brain
sciences
Systematic Review
Graph-Based Analysis of Brain Connectivity in Multiple
Sclerosis Using Functional MRI: A Systematic Review
Sara Hejazi 1, *, Waldemar Karwowski 1 , Farzad V. Farahani 2 , Tadeusz Marek 3 and P. A. Hancock 4
Citation: Hejazi, S.; Karwowski, W.;
Farahani, F.V.; Marek, T.; Hancock,
P.A. Graph-Based Analysis of Brain
Connectivity in Multiple Sclerosis
Using Functional MRI: A Systematic
Review. Brain Sci. 2023, 13, 246.
https://doi.org/10.3390/
brainsci13020246
Academic Editor: Jordi A.
Matias-Guiu
Received: 6 December 2022
Revised: 16 January 2023
Accepted: 17 January 2023
Published: 31 January 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Brain Sci. 2023, 13, 246. https://doi.org/10.3390/brainsci13020246
1 Computational Neuroergonomics Laboratory, Department of Industrial Engineering and Management
Systems, University of Central Florida, Orlando, FL 32816, USA
2 Department of Biostatistics, Johns Hopkins University, Baltimore, MD 21218, USA
3 Department of Cognitive Neuroscience and Neuroergonomics, Institute of Applied Psychology,
Jagiellonian University, 30-348 Kraków, Poland
4 Department of Psychology, University of Central Florida, Orlando, FL 32816, USA
* Correspondence: sara.hejazi@knights.ucf.edu
Abstract: (1) Background: Multiple sclerosis (MS) is an immune system disease in which myelin in
the nervous system is affected. This abnormal immune system mechanism causes physical disabilities
and cognitive impairment. Functional magnetic resonance imaging (fMRI) is a common neuroimaging
technique used in studying MS. Computational methods have recently been applied for disease
detection, notably graph theory, which helps researchers understand the entire brain network and
functional connectivity. (2) Methods: Relevant databases were searched to identify articles published
since 2000 that applied graph theory to study functional brain connectivity in patients with MS
based on fMRI. (3) Results: A total of 24 articles were included in the review. In recent years, the
application of graph theory in the MS field received increased attention from computational scientists.
The graph–theoretical approach was frequently combined with fMRI in studies of functional brain
connectivity in MS. Lower EDSSs of MS stage were the criteria for most of the studies (4) Conclusions:
This review provides insights into the role of graph theory as a computational method for studying
functional brain connectivity in MS. Graph theory is useful in the detection and prediction of MS and
can play a significant role in identifying cognitive impairment associated with MS.
Keywords: graph theory; network analysis; multiple sclerosis (MS); brain connectivity; functional
magnetic resonance imaging (fMRI); neuroimaging
1. Introduction
Multiple sclerosis (MS) is an autoimmune inflammatory disorder that occurs in the
central nervous system (CNS) and, in contrast to other neurological diseases, primarily
affects young people. MS refers to the demyelination of myelin sheaths due to the immune
system’s attack of the CNS [1,2]. Disabilities resulting from MS in young people have
deleterious lifestyle effects and often restrict physical activity. Other MS symptoms include
difficulty in walking and controlling body movements, fatigue, vision problems (blurry
vision), and low cognitive performance [3]. People with MS are more likely than unaffected
individuals to experience depression [4–6]. Moreover, some patients in advanced disease
stages (high Expanded Disability Status Scale (EDSS) scores) experience impaired cognitive
function, such as difficulty in recalling memories. In some cases, vocal fluency is affected [7].
The EDSS categorizes patients according to their disabilities on a scale of 0 (no/minor
disability) to 10 (death due to MS) [8].
Although MS is widely believed to be a disease affecting western or northern countries,
recent studies have revealed that MS is, in fact, a global disease, and substantial evidence
has indicated a high incidence in the eastern Mediterranean [9–11]. Some findings have
suggested that the incidence of MS may be due to a lack of vitamin D. Therefore, MS risk
factors include sunlight exposure, genetic factors, and other environmental factors [12].
https://www.mdpi.com/journal/brainsci
Brain Sci. 2023, 13, 246 2 of 23

Recent findings have revealed that Epstein–Barr virus (EBV) is a major factor that may
increase the risk of MS, by as much as 32-fold [13].
There are several clinical MS phenotypes, as follows. Clinically isolated syndrome
(CIS) defines the initial episode of MS but may not meet all criteria for MS. Many people
with CIS have CNS demyelination and may show disease progression to more advanced
stages. Relapse/remitting MS (RRMS) involves deterioration of neural function and includes
occasional relapses (85% of all patients). Patients with RRMS show no new signs after
experiencing a period of relapses. Secondary progressive MS (SPMS) may develop in patients
who progress from RRMS with more severe symptoms. Progressive relapsing MS (PRMS) is
characterized by neurological malfunction without early relapse or remission [1,14].
EDSS scores are used to identify the extent of MS progression. This scale categorizes
patients on a scale ranging from 1, indicating minor signs of disability/impairment in a
single function, to 10, indicating death due to MS [8].
The McDonald criteria are widely used to diagnosis MS [15]. The number of attacks
and the number of clinical lesions is the basis for MS diagnosis [16]. For an early-stage
diagnosis, cerebrospinal fluid is among the most critical factors. In contrast, diagnosis for
disease progression involving brain lesions, spinal cord lesions, and positive visual evoked
potential should be considered [15]. EDSS (Expanded Disability Status Scales) is used to
identify the level of MS progression. This scale categorized patients from 1 with small sign
of disability/impairment to 10 (death to MS) [8].
Neuroimaging techniques are used to study neurological disorders including Alzheimer’s
disease, epilepsy, and Parkinson’s disease [17]. As previously described, some symptoms can
be used to diagnose MS. However, many symptoms, such as weakness, fatigue, and difficulty
in movement, are common to multiple neurological disorders. One method to increase
diagnostic accuracy is precise neuroimaging, which provides compelling evidence of any
malfunctions in the nervous system [18]. Several neuroimaging techniques are applicable in
MS studies. fMRI is a neuroimaging technique that can be used when high spatial resolution is
required to make an accurate diagnosis. Lesions are located in the periventricular, juxtacortical,
and infratentorial regions. Because of its high spatial resolution, MRI/fMRI is an appropriate
technique for studying the effects of lesions on brain connectivity and can enable faster
diagnosis. fMRI has been applied to assess movement- and cognitive-associated impairment
in MS patients [19].
The role of quantitative and computational approaches is indisputable in any field
of research involving diagnoses of conditions such as cancer and nervous system dis-
eases [20,21]. In diagnosing these types of diseases, including MS, the timing of diagnosis
is important. The use of computational approaches may lead to rapid diagnoses. Timely
diagnoses result in more effective treatment and medication applications to prevent the
progression of the disease. This review presents graph theory applications in MS studies.
Studying brain functional connectivity is critical to identify biomarkers for MS diagnosis.
In recent years, computational methods, including machine learning and deep learning,
have been widely applied to MS data [22]. In applying them, there are some limitations
that may affect the result including, but not limited to, the high impact of artifacts and MRI
image quality in the results [23]. In brain functional connectivity studies, graph theory is
one of the best methods for determining the activation of regions and interactions between
regions [24]. Graph theory considers interactions between nodes (vertices), and the analysis
of correlations between regions provides insights into regional activation and alterations.
Another advantage of applying graph theory in the MS field lies in the idea of “economy of
brain network organization”. According to this, MS is a neurological disorder in which the
longest connections in the network have been influenced by the disease [25]. Graph theory,
by studying interactions between regions, may represent network alteration for patients
with MS.
This paper aims to review the application of graph theory in MS studies based on
fMRI. To accomplish these objectives, we reviewed the applications of neuroimaging and
computational modeling in MS. We focused on applying graph theory as a computational
 [25]. Graph theory, by studying interactions between regions, may represent network al-
teration for patients with MS.
Brain Sci. 2023, 13, 246
This paper aims to review the application of graph theory in MS studies based on
3 of 23
fMRI. To accomplish these objectives, we reviewed the applications of neuroimaging and
computational modeling in MS. We focused on applying graph theory as a computational
method and fMRI as a neuroimaging technique. We applied PRISMA guidelines to iden-
method
tify and fMRI
relevant as asystematically.
articles neuroimaging Then,
technique. We applied
we discussed PRISMA guidelines
applications of graphto identify
theory in
relevant articles systematically. Then, we discussed applications of graph theory
MS diagnosis to the disease progression tracking. This systematic review was performed in MS
diagnosis
to tothe
highlight theimportant
disease progression tracking.
role of graph theory This
in MSsystematic
studies. review was performed to
highlight the important role of graph theory in MS studies.
2. Materials and Methods
2. Materials and Methods
The
The present systematic review
present systematic applied the
review applied the Preferred
Preferred Reporting
Reporting Items
Items for
for Systematic
Systematic
Reviews
Reviews and
and Meta-Analyses (PRISMA) approach
Meta-Analyses (PRISMA) approach [26],
[26], as
as shown
shown in
in Figure 1. The
Figure 1. The PRISMA
PRISMA
guidelines
guidelines were formulated to guide the collection of related articles to create aa reliable
were formulated to guide the collection of related articles to create reliable
systematic review. To accomplish this, duplicate articles from different databases
systematic review. To accomplish this, duplicate articles from different databases are are
ex-
cluded as instructed in the PRISMA.
excluded as instructed in the PRISMA.

