute imag-
ing or on follow-up imaging. The former approach aims for
an exact match between radiologist segmentation and
automated identification but assumes that tissue that is
irreversibly damaged or at risk of infarction in the absence
of reperfusion can be unambiguously outlined, which in
practice is challenging. Using follow-up imaging, the
assumption is that the core corresponds to the final tissue
outcome in patients with successful recanaliza-tion and
the at-risk lesion corresponds to the final tissue outcome
in patients with persistent occlusion. Of course, most
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patients do not show all-or-none reperfusion and there are
various confounders (such as who gets treat-ment) such
that this is a difficult method to implement in practice.
An example of automated lesion detection is RAPID18
software, which uses a threshold-based approach. Using
data from the DEFUSE clinical trial, 19 core tissue is iden-
tified by having an ADC of <600×10−6 mm2/s, with at-risk
tissue being defined as having a Tmax ≥6 seconds.
Thresholding is followed by morphological opening to
reduce noise in thresholded images. The algorithm was
validated against a manual reader, who used the same
thresholds for mismatch detection. In 63 patients from the
DEFUSE trial, this yielded 100% sensitivity and 93%
specificity for mismatch detection. Threshold-based
methods are highly sensitive to the particular choice of
cutoff value and can lead to significantly different lesion
volumes,20,21 and much variability is reported across avail-
able threshold-based software packages.22
CNNs have been applied to perform segmentation of
acute stroke lesions from DWI images. 23 In one study,
an initial network identified possible DWI lesions but
had many false positives. Next, another network using
only a few deep layers refined these predictions. With
380 training patients and 361 test patients, the authors
demonstrate an average Dice score in the test set of
0.61 and 0.83 for small and large lesions, respectively.
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Artificial Intelligence Applications in Stroke
This compared to 0.43 and 0.79 for a standard
single-network approach using a U-Net, 24 a popular
choice for image segmentation.
While MR manual delineation of core and at-risk tissue
can be used as target for AI algorithms, manual identifi-
cation of core lesions with CT perfusion is more difficult.
One way to train such a network is on paired sets of CT
and MRI acquired in close temporal proximity. This was
the task for the Ischemic Stroke Lesion Segmenta-tion
(ISLES) 2018 Challenge, where the top-performing
algorithm25 used a 3D neural network architecture to
achieve a Dice score of 0.56. Training (63 patients) and
validation (40 patients) data was from patients present-ing
within 8 hours of symptom onset and with MR DWI
acquired within 3 hours of the CT perfusion.
There is a clear trend that lesion identification and
prediction of short-term tissue outcome is increasingly
often attempted with DL.26 This is clearly seen with the
recent ISLES Challenges (http://www.isles-challenge.
org/). These are open competitions where participants
train algorithms on standardized datasets. Performance
is evaluated on an independent test set where the out-
comes remain unknown to the participants. The com-
petition has focused on lesion detection in MR (2015,
2016), CT (2018), and the prediction of short-term tis-
sue outcome (2019). Such competitions offer a natural
benchmark for algorithm performance and mitigates the
problem of comparing performance between algorithms
due to differences in cohorts, acquisition, and image
preprocessing. The number of DL-based algorithms
increased from 2016 to 2017 with all submitted meth-
ods in 2017 based on deep neural networks.
PREDICTING SHORT-TERM
IMAGING BIOMARKERS
The perfusion-diffusion mismatch can be considered a
very simple dichotomous predictive model. This model
assumes that if a patient recanalizes, the expected out-
come coincides with the acute core lesion. If the patient
does not recanalize, the expected infarct will include also
the previous at-risk tissue. From a physiological as well as
ML point of view, effort may be better spent to directly
predict the short-term tissue outcome based on acute
imaging. Short-term imaging outcome is often defined by
lesions identified on subacute DWI or T2-FLAIR.