Figure 1. PRISMA diagram for the present literature review.

review.

2.1. Research
2.1. Research Questions
Questions for
for Literature
Literature Review
Review
After reviewing previous studies ininthis
After reviewing previous studies thisfield,
field,
wewe aimed
aimed to to address
address thethe following
following re-
research questions (RQ) in the literature review:
search questions (RQ) in the literature review:
RQ1: What is the role of fMRI in studying brain connectivity in people with MS?
RQ2: How is brain connectivity altered in the brain network in people with MS?
RQ3: What is the value of applying graph theory for neurological disorders such as MS?
RQ4: How does graph theory help detect early stages of MS or MS progression?
Brain Sci. 2023, 13, 246 4 of 23

2.2. Study Search and Selection Process

In the first step, various databases were used to find relevant articles. Six categories of
keywords were searched, and the PRISMA guidelines were followed in finding relevant
articles. The population, modeling, outcomes, and conditions were considered to avoid bias.
Different resources were used to search the content, including journal articles, textbooks,
proceedings, and published conference proceedings. Many search engines were used in
this study, including Google Scholar, IEEE Xplore, PubMed, EBSCO HOST, Web of Science,
Scopus, and Science Direct. The six categories of keywords were used to find relevant
studies as follows:
“Multiple sclerosis” OR “MS” AND “fMRI” AND “graph theory”;
“Multiple sclerosis” OR “MS” AND “fMRI”
“Multiple sclerosis” OR “MS” AND “graph theory”;
“Multiple sclerosis” OR “MS” AND “brain connectivity”;
“Multiple sclerosis” OR “MS” AND “brain network”;
“Multiple sclerosis” OR “MS” AND “graph theory” AND “node”.

2.3. Eligible Studies and Quality Assessment

The following eligibility criteria were used to select articles for this systematic review:
Articles in English, original peer-reviewed articles,
articles collecting functional magnetic resonance imaging (fMRI) data,
articles with precise methods and explanations of the results,
articles using graph theory for the analysis.
The following exclusion criterion was used:
Articles not answering or aligning with the research questions.
Quality assessment was performed by both reviewers (S.H. and W.K.), and the Risk
of Bias in Systematic Reviews (ROBIS) approach was applied [27]. This approach has
three phases: considering the relevance of the studies, finalizing the review process, and
assessing the risk of bias.

3. Results
Taking keywords into account, we identified 2445 journal and conference articles in
the first step of the PRISMA guidelines. Because most relevant articles were found via
Google Scholar, few duplicate articles were detected in the other sources (n = 450). Another
reason for the few duplicate articles was that the other database results for the keywords
used in the present literature review were limited. For instance, the results for one set
of keywords (“multiple sclerosis” or “MS” and “graph theory” & “fMRI”) in the Web of
Science yielded only 32 articles. After reviewing the abstracts of the identified articles, only
152 articles were selected according to the inclusion criteria, such as articles in English,
articles with fMRI applied in the methods, and articles using graph theory in the analysis.
In the screening stage, full-text articles were searched to identify eligible articles. As shown
in Figure 1, a total of 24 articles aligning with our research questions and with all inclusion
criteria were identified.

3.1. Quality Assessment of the Selected Articles

As described in the methods section, ROBIS was followed by both reviewers (S.S. and
W.K.) in the present literature review [27]. According to the ROBIS guidelines, the current
literature review was categorized under the diagnosis and prognosis review type. In
reviewing article types, patients, outcomes, the intended use of the model, and conditions
should be identified. In Table 1, the sample size for each article, findings, EDSS, experiment
types (conditions for experiments), and graph properties for each specific study are shown.
As shown in Figure 2, among all articles included in this systematic review, 20 were of
good quality, met the inclusion criteria, and had low bias; the remaining articles (16% of all
articles included in this study) had a high risk of bias.
Brain Sci. 2023, 13, 246 5 of 23

Table 1. MS studies using graph theory.

Authors, Number of Graph Theory Imaging/Cognitive

EDSS Findings
Year Participants Parameters Tests
Decrease in regional efficiency
- Small-worldness
for the insula, precentral gyrus,
[28] 330 (RRMS) - Global efficiency - RS-fMRI
and prefrontal and temporal
- Local efficiency
association cortices
16 (MS) Increase in network modularity
[29] - Modularity Less than 2.5 PASAT
20 (HC) values for patients with MS
Fatigue in patients with MS
causing decreased in degrees in
60 (MS) - Small-worldness the bilateral thalamus;
[30] - RS-fMRI
59 (HC) - Centrality decreased degree in the
bilateral caudate nucleus in
non-fatigued patients
Increase in eigenvector
centrality in the bilateral
thalamus and posterior
128 (MS) - Eigenvector cingulate areas; decrease in
[31] Median 2.0 RS-fMRI
50 (HC) centrality eigenvector centrality in
sensorimotor and ventral
stream areas in patients
with MS
Decrease in the nodal degree in
246 (MS) - Global efficiency the bilateral caudate nucleus
[32] Less than 3.0 PASAT
55 (HC) - Small-worldness and right cerebellum in patients
with MS
Decrease in brain functional
- Nodal efficiency
38 (MS) connectivity enhancement after
[33] - Local efficiency 0–7.0 RS-fMRI
42 (HC) advanced disease and during
- Connectivity index
disease progression
Increase in modularity in the
- Clustering brain network in patients
18 (RRMS)
[34] coefficient - RS-fMRI with MS;
25 (HC)
- Modularity increase in clustering coefficient
and local efficiency
25 (MS) Increase in modularity in
[35] - Modularity - RS-fMRI
35 (HC) patients with MS
Centrality increase in the
332 (MS)
[36] - Degree centrality Median 3.0 RS-fMRI default-node network in
96 (HC)
patients with MS
- Global efficiency
- Local efficiency With the definition of the rich
T25FW
37 (PPMS) - Betweenness club, rich club connectivity
[37] Less than 7.00 NHPT
21 (HC) centrality decreases among patients
SDMT
- Characteristic path with MS
length
34 (MS)
- Local efficiency Decrease in brain
[38] 34 (CIS) 0–6.5 PASAT
- Global efficiency network efficiency
36 (HC)
- Global efficiency
- Assortativity
- Characteristic path Weaker connectivity strength,
[39] 46 (RRMS) length Median 2 RS-fMRI decrease in network density,
- Modularity reduction of global changes
- Rich club coefficient
- Transitivity
No differences between CIS
and HC;
- Modularity
decrease in inter-module
41 (CIS) - Intra-module
efficiency between
[40] 32 (MS) efficiency 0–6.5 PASAT2,3
sensory-motor network and
35 (HC) - Inter-module
frontoparietal network and
efficiency
between visual network and
frontoparietal in MS
Brain Sci. 2023, 13, 246 6 of 23

Table 1. Cont.

Authors, Number of Graph Theory Imaging/Cognitive

EDSS Findings
Year Participants Parameters Tests
- Global efficiency
- Local efficiency
- Betweenness Changes in serotonergic,
29 (MS) centrality noradrenergic, and cholinergic
[41] 3.2 ± 1.3 SDMT
24 (HC) - Characteristic path network functional connectivity
length in MS
- Clustering
coefficient
PASAT
- Clustering ANT Increase in modularity, increase
coefficient SDMT in clustering and decrease in
37 (MS)
[42] - Characteristic path - MFIS global efficiency in functional
23 (HC)
length NFI-MS networks, and longer average
- Global efficiency BDI-II path length
PSQI
- Global efficiency
- Characteristic path
SDMT Increase in functional
33 (RRMS) length Median 2
[43] PASAT connectivity due to
29 (HC) - Clustering 0–4
TAP maladaptive process
coefficient
- Nodal strength
Alteration in the brain network
119 (MS) - Global efficiency
[44] 2 (0–7.5) PASAT in patients with MS according
42 (HC) - Degree centrality
to disease duration
Median EDSS=1
41 PWCIS No global efficiency difference
[45] Start: 0–3 RS-fMRI
19 (HC) between CIS and HC
After 1 year: 0–5
CVLT-II,
PASAT, Decreased global efficiency in
25 (RRMS)
[46] - Global efficiency Mean 4.3 SDMT, patients with MS with
18 (HC)
JLOT, cognitive impairment
COWAT
- Number of edges
- Characteristic path
SDMT
length No significant link between
50 (MS) CVLT-II
[47] - Local efficiency Less than 6.0 brain network alterations
26 (HC) BVMT-R
- Global efficiency and cognition
COWAT
- Transitivity
- Small-worldness
- Centrality (degree
and betweenness
Significant increase in
centrality)
32 (MS) structural-functional coupling
[48] - Clustering 0–3.0 RS-fMRI
10 (HC) among patients with MS after
coefficient
5 years
- Characteristic path
length
- Centrality Best sensitivity in MS analysis
8 (MS) - Modularity acquired from two global
[49] 0–3.5 PASAT
12 (HC) - Transitivity values of modularity and
- Small-worldness small-worldness index
- Strength
Decrease in verbal memory
32 (MS) - Centrality First episode SRT
[50] function associated with
10 (HC) - Clustering suggestive of MS BVMT-R
hippocampal volume loss
coefficient
- Local efficiency Mixed observations in graph
[51] 10 (RRMS) - RS-fMRI
- Global efficiency properties for walking exercise
- Density No significant difference for MS
- Strength patients with and without optic
[52] 48 (PPMS) - RS-fMRI
- Local efficiency neuritis in functional
- Modularity graph metrics.
MS: Multiple sclerosis, HC: healthy control, EDSS: Expanded Disability Status Scale, RS: resting state, RRMS:
remitting/relapsing MS, PASAT: Paced Auditory Serial Addition Test, T25FW: timed 25-foot walk, NHPT: nine-
hole peg test, SDMT: Symbol Digit Modalities Test, ANT: Attention Network Test, MFIS: Modified Fatigue Impact
Scale, BDI-II: Beck Depression Inventory 2nd edition, PSQI: Pittsburgh Sleep Quality Index, COWAT: Controlled
Oral Work Association Test, JLOT: Judgment of Line Orientation Test, CVLT: California Verbal Learning Test-II,
BVMT-R: Brief Visuospatial Memory Test Revised, TAP: Test battery of Attentional Performance.

Brain Sci. 2023, 13, 246
literature review was categorized under the diagnosis and prognosis review type. In re-
viewing article types, patients, outcomes, the intended use of the model, and conditions
should be identified. In Table 1, the sample size for each article, findings, EDSS, experi-
ment types (conditions for experiments), and graph properties for each specific study are
shown. As shown in Figure 2, among all articles included in this systematic review, 20 7 of 23
were of good quality, met the inclusion criteria, and had low bias; the remaining articles
(16% of all articles included in this study) had a high risk of bias.

Figure 2.
Figure 2.ROBIS
ROBISapproach
approachforfor
identifying bias bias
identifying in theinpresent review.
the present review.

Table
3.2. 1. MS Characteristics
Study studies using graph theory.