Simple combinations of acute imaging modali-ties
using logistic regression have been reported for MR as
well as CT. In one MR study with 14 patients scanned
within 12 hours of onset, it was shown that the final
infarct observed at least 5 days after onset could be
predicted with 84% specificity and 66% sen-sitivity.27
This regression approach has been extended to
acknowledge that relatively few patients account for a
large number of voxels.28 With CT, an overall AUC
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 Mouridsen et al
of 0.85±0.07 was demonstrated in 161 patients in a
study based on CT perfusion and CT angiography
imag-ing <7 hours after onset to predict tissue outcome
after 2 to 7 days.29 However, tissue infarction likely
depends on interactions between imaging markers; that
is, the effect of a change in blood volume might be
modu-lated by concurrent changes in flow. Linear
models can handle such interactions, although this has
been rarely exploited. With logistic regression,
interactions must be explicitly stated before analysis,
which becomes inef-ficient with more complex
interactions and as the num-ber of predictors increase.
Tree-based methods offer a natural framework for
automatically identifying modulations of predic-tor
effects.30 The computationally optimized XGBoost31
extends previously discussed tree-based models. This
algorithm builds a large number of small classification
trees with comparatively low predictive performance but
subsequently combines the weak classifers into a stronger
one. In one report31 using data from the Euro-pean I-Know
study32 and the ischemic per-conditioning study, 28 2
models were trained separately for recanaliz-ing and
nonrecanalizing patients based on perfusion-weighted
imaging and DWI. Predictive performance in the 2 groups
was good, with AUC 0.89 and 0.90, respec-tively, in the
recanalized and nonrecanalized patients.
Neural networks further increase the flexibility in pre-
dicting outcome by simultaneously allowing nonlinearity
and automatically constructing predictive features
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based on raw data. A simple CNN has been used to
predict short-term outcome based on Tmax.33 The
network was comprised of 2 convolution and pooling
layers to predict tissue outcome for the center voxel in
a 23×23 voxel patch. The target was the T2-FLAIR
hyperintense tis-sue region on day 4. The mean
accuracy for the CNN in 19 patients was 85%, higher
than that obtained with a regression model (78%).
Performance can be improved by using multimodal
input as well as adding more layers to the neural net-
work.34 In this implementation, a network is constructed
with 37 layers taking 64×64 image patches as input. In
contrast to,33 a prediction is made for every voxel in the
patch. The network further combines perfusion-weighted
imaging and DWI markers. Training was performed on 158
patients receiving rtPA therapy, and performance was
evaluated on an independent set of 29 patients, yielding
an AUC of 0.88±0.12. The authors compared this to a
shallow CNN, which used the same input modal-ities but
had only 3 layers, with performance decreas-ing to
0.85±0.11. With a 4-layer CNN using only Tmax as input,
there was a marked reduction in performance, with AUC
0.72±0.14. The original deep CNN was further trained on
29 patients who did not receive rtPA therapy and an AUC
of 0.85±0.15 was observed in the remain-ing 6, matching
performance in the rtPA-treated cases. It was shown that
the mean predicted lesion volume for
Stroke. 2020;51:2573–2579. DOI: 10.1161/STROKEAHA.119.027479
Artificial Intelligence Applications in Stroke
rtPA-treated cases (16 mL) was significantly lower than for
untreated patients (29 mL). A more recent study eval-
Topical Review
uated a larger cohort of patients with LVOs. 35 As a first
step, the authors trained the network without knowledge of
reperfusion, yet still achieved better performance in both
minimal and maximal reperfusion patients than by using
current standard-of-care thresholding software. In addition,
this allowed prediction in patients with partial or unknown
reperfusion, which comprise a large num-ber of patients
with stroke. While it is nonintuitive that DL can predict
tissue stroke outcomes regardless of perfusion status
better than current methods that take this into account,
there may be information on the ini-tial images that is
related to the likelihood of subsequent reperfusion. One
approach that maximizes the use of the available patient
data is one in which a model trained on partial or unknown
reperfusion status can then be fine-tuned using smaller
number of cases of minimal and maximal reperfusion, a
powerful method known as trans-fer learning (described in
more detail below).