Authors, Number of As shown in Table 1, the number of participants ranged from 8 to 332 (mean = 75,
Imaging/Cognitive
Graph Theory Parameters EDSS Findings
Year Participants median = 37.5). Among the selected articles Tests in this field, 87% used a healthy control
group to study the effect of the disease on brain network Decrease in regional efficiency
connectivity. for
All selected articles
- Small-worldness
the insula, precentral gyrus, and
[28] 330 (RRMS) focused
- Global on patients with EDSS
efficiency - scores below 7.5 because patients with higher EDSS, owing
RS-fMRI
prefrontal and temporal association
to movement
- Local efficiency limitations, have difficulty participating in fMRI studies. The database
cortices
16 (MS) searching was conducted from 2000 to the present. However, all articles included in this
Increase in network modularity
[29] - Modularity
20 (HC) systematic review wereLess than 2.5
published PASAT
between 2009 and 2021.
values The publication
for patients with MStrend for the
articles included in this review is shown in Figure 3B. The
Fatigue increase
in patients withinMS
the use of graph
causing
theory is illustrated by the number of publications decreased
from in degrees
recent years. in the bilateral
60 (MS) - Small-worldness
[30] - RS-fMRI thalamus; decreased degree in the
59 (HC) - Centrality
3.3. Overview of the Review bilateral caudate nucleus in non-
fatigued patients
To answer research questions 1–4, the valueIncrease of fMRI in MS studies
in eigenvector must
centrality in first be
understood; therefore, we provide a review of neuroimaging techniques in this
the bilateral thalamus and posterior field (RQ1).
128 (MS) We then give a brief review of brain connectivity and the role of
cingulate graph
areas; theory
decrease in in studying
[31] - Eigenvector centrality Median 2.0 RS-fMRI
50 (HC) functional and effective brain connectivity for patients with MS (RQ2).
eigenvector To in
centrality understand the
applications of graph theory in MS studies, we provide sensorimotor and ventral
an introduction stream properties
to graph
areas in patients with MS
(RQ3). In the results and discussion, we (S.H. and W.K.) discuss how graph theory can help
Decrease in the nodal degree in the
[32]
246 (MS) detect
- Global the incidence of MS
efficiency or disease
Less than 3.0
progression
PASAT
(RQ4).
bilateral caudate nucleus and right
55 (HC) - Small-worldness
cerebellum in patients with MS
4. Discussion Decrease in brain functional
- Nodal efficiency
38 (MS) Since the main focus of this paper is to review theconnectivity
application of graph after
enhancement theory to fMRI
[33] - Local efficiency 0–7.0 RS-fMRI
42 (HC) data acquired from MS patients, the following topics advanced
are diseaseinand
discussed during
this section:
- Connectivity index
disease progression
18 (RRMS)
• The role of fMRI as a neuroimaging method in Increase
- Clustering coefficient
studying MS;
in modularity in the brain
[34] • Brain connectivity in MS - (includingRS-fMRI
brain functional connectivity andMS;brain effective
25 (HC) - Modularity network in patients with
connectivity in MS);
• The role of graph theory as a computational approach in studying MS (including
referring to other computational approaches, graph theory for disease detection,
disease progression, and network alterations in MS);
• Limitations and considerations of applying graph theory to fMRI data on MS patients.

4.1. fMRI in MS Studies

As shown in Figure 3, several neuroimaging techniques, such as fMRI, fNIRS, EEG,
MEG, and DTI, were applied to investigate different impairments in MS, including attention,
walking, and diagnosis (Figure 3A). fMRI has been used in various studies of neurological
disorders, including multiple sclerosis, epilepsy, and Alzheimer’s disease. In the field of MS,
owing to its high spatial resolution, fMRI has been applied more than other neuroimaging
 4.1. fMRI in MS Studies
As shown in Figure 3, several neuroimaging techniques, such as fMRI, fNIRS, EEG,
MEG, and DTI, were applied to investigate different impairments in MS, including atten-
Brain Sci. 2023, 13, 246 tion, walking, and diagnosis (Figure 3A). fMRI has been used in various studies of neuro- 8 of 23
logical disorders, including multiple sclerosis, epilepsy, and Alzheimer’s disease. In the
field of MS, owing to its high spatial resolution, fMRI has been applied more than other
neuroimaging
techniques when techniques whenisgraph
graph theory chosentheory is chosen
to model to model(Figure
the network the network (Figure
3B). Two types 3B).
of
Two
fMRItypes of fMRI
are used in MSarestudies:
used in resting-state
MS studies: resting-state
fMRI (applied fMRI (applied
to study to studypart
a specific a specific
of the
part
brainofinthe brainstate)
resting in resting state) and task-based
and task-based (including a(including
particularataskparticular taskto
pertaining pertaining
topics suchto
topics such asand
as plasticity plasticity
memory) and[22,53].
memory) [22,53]. In task-based
In task-based studies inwith
studies in patients patients
MS, awith MS, a
designed
task, suchtask,
designed as asuch
pacedas aauditory serial addition
paced auditory test (PASAT),
serial addition is performed
test (PASAT), duringduring
is performed fMRI
recording [7,54,55]. The increase in published articles in the MS field applying
fMRI recording [7,54,55]. The increase in published articles in the MS field applying graph graph theory
to fMRItodata
theory fMRI is data
shown in Figure
is shown in 3C.
Figure 3C.

Number of the articles 7

Frequency
applying graph theory 6
9% 6% 5
0% 6%
4
79% 3
2
1

EEG fNIRS MEG DTI FMRI 0

1 2 3 4 5 6 7 8 9 10 11 12 13
(A) (B)

(C)

Figure 3. Graph Theory and neuroimaging: Several neuroimaging methods can be applied for
studying MS, such as functional near-infrared spectroscopy (fNIRS), EEG, MEG, DTI, and fMRI.
Patients with MS experience difficulties in walking. fNIRS is applied primarily in walking analysis
studies and multi-tasking studies, including physical and mental activity [56–58]. In addition, fNIRS,
because of its capability of measuring hemodynamic response in dual tasks, is used in working
memory tasks in patients with MS [59]. Electroencephalography (EEG) is used for motor-cognitive
impairments to aid in the study of gait kinematics with high resolution [60]. Early physical fatigue,
a sign of MS, is studied primarily with EEG and fNIRS [61,62]. According to EEG data, higher beta
temporal-parietal functional connectivity (in the resting state) is a possible sign of early fatigue in
MS [63,64]. Diffusion tensor imaging (DTI) is an important neuroimaging technique to investigate
 Brain Sci. 2023, 13, 246 9 of 23

cognitive status in patients with MS at the macro and micro levels [65]. Moreover, magnetoen-
Brain Sci. 2023, 13, x FOR PEER REVIEWcephalography (MEG) is another neuroimaging technique applied to MS data. In some studies,
9 of 24MEG
has been performed along with fMRI Combining these methods provides better insight into the
Brain Sci. 2023, 13, x FOR PEER REVIEWextent of integration in the brain functional network [66–68]. MEG has been applied to investigate
9 of 24
thalamic atrophy [68,69]. (A) Classifying neuroimaging techniques applying graph theory in MS;
in patients with MS [7]. Thalamic connectivity increases in the resting state when cognitive
Brain Sci. 2023, 13, x FOR PEER REVIEW(B) Frequency of papers that apply graph theory and fMRI in MS field included in this 9 ofreview;
24
performance is limited by severe MS [72,73]. The more severe
(C) Application of different types of neuroimaging in MS studies. the disease, the greater the
in patients
thalamic with MS [7].
functional Thalamic[73].
connectivity connectivity
Frontoparietalincreasesandinoccipital
the resting state
brain whenhave
regions cognitive
been
performance
reported
4.2. Brain to showis limited
changes
Connectivity byinin
severe
MS parallel MS to [72,73].
thalamicTheconnectivity
more severein the disease,with
patients the MSgreater
[72].the
in patients
thalamic with MS [7].
functional Thalamic connectivity
connectivity increasesandinoccipital
the resting state whenhave cognitive
Brain Sci. 2023, 13, x FOR PEER REVIEW Functional and structural[73]. Frontoparietal
connectivity were applied to MS databrain regions
[70]. Nodes and 9 been
of edges
24
performance
reported
Table 2. to
Regions is limited
show with changes by in
altered severe
parallel
functional MSconnectivity
[72,73].
to thalamicThein more severein
connectivity
MS. the disease,with
patients the MSgreater
[72]. the
illustrate inter-neuronal and regional connectivity [71]. As shown in Table 2, alterations
thalamic functional connectivity [73]. Frontoparietal and occipital brain regions have been
Papers Regions with AlteredTable in functional
Functional connectivity
Connectivity in density under disability progression have
MS been observed
Alteration FC [33].
Brain Sci. 2023, 13, x FOR PEER REVIEW reported to show
2. Regions with changes
alteredin parallel
functional to thalamicin
connectivity connectivity
MS. in patients with MSin[72].9 of 24
Structural–functional
in patients coupling is an approach to visualize the progression of MS that can
[74] Bilateral inferior parietal cortex, with posteriorMS [7]. Thalamic
cingulate, connectivity
medial prefrontal increases
cortexin the resting state when ⬆ cognitive
Brain Sci. 2023, 13, x FOR PEER
Papers Regions with AlteredTable REVIEW serve as anConnectivity
Functional
performance isindex
limited in diagnosing
in
by severe MS MS early-stage
[72,73]. The MSmore
[48]. Alteration 9
in FC of 24
2. Regions with altered functional connectivity in MS. severe the disease, the greater the
[75]
Brain Sci. Caudate nucleus and motor cortex
2023, 13, x FOR PEER REVIEW Infunctional
addition to functional [73]. connectivity, which and we discuss ⬆ thalamic
9 of 24and
[74] Bilateral inferior parietal thalamic
cortex, posteriorconnectivity
cingulate, medial Frontoparietal
prefrontal cortex occipitalbelow,
brain specific
regions ⬆ have been
Brain Sci. 2023, 13, x FOR
Papers Regions
Anterior andPEER
with REVIEW
Altered
middle in hippocampal
patients
Functional
parts
reported of the towith MSconnectivity
Connectivity
putamen,
show [7].adjacent
changes Thalamic was
in parallel
in MS globus examined
connectivity
topallidus,
thalamic in MS
increasesstudies.
anterior in
and
connectivity Thalamic
the resting
in patients connectivity
state when
Alteration
with MS
9FCof
in[72]. 24
studies
cognitive
[76]
[75] Caudate nucleus and motorhave cortex
shown is that damage to the grey matterThe nuclei canin be traced to state
track when ⬆
cognitive
[74] posterior
Brain Sci. 2023,
Bilateral thalamus,
13, x FOR PEERparietal
inferior REVIEWperformance
subthalamic
cortex,
in patients limited
nucleus,
posterior
with MS [7]. motorby severe
cingulate,network
Thalamic MS
medial [72,73].
prefrontal
connectivity more
cortex
increases severe
the the disease,
resting the⬆greater 9function
ofthe
cognitive 24
Anterior and middle parts in in
thalamic patients
of
patients the with
functional
putamen,
with MS MS [7].
adjacent
[7]. Thalamic
connectivity
Thalamic [73].
globus connectivity
Frontoparietal
pallidus,
connectivity increases
and
anterior
increases and
in in
the the
occipital resting
brain
resting statestate
regions
whenwhenhave cognitive
been
cognitive
[77]
[76]
[75] Sensorimotor
Caudate nucleus andand Table
somatosensory
motor
2.
performance Regions
cortex is with
limited
association altered
by functional
severe MS connectivity
[72,73]. The in MS.
more severe the disease, the ⬇
⬆ greater the
posterior
Brain Sci. 2023, thalamus,
13, x FOR PEER REVIEW performance
reported
subthalamic
in patients towith
show
nucleus, ischanges
MS limited
motor
[7]. by by
in severe
parallel
network
Thalamic MSMS to
connectivity [72,73].
thalamic The more
connectivity
increases severein the disease,
patients thethe
with MS greater
of 24the
[72].
9 been
Brain Sci. 2023, 13, x FOR PEER REVIEW performance
thalamic is limited
functional severe
connectivity [73]. [72,73]. The
Frontoparietal moreandin the
severe resting
occipital the state
disease,
brain when
regions cognitive
greater
have 9 ofthe
Papers
[78,79] Regions with
Right sensory-motor
Anterior Alteredand
and middle Functional
parts premotor
of
thalamic the Connectivity
cortex,
putamen,
functional and
adjacentin MS
anterior
connectivity globuscingulate
[73].pallidus, gyrus
anterior
Frontoparietal and
and occipital Alteration
brain ⬆
regions FC 24
inhave been
[77]
[76] Sensorimotor and somatosensory performance
thalamic
reported