A fundamental limitation of data-hungry methods such
as DL is the inherent lack of large imaging datas-ets. This
is often mitigated by the use of either pretrain-ing or data
augmentation. With pretraining, a deep neural network is
first trained on a larger dataset of typically nonmedical
images. Then, using the settings obtained from this
training procedure as initial values, the network is adapted
to the particular medical setting, an approach known as
transfer learning. As an alternative or comple-mentary
procedure, a smaller dataset of medical images may be
augmented by adding slightly altered versions of the
original images. Alterations typically include rotations,
magnifications, and adding noise. In this way, a virtually
unlimited number of training images may be created. The
effects of these optimization methods are being studied,
but often lead to significant improvements.36
Hemorrhagic Transformation
Hemorrhagic transformation) is one of the most feared
complications of ischemic stroke. Although proxy-markers
such as a large DWI lesion are used for risk stratification,
predicting this complication or locating where it will occur
remains suboptimal. With MR, a range of ML techniques
have been compared using perfusion-weighted imaging
and DWI for predicting both hemorrhagic transformation
occurrence and location. One study37 compared perfor-
mance of a neural network with a single hidden layer to
many classical ML techniques, including linear regression,
classification, regression trees, support vector machine
with radial basis function kernel, and spectral- and ker-nel
spectral regression extensions of linear discriminant
analysis. In 155 patients, optimal performance was seen
with kernel spectral regression, reaching an AUC of 0.84
and a Dice score of 0.71. Recently, the performance of a
CNN has been reported based on 77 patients from 2
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 Mouridsen et al
stroke centers who experienced hemorrhagic transfor-
mation after reperfusion therapy.38 Sensitivity and speci-
Topical Review
ficity for hemorrhagic transformation location prediction in
anterior circulation was 89% and 60%, respectively, with
an AUC of 0.88. For CT, most studies used classical ML
methods, such as the support vector machine. For
instance, in one study39 with 116 rtPA patients, an AUC of
0.62 was demonstrated. This performance was com-
parable to the radiological SEDAN score (AUC 0.63), but
lower than the HAT score (AUC 0.72). Interestingly, with
the addition of the clinical feature of the acute NIHSS, ML
performance increased significantly (AUC 0.74).
PREDICTION OF LONG-TERM OUTCOMES
While considerable attention has been afforded to lesion
identification and short-term imaging progression, long-
term functional outcome is arguably most significant.
Random forests have been used to predict functional
independence, defined as 90-day modified Rankin Scale
score ≤2, and good reperfusion, defined as modified TICI
≥2b.40 In 1383 patients from the MR CLEAN Registry, the
authors demonstrated poor performance to pre-dict
reperfusion (AUC, 0.53–0.57). However, functional
independence could be moderately well predicted using
baseline variables only (AUC, 0.77–0.79) but well pre-
dicted when treatment variables were included (0.88–
0.91). While random forests performed optimally, other ML
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techniques such as logistic regression yielded vir-tually
identical performance. A random forest approach using
the computationally optimized XGBoost version has also
demonstrated good performance41 in predict-ing good 90-
day clinical outcome. In 512 patients who underwent CT,
CTA, and CT perfusion imaging, an AUC of 0.75 for
prediciting day 90 modified Rankin Scale score ≤2 was
demonstrated. The inclusion of NIHSS at 24 hours
increased performance to an AUC of 0.89.