in patients towith is limited
functional
association
show MS changes
[7]. by in
severe
connectivity
Thalamic parallel MS to
[73]. [72,73].
connectivitythalamicThe
Frontoparietal moreandinsevere
connectivity
increases occipital
the the
in disease,
brain
patients
resting state the⬆
regions
with
when ⬇MS
greater
have[72].
cognitivethe
been
[74]
[80] posterior
Bilateral
Subcortical thalamus,
inferior
and Table
parietal
PEERdefault-mode
reported
subthalamic 2.
cortex,
thalamic
reported Regions to show
toposterior
functional
networks
show with
nucleus, changes
altered
motor
cingulate,
connectivity
changes in inmedial
functional
network parallel
[73].
parallel to to thalamic
connectivity
prefrontal
Frontoparietal
thalamic in connectivity
MS.
cortex
andsevere
occipital inbrain
patients
regions ⬆
with
⬇MS MS
have [72].
9 been
Brain Sci. 2023, 13, x FOR
[78,79] Right sensory-motor and
REVIEWperformance
premotoriscortex, limited andbyanterior
severe MS [72,73].
cingulate Theconnectivity
gyrus more in patients
the disease, with
the⬆ [72].
greater ofthe
24
[77] Sensorimotor and somatosensory
reported
Table
in 2.
patients to
Regions association
show
with with
MS changes
altered
[7]. in parallel
functional
Thalamic to thalamic
connectivity
connectivity connectivity
in MS.
increases in the in patients
resting state with
when ⬇
⬆MS [72].
cognitive
Papers
[75]
[81] Regions
Caudate
Insula andwith
nucleus Altered
the dACC Functional
and thalamic
motor
to patients
in the
Table
cortex
striatum
2.
Connectivity
functional
with with
Regions MSwith [7]. in
connectivity
Thalamic
altered
MS [73]. Frontoparietal
connectivity
functional inand
increases
connectivity MS. inoccipital
the resting brain Alteration
regions
state when ⬆ have
in FCbeen
cognitive
[80] Subcortical
Brain Sci. 2023, 13, x FORandPEERdefault-mode
REVIEWTable
performance networks
2. Regions is limited altered
by functional
severe MS connectivity
[72,73]. The inmore
MS. severe the disease, the ⬇greater9 ofthe24
[78,79]
[74]
Papers
[82]
Right
Anteriorsensory-motor
Bilateral
Regions
Thalamus and middle
inferior
with
and
reported
and
parts
parietal
Altered
several
premotor
of
cortex,
Functional
performance
cortical theto show cortex,
putamen,
posterior
regions
changes
Connectivity
is limited and in
cingulate,in
by severeparallel
anterior
adjacent MS globus
medial to
cingulate thalamic
pallidus, gyrus
prefrontal
MSconnectivity
[72,73]. connectivity
anterior
Theincortex
more and in patients
severe the disease, with
Alteration⬆MS [72].
in9FC
the⬇greater the
[76]
Brain Sci. 2023, 13, x FOR PEER REVIEWTable
thalamic 2. Regions
functional with altered functional
connectivity [73]. Frontoparietal MS.and ⬆
⬆ have of 24
[81]
Papers
[80]
[74]
[75]
Insula and
Regions
Papers
posterior
Subcortical
Bilateral
Caudate
Brain Sci. 2023,
the
with dACC
Altered
Regions
thalamus,
and
inferior
nucleus
13, x FOR
with toFunctional
in the striatum
patients
Altered
subthalamic
thalamic
PEERdefault-mode
parietal
and
REVIEW motor cortex, with
nucleus,
functional
networks
cortex posteriorMS [7].
Connectivity
Functional motorThalamic
cingulate,in
Connectivity MS
network
connectivity connectivity
in MS
[73].
medial Frontoparietal
prefrontal increasesandinoccipital
cortex the resting
occipital brain
brain regions
state when
Alteration
Alteration
regions ⬇ have
⬆
been
cognitive
inFC
in FC
9 been
of 24
[82]
Papers Intra- and inter-thalamic
Regions inferior
with Altered Table connectivity
reported 2.
Functional
performance to
Regions show with changes
Connectivity
is limited altered in
by inin parallel
functional
severeMS to thalamic
connectivity
MSmedial
[72,73]. connectivity
in MS.
Theconnectivity
more severein in patients
the with
Alteration
disease, the⬇⬆MS [72].
in[72].
greaterFCthe
[82]
[77] Thalamus
Sensorimotor
[74] [74] Bilateral and several
and
Bilateral reported
cortical
somatosensory
parietal
inferior cortex,
parietal toposterior
show
regions changes
association
cortex, cingulate,
posterior parallel
medial
cingulate, to thalamic
prefrontal cortex
prefrontal cortex patients with ⬆MS
[81]
[75] Anterior
Insula
Caudate andandthemiddle
nucleus dACCand parts
to patients
motor
in
thalamic thewith
theofstriatum
cortex putamen,MS [7]. adjacent
Thalamic globus pallidus,increases
connectivity anterior
andin andthe resting state when ⬆ cognitive
⬆ have
[83]
[74] [75] Left
[76]
Papers hippocampus
Bilateral
Regions inferior
Caudate
with Alteredand
parietal
nucleus and functional
cortical
cortex,
Functional regions
posterior
motor cortex
Connectivity connectivity
cingulate,in MS [73].
medial Frontoparietal
prefrontal cortex occipital brain regions
Alteration in9FC been
[82]
[78,79]
Brain
[82]
Intra-
Right
[75] Sci. 2023,
Caudate
posterior
Anterior and
Thalamusand
inter-thalamic
13,sensory-motor
nucleus
and
PEER and
thalamus,
x FOR
middle
several
Anterior and
and
motor
Table
parts connectivity
reported
Table premotor
subthalamic
REVIEWincortical
middle
2.
patients
performance
of cortex
Regions
the
2. Regions
regions
parts
cortex,
with
nucleus,
towith MS
isoflimited
putamen,
show with
the
and
altered
motor
[7]. anterior
by in
altered
putamen,
functional
network
Thalamic
severe
adjacent
changes functional
adjacent
cingulate
connectivity
connectivity
MSglobus
globus
parallel [72,73].
topallidus, gyrus
thalamic
connectivity The in MS.
increases
more
anterior in the
severe
and
connectivity
in
pallidus, MS.
anterior and resting
the
in disease,
patients the⬆
statewith
when greater
⬇MS
ofthe
cognitive
[72]. 24
[84]
[76]
[74]
[75] Medial
[76] Bilateral
Caudate prefrontal
inferior
nucleus andin
parietal
and frontal
motor cortex,
patients pole
cortex withregions
posterior cingulate,
MSnucleus,
[7]. Thalamic medial prefrontal
connectivity cortex
increasesandin the resting state when ⬆ cognitive
[77]
[83]
[80]
Papers Anterior
Sensorimotor
Left and
hippocampus
posterior
Subcortical
Regions middle
and
posterior
thalamus,
and performance