In 204 patients, a combination of neural networks was
trained to predict improvement in the NIHSS of ≥4 points at 24
hours and a modified Rankin Scale score of 0 to 1 at 90
days.42 A CNN was trained on noncontrast CT data, and a
fully connected feed-forward neural network with 2 hidden
layers was trained with clinical data including blood pressure
and NIHSS at presentation. In combination, they provided
accuracies of 71% (for NIHSS improvement) and 74% (for
good clinical outcome). For comparison, 3 clinical prognos-tic
scores (HIAT, THRIVE, and SPAN-100) achieved maxi-mum
accuracies of 65% (NIHSS improvement) and 68% (good
clinical outcome), emphasizing that ML methods can
outperform existing outcome prediction tools.
FUTURE CONSIDERATIONS
There are many clinically valuable opportunities for AI in
the acute and subacute phases of ischemic stroke. Most
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Artificial Intelligence Applications in Stroke
studies have used retrospective data with sample sizes
ranging typically from 20 to a few hundred. There is a
clear need for larger and especially prospective evalua-
tions building on the successful proof-of-concept
reports. While much work has yet to be done, some of
the meth-ods reviewed here have obtained regulatory
clearance and are commercially available.
While most attention currently is devoted to increas-
ing predictive accuracy, endowing AI solutions with the
ability to account for their predictions would likely facili-
tate even better clinical applicability and acceptance.
Leveraging AI to identify new disease mechanisms and
unrealized connections between imaging and clini-cal
findings predictive of short- and long-term outcome
would allow AI to accelerate patient management and
increase safety. It may also serve as means of
hypothe-sis generation—paving the way to real deep
learning and understanding of acute ischemic stroke.
ARTICLE INFORMATION
Affiliations
Center of Functionally Integrative Neuroscience and MINDLab, Institute of
Clini-cal Medicine, Aarhus University, Denmark (K.M.). Universitätsklinik für
Radiologie und Nuklearmedizin, Vienna General Hospital, Austria (P.T.).
Diagnostic Radiology, Stanford University School of Medicine, CA (G.Z.).
Disclosures
Dr Mouridsen participates in Cercare Medical, equity, and salary concerns. Dr
Thurner participated in Cercare Medical and consultancy. Dr Zaharchuk received
funding support through National Institutes of Health, GE Healthcare, and Bayer
Healthcare, received GPU donation from Nvidia, and equity from Subtle Medical.
REFERENCES
1. Saver JL. Time is brain–quantified. Stroke. 2006;37:263–266. doi:
10.1161/01.STR.0000196957.55928.ab
2. Krizhevsky A, Sutskever I, Hinton GE. Imagenet classification with
deep convolutional neural networks. Proc NIPS. 2012; 1097–1105.
3. Kim KH, Choi SH, Park SH. Improving arterial spin labeling by using deep
learning. Radiology. 2018;287:658–666. doi: 10.1148/radiol.2017171154
4. Yoon J, Gong E, Chatnuntawech I, Bilgic B, Lee J, Jung W, Ko J,
Jung H, Setsompop K, Zaharchuk G, et al. Quantitative susceptibility
mapping using deep neural network: QSMnet. Neuroimage.
2018;179:199–206. doi: 10.1016/j.neuroimage.2018.06.030
5. Gong E, Pauly JM, Wintermark M, Zaharchuk G. Deep learning
enables reduced gadolinium dose for contrast-enhanced brain MRI. J
Magn Reson Imaging. 2018;48:330–340. doi: 10.1002/jmri.25970
6. Chen H, Zhang Y, Zhang W, Liao P, Li K, Zhou J, Wang G. Low-dose
CT via deep neural network. Biomed Opt Express. 2017;8:679–694.
doi: 10.1364/ BOE.8.000679
7. Xiao Y, Liu P, Liang Y, Stolte S, Sanelli P, Gupta A, Ivanidze J, Fang
R. STIR-Net: Deep Spatial-Temporal Image Restoration Net for
Radiation Reduction in CT Perfusion. Front Neurol. 2019;10:647. doi:
10.3389/ fneur.2019.00647
8. Guo J, Gong E, Fan AP, Goubran M, Khalighi MM, Zaharchuk G. Predicting
(15)o-water PET cerebral blood flow maps from multi-contrast MRI using a
deep convolutional neural network with evaluation of training cohort bias.