thalamic
parts
somatosensory
and cortical
thalamus,
subthalamic
default-mode the is limited
functional
putamen,
of subthalamicassociation
regions
nucleus,
networks motorby severe
connectivity
adjacent motor
network MS Frontoparietal
[73].
globus
network[72,73].
pallidus, The more
anterior severe
occipital
and thebrain
disease, the⬆
regions ⬇greater
have the
been
[76]
[82]
Papers Intra-
[77] Regions
andwith Altered
inter-thalamic
with Altered Functional
connectivity
Functional Connectivity
Connectivity in
in MS
MS Alteration
the⬆
Alteration in FC
in[72].
FC
[85]
[75]
[77]
Anterior
Fusiform
Caudate
posterior
Sensorimotor
and
gyrus
nucleusmiddle
thalamus,
andwith
Sensorimotor
and performance
thalamic
parts
reported
the
Table
motor of
right
and
subthalamic
somatosensory
theto
lateral
somatosensory
2. Regions
cortex is limited
functional
putamen,
show occipital
with
nucleus,
association
by
altered
motor severe
connectivity
adjacent
changes in
cortex
association
functional
network MSconnectivity
[73].
globus
parallel [72,73].
topallidus,
thalamicThe
Frontoparietal moreandsevere
anterior
connectivity
in MS. occipital
and the
in disease,
brain
patients regions
with ⬇
⬆
⬇
greater
MShave the
been
[78,79]
[76]
[84]
[81]
[74] Right
Insulasensory-motor
Medial
Bilateral prefrontal
and the
inferior dACC and and
parietal premotor
tofrontal
the
cortex, pole
striatum cortex,cingulate,
regions
posterior and anterior medialcingulate gyruscortex
prefrontal ⬆
[74]
[83]
[77] Bilateral
[78,79]
Left inferior
Right
hippocampus
posterior
Sensorimotor
Anterior with thalamus, and
cerebellum
and middle
and
thalamic
reported
parietal
sensory-motor cortex,
cortical
subthalamic
in patients
parts
somatosensorywith
of the
functional
to
and show
posterior
premotor
regions
nucleus,
with
cerebellar,
putamen,MS [7].
association
connectivity
changes
motor
thalamic,in
cingulate,
cortex,
adjacent and
network
Thalamic and [73].
parallel
medial
anterior Frontoparietal
to
connectivity
globuscortical thalamic
prefrontal
cingulate
(frontal,
pallidus, gyrus
increasesand
connectivity
cortex in
parietal,
anterior
occipital
andtheand in brain
patients regions
with
resting state when ⬆MShave
⬇ cognitive
been
[72].
Papers
[86]
[78,79] Regions
Right Altered
13,sensory-motor andFunctional
premotor Connectivity
cortex, and in MS
anterior cingulate gyrus Alteration⬆MS in[72].
9FC
[76]
[80]
Brain [80]
[85]
[82]
[75] Subcortical
Sci. 2023,
Fusiform
Thalamus
Caudate x FOR and
andPEER
gyrus
nucleus default-mode
REVIEW
with
Subcortical
several
and reported
the
and
Table
motor right networks
to show
lateral
default-mode
cortical2.cortex
performance Regions
regions is changes
occipital
networks
with
limited altered
by in
cortex parallel
functional
severe MS to thalamic
connectivity
[72,73]. The connectivity
in MS. severein
more patients
the disease, with
the ⬇
⬆
⬇greater
of 24
the
[77]
[75]
[84] Sensorimotor
temporal)
Caudate
posterior
Medial areas
nucleus and
thalamus,
prefrontal somatosensory
and
and motor
subthalamic
frontal cortex
pole association
nucleus,
regions motor network ⬆
[78,79]
Brain
[74] [81] Right
Sci. 2023, 13,sensory-motor
Bilateral x FOR PEERparietal
inferior
Insula REVIEW
and and
the
Table premotor
cortex,
dACC2. to
Regions the cortex,
posterior
striatum
with and anterior
cingulate,
altered medial
functional cingulate gyrus
prefrontal
connectivity incortex
MS. ⬆
⬇
9 of 24
[80]
[81]
[82]
Papers
[86]
Sensorimotor
Subcortical
Anterior
Insula
Intra-
Regions and
and
Sensorimotor and and
the cerebellum
dACC
inter-thalamic
with Altered
cerebellum thalamic
default-mode
middle parts
to with
the of cerebellar,
functional
networks
the
striatum
connectivity
Functional
with putamen,
Connectivity
insular areas
thalamic,
connectivity
adjacentin MSand
globuscortical
[73]. (frontal,
Frontoparietal
pallidus, parietal,
and
anterior and and
occipital brain regions
Alteration⬆ have
⬇ in9FC been
[77]
[78,79]
[76]
Brain
[85]
[76]
Anterior
Right
Sci. 2023,
Fusiform
[80] [82] posterior
and
x FOR
Subcortical
middle
and
13,sensory-motor
PEER
gyrus
Thalamus
and
REVIEW
with parts
somatosensory
and
the
and
Table
default-mode
of
right
several the
premotor putamen,
lateral association
cortical
2. Regions
networks
cortex,
occipital
regions
with adjacent
and
altered anterior
cortex globus
functional pallidus,
cingulate
connectivity anterior
gyrusin MS. and ⬆
⬇
⬇MSin[72].
⬆
of 24
[75]
Papers temporal)
Caudate
Regions areas
nucleus
thalamus,
with and
Altered reported
motor
subthalamic
Functional to nucleus,
cortex show changes
Connectivity motor in parallel
network
in MS to thalamic connectivity in patients with⬆
Alteration
[81]
[82]
Brain
[74]
[83] [82] Insula
Thalamus
posterior
Sci. 2023, 13,
Bilateral
Left
Right and the
and
inferior
Intra-
hippocampus
medial dACC
several
thalamus,
x FOR PEER REVIEW
parietal
and
thalamicand to the
cortical
subthalamic striatum
cortex,
inter-thalamic
cortical
nuclei regions
nucleus,
posterior
connectivity
regions
connectivity motor
cingulate,
with network
bilateralmedial prefrontal
caudate/thalamus cortex
and left ⬇
⬆ 9FCof 24
[78,79] Regions
[80] Right sensory-motor
Sensorimotor
Subcortical and cerebellum and
default-mode
in premotor
withnetworks
patients with cortex,
cerebellar, MS and
[7]. anterior
thalamic,
Thalamic cingulate
andconnectivity gyrus
cortical (frontal, parietal,
increases in theandresting state when ⬆
⬇ cognitive
[87]
Papers
[86]
[77]
[81]
[74] [83] Sensorimotor
Anterior
Insula
Bilateral andwith
andthe
inferior
Left Altered
cerebellum
middle
and
dACC Functional
parts
somatosensory
parietalto
hippocampus with
the of the
striatum
cortex,
and Connectivity
insular
putamen, areas
association
posterior
cortical adjacent
cingulate,
regions in MS globus
medial pallidus,
prefrontal anterior
cortex and Alteration⬇
⬆ in FC
[77]
[76]
[82] cerebellar
Sensorimotor
Thalamus
Intra-
temporal)and areas
and and somatosensory
several
inter-thalamic