JCBFM. 2019. doi: 10.1177/0271678X19888123
9. Ho KC, Scalzo F, Sarma KV, Speier W, El-Saden S, Arnold C. Predicting
ischemic stroke tissue fate using a deep convolutional neural network on
source magnetic resonance perfusion images. J Med Imaging (Bellingham).
2019;6:026001. doi: 10.1117/1.JMI.6.2.026001
10. Thomalla G, Cheng B, Ebinger M, Hao Q, Tourdias T, Wu O, Kim JS,
Breuer L, Singer OC, Warach S, et al; STIR and VISTA Imaging Inves-
tigators. DWI-FLAIR mismatch for the identification of patients with
Stroke. 2020;51:2573–2579. DOI: 10.1161/STROKEAHA.119.027479
 Mouridsen et al
acute ischaemic stroke within 4·5 h of symptom onset (PRE-FLAIR): a
multicentre observational study. Lancet Neurol. 2011;10:978–986. doi:
10.1016/S1474-4422(11)70192-2
11. Ho KC, Speier W, El-Saden S, Arnold CW. Classifying acute ischemic
stroke onset time using deep imaging features. AMIA Annu Symp
Proc. 2017;2017:892–901.
12. Wouters A, Dupont P, Christensen S, Norrving B, Laage R, Thomalla G, Kemp S,
Lansberg M, Thijs V, Albers GW, et al. Multimodal magnetic resonance imaging to
identify stroke onset within 6 h in patients with large vessel occlu-sions. Eur
Stroke J. 2018;3:185–192. doi: 10.1177/2396987317753486
13. Schröder J, Thomalla G. A critical review of alberta stroke program
early CT score for evaluation of acute stroke imaging. Front Neurol.
2016;7:245. doi: 10.3389/fneur.2016.00245
14. Nagel S, Sinha D, Day D, Reith W, Chapot R, Papanagiotou P, Warburton
EA, Guyler P, Tysoe S, Fassbender K, et al. e-ASPECTS software is non-
inferior to neuroradiologists in applying the ASPECT score to computed
tomogra-phy scans of acute ischemic stroke patients. Int J Stroke.
2017;12:615– 622. doi: 10.1177/1747493016681020
15. Guberina N, Dietrich U, Radbruch A, Goebel J, Deuschl C, Ringelstein A,
Köhrmann M, Kleinschnitz C, Forsting M, Mönninghoff C. Detection of early
infarction signs with machine learning-based diagnosis by means of the
Alberta Stroke Program Early CT score (ASPECTS) in the clinical routine.
Neuroradiology. 2018;60:889–901. doi: 10.1007/s00234-018-2066-5
16. Amukotuwa SA, Straka M, Smith H, Chandra RV, Dehkharghani S, Fischbein NJ,
Bammer R. Automated detection of intracranial large vessel occlu-sions on
computed tomography angiography: a single center experience. Stroke.
2019;50:2790–2798. doi: 10.1161/STROKEAHA.119.026259
17. Chatterjee A, Somayaji NR, Kabakis IM. Artificial intelligence detection
of cerebrovascular large vessel occlusion - nine month, 650 patient
evaluation of the diagnostic accuracy and performance of the viz.Ai
lvo algorithm. Proc AHA Stroke. 2019;50:AWMP16-AWMP16.
18. Straka M, Albers GW, Bammer R. Real-time diffusion-perfusion
mismatch analysis in acute stroke. J Magn Reson Imaging.
2010;32:1024–1037. doi: 10.1002/jmri.22338
19. Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E,
Bammer R, Kakuda W, Lansberg MG, Shuaib A, et al; DEFUSE
Investigators. Mag-netic resonance imaging profiles predict clinical
response to early reper-fusion: the diffusion and perfusion imaging
Downloaded from http://ahajournals.org by on November 16, 2020
evaluation for understanding stroke evolution (DEFUSE) study. Ann
Neurol. 2006;60:508–517. doi: 10.1002/ana.20976
20. Olivot JM, Mlynash M, Thijs VN, Kemp S, Lansberg MG, Wechsler L,
Bammer R, Marks MP, Albers GW. Optimal Tmax threshold for
predict-ing penumbral tissue in acute stroke. Stroke. 2009;40:469–
475. doi: 10.1161/STROKEAHA.108.526954
21. Huang X, Kalladka D, Cheripelli BK, Moreton FC, Muir KW. The
impact of CT perfusion threshold on predicted viable and nonviable
tissue vol-umes in acute ischemic stroke. J Neuroimaging.
2017;27:602–606. doi: 10.1111/jon.12442
22. Austein F, Riedel C, Kerby T, Meyne J, Binder A, Lindner T, Huhndorf
M, Wodarg F, Jansen O. Comparison of perfusion CT software to
predict the final infarct volume after thrombectomy. Stroke.
2016;47:2311–2317. doi: 10.1161/STROKEAHA.116.013147
23. Chen L, Bentley P, Rueckert D. Fully automatic acute ischemic lesion
seg-mentation in DWI using convolutional neural networks.
Neuroimage Clin. 2017;15:633–643. doi: 10.1016/j.nicl.2017.06.016
24. Ronneberger O., Fischer P., Brox T. (2015) U-Net: Convolutional Networks for
Biomedical Image Segmentation. In: Navab N., Hornegger J., Wells
W., Frangi A. (eds) Medical Image Computing and Computer-Assisted
Intervention - MICCAI 2015. MICCAI 2015. Lecture Notes in
Computer Science, vol 9351. Springer, Cham.
25. Song T. 3D multi-scale U-net with atrous convolution for ischemic stroke
lesion segmentation. Proc MICCAI ISLES 2018 Challenge. 2018.
26. Winzeck S, Hakim A, McKinley R, Pinto JAADSR, Alves V, Silva C,
Pisov M, Krivov E, Belyaev M, Monteiro M, et al. ISLES 2016 and
2017-Benchmarking ischemic stroke lesion outcome prediction based
Stroke. 2020;51:2573–2579. DOI: 10.1161/STROKEAHA.119.027479
Artificial Intelligence Applications in Stroke
on multispectral MRI. Front Neurol. 2018;9:679. doi: 10.3389/fneur.
2018.00679
27. Wu O, Koroshetz WJ, Ostergaard L, Buonanno FS, Copen WA,
Topical Review
Gonzalez RG, Rordorf G, Rosen BR, Schwamm LH, Weisskoff RM, et
al. Predicting tissue outcome in acute human cerebral ischemia using
combined diffu-sion- and perfusion-weighted MR imaging. Stroke.
2001;32:933–942. doi: 10.1161/01.str.32.4.933
28. Hougaard KD, Hjort N, Zeidler D, Sørensen L, Nørgaard A, Hansen TM,
von Weitzel-Mudersbach P, Simonsen CZ, Damgaard D, Gottrup H, et al.
Remote ischemic perconditioning as an adjunct therapy to throm-bolysis in
patients with acute ischemic stroke: a randomized trial. Stroke.
2014;45:159–167. doi: 10.1161/STROKEAHA.113.001346
29. Kemmling A, Flottmann F, Forkert ND, Minnerup J, Heindel W,
Thomalla G, Eckert B, Knauth M, Psychogios M, Langner S, et al.
Multivariate dynamic prediction of ischemic infarction and tissue
salvage as a function of time and degree of recanalization. J Cereb
Blood Flow Metab. 2015;35:1397– 1405. doi: 10.1038/jcbfm.2015.144
30. Hastie T, Tibshirani R, Friedman JH. The elements of statistical
learning: Data mining, inference, and prediction. Springer; 2009.
31. Livne M, Boldsen JK, Mikkelsen IK, Fiebach JB, Sobesky J,
Mouridsen K. Boosted tree model reforms multimodal magnetic
resonance imag-ing infarct prediction in acute stroke. Stroke.
2018;49:912–918. doi: 10.1161/STROKEAHA.117.019440
32. Alawneh JA, Jones PS, Mikkelsen IK, Cho TH, Siemonsen S, Mouridsen K,
Ribe L, Morris RS, Hjort N, Antoun N, et al. Infarction of ‘non-core-non-pen-
umbral’ tissue after stroke: multivariate modelling of clinical impact. Brain.
2011;134(pt 6):1765–1776. doi: 10.1093/brain/awr100
33. Stier N, Vincent N, Liebeskind D, Scalzo F. Deep learning of tissue fate features
in acute ischemic stroke. Proceedings (IEEE Int Conf Bioinformatics Biomed).
2015;2015:1316–1321. doi: 10.1109/BIBM.2015.7359869
34. Nielsen A, Hansen MB, Tietze A, Mouridsen K. Prediction of tissue
out-come and assessment of treatment effect in acute ischemic stroke
using deep learning. Stroke. 2018;49:1394–1401. doi: 10.1161/
STROKEAHA.117.019740
35. Yu Y, Xie Y, Thamm T, Gong E, Quyang J, Huang C, Christensen S, Marks
MP, Lansberg MG, Albers GW, et al. Use of deep learning to predict final
ischemic stroke lesions from initial magnetic resonance imaging. JAMA
Net-work Open. 2020. doi: 10.1001/jamanetworkopen.2020.0772.
36. Pérez Malla CU, Valdés Hernández MDC, Rachmadi MF, Komura T.
Evalu-ation of enhanced learning techniques for segmenting
ischaemic stroke lesions in brain magnetic resonance perfusion
images using a convo-lutional neural network scheme. Front
Neuroinform. 2019;13:33. doi: 10.3389/fninf.2019.00033
37. Yu Y, Guo D, Lou M, Liebeskind D, Scalzo F. Prediction of hemorrhagic
trans-formation severity in acute stroke from source perfusion MRI. IEEE
Trans Biomed Eng. 2018;65:2058–2065. doi: 10.1109/TBME.2017.2783241
38. Yu Y, Guo D, Lou M, Liebeskind D, Scalzo F. The prediction of the hemor-rhagic
transformation locations after reperfusion therapy in acute stroke patients: a
perfusion study using deep learning. Neurology. 2018;90:P3.212.
39. Bentley P, Ganesalingam J, Carlton Jones AL, Mahady K, Epton S,
Rinne P, Sharma P, Halse O, Mehta A, Rueckert D. Prediction of
stroke thrombolysis outcome using CT brain machine learning.
Neuroimage Clin. 2014;4:635– 640. doi: 10.1016/j.nicl.2014.02.003
40. van Os HJA, Ramos LA, Hilbert A, van Leeuwen M, van Walderveen MAA,
Kruyt ND, Dippel DWJ, Steyerberg EW, van der Schaaf IC, Lingsma HF, et
al. Predicting outcome of endovascular treatment for acute ischemic stroke:
potential value of machine learning algorithms. Front Neurol. 2018;9:784.
41. Xie Y, Jiang B, Gong E, Li Y, Zhu G, Michel P, Wintermark M, Zaharchuk
G. Use of gradient boosting machine learning to predict patient outcome in
acute ischemic stroke on the basis of imaging, demographic, and clinical
information. Am J Roentgenol. 2019;212:44–51.
42. Bacchi S, Zerner T, Oakden-Rayner L, Kleinig T, Patel S, Jannes J.
Deep Learning in the prediction of ischaemic stroke thrombolysis func-
tional outcomes: a pilot study. Acad Radiol. 2020;27:e19–e23. doi:
10.1016/j.acra.2019.03.015
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