areas incortical regions
connectivity
patients association
with MS [7]. Thalamic connectivity increases
MS. in the resting the⬆
state when ⬇greater
⬆ cognitive
[75]
[84] Caudate
Medial nucleus
prefrontal and
and Table
motor 2.cortex
performance Regions with
is limited altered functional
by severe MSconnectivity
[72,73]. The inmore severe the disease, the
[80]
[74] Subcortical
[81] [84] Bilateral
Insula
posterior
Right and and
the
inferior
medial MedialdACC
thalamus, parietaltofrontal
default-mode
prefrontal
thalamic the
subthalamic
cortex,
nuclei and
pole
networks
striatum regions
nucleus,
posterior
frontal
connectivity polemotor
cingulate,
regions
with network
bilateralmedial prefrontal
caudate/thalamus cortex
and left ⬇
⬆
[82]
[78,79]
Brain
[75] Sci. Thalamus
Right
2023,
Left 13, x FOR
anterior
Caudate and
sensory-motor
PEERseveral
REVIEW
thalamic
nucleus and incortical
and
nuclei
motor premotor
patients
performance andregions
cortex with cortex,
anterior
is MS
limited and
[7]. anterior
Thalamic
cingulate
by severe cingulate
connectivity
cortex,
MS bilaterally
[72,73]. gyrus
increases
The more in the
severe resting
the state
disease, when
the ⬇
⬆
⬆ 9 been
ofthe
cognitive
greater 24
[87]
[78,79]
[86]
[82]
[83]
[85]
Papers Right
Intra-
[85] Left
Regions sensory-motor
Sensorimotor
Anterior and
andwith cerebellum
middle
inter-thalamic
hippocampus
Fusiform gyrus
Fusiformwith
Alteredand thalamic
and
parts
the
gyrus premotor
with
of functional
theinsular
connectivity
cortical
right
with
Functional regions
lateral
the cortex,
putamen,
right areasconnectivity
occipital
Connectivity and anterior
adjacent
cortex
lateral occipital
in MS
[73].
globus
cortex
Frontoparietal
cingulate
pallidus, gyrus and
anterior occipital
and brain regions
Alteration⬇
⬆
⬇ have
in FC
[77]
[81]
[82]
[76]
[75] cerebellar
Sensorimotor
Insula
Thalamus
Caudate and areas
the
and and
dACC somatosensory
several to
in the
cortical striatum
patients regionsassociation
with MS [7]. Thalamic connectivity increases in the resting state when ⬇
⬆ cognitive
[82]
[80]
[88] Anterior
Intra- andnucleus
Subcortical
posterior
Superior
Right and andmiddleand parts
inter-thalamic
thalamus,
ventral
medial
motor
thalamic
reported
default-mode
striatum
Sensorimotor
thalamic ofcortex
performance
and
cerebellum
nuclei the
connectivity
subthalamic is limited
functional
to nucleus,
show
putamen,
networks
posterior
connectivity changes by in
severe
connectivity
adjacent
motor
cingulate
with cerebellar,
with parallel
network MSand
[73].
globus
cortex
thalamic,
bilateral
[72,73].
to thalamic
pallidus, The
Frontoparietal moreand
anterior
cortical (frontal,
caudate/thalamus
severe
connectivityoccipital
and
parietal,
and leftand
the
in disease,
brain
patients the⬇
regions
with ⬆
⬆
greater
MShave
⬇greater
the
been
[72].
[80] [86] Left
[83]
[76]
[84]
[74] Subcortical
Medial
Left hippocampus
Sensorimotor
Bilateral
anterior and
prefrontal
inferior default-mode
thalamic and
cerebellum
and
parietal cortical
nucleiwith
frontal
cortex,
performance
thalamic networks
and regions
cerebellar,
pole regions
posterior
anterior
is
functional limited thalamic,
cingulate,
cingulate
by severe
connectivity and
medial
cortex,cortical
MS
[73]. (frontal,
prefrontal
bilaterally
[72,73]. The
Frontoparietal parietal,
cortex
moreand severe
occipital the disease,
brain the
regions ⬆
⬆
⬇ have the
been
[87]
[78,79]
[82]
[86] Right
Thalamus
Anterior
Intra-
posteriorsensory-motor
and and
and several
middle
inter-thalamic
and temporal)
thalamus, reported
and premotor
cortical
parts of to show
regions
the
connectivity
areas
subthalamic cortex,
putamen,
nucleus, changes
and in
adjacent
motor network parallel
anterior globus to
cingulate thalamic
pallidus, gyrus connectivity
anterior and in patients with ⬆
⬇
MS [72].
[77]
[83]
[81]
[76]
[89] cerebellar
Sensorimotor
Left
Insula
temporal)
DMN in areas
hippocampus
and the
areas
the and
dACC
posteriorsomatosensory
and to cortical
the
cingulate striatum association
regions
cortex and bilateral inferior parietal cortex ⬆
⬆
[81]
[84]
[85] [86] Insula
Medial
Fusiform and the
prefrontal
gyrus dACC and
with
Sensorimotor thalamic
reported
to
Table
the
in the
frontal2.
right functional
to
striatum
Regions
cerebellum
patients pole show
lateral with
with with
regions connectivity
changes
occipitalaltered
insular
MScingulate
[7]. in
functional
cortex
areas
Thalamic [73].
parallel Frontoparietal
to thalamic
connectivity in MS.and
connectivityoccipitalin
connectivity increases in the resting state when brain
patients regions
with ⬆
⬇
⬆MShave been
[72].
[75]
[88]
[80]
[82]
[77]
[83]
[87]
Caudate
posterior
Superior
Intra- andnucleus
Subcortical
Sensorimotor
Left
Left
thalamus,
ventral
hippocampus
anterior and and and
striatummotor
subthalamic
default-mode
inter-thalamic
thalamic and and
cortical
nuclei
cortex nucleus,
posterior
networks
connectivity
somatosensory association
regions motor network
cortex ⬇ cognitive
⬆
⬆
[78,79]
[86]
[84]
[82]
[72] Right
Medial
Thalamus
Bilateralsensory-motor
Sensorimotor
prefrontal
and
Right several
hippocampalmedial reported
andand
cerebellum Table
and 2.and
premotor
with
frontal
cortical
thalamic to
Regions anterior
show
insular
pole
regions
dorsal-frontal
performance cortex,
with
regions
nuclei
is areas cingulate
changes
and
altered
connectivity
limited components
by in
anterior
with
severe
cortex,
parallel
functionalbilateral
MS
bilaterally
to
cingulate thalamic
connectivity gyrus connectivity
in MS. severe
caudate/thalamus
[72,73]. The more and in patients
the disease, with
the ⬆
⬇
⬆MS [72].the
greater
[82]
[77]
[85]
Papers
[89] Sensorimotor
Thalamus
Anterior
Fusiform
[87] Regions
DMN in and
and
gyrus
with
the cerebellum
several
middle
andwith
Altered
posterior the with
cortical
parts
somatosensory of the
right
Functional
cingulate cerebellar,
regions
putamen,
lateral association
occipital
Connectivity
cortex thalamic,
adjacent
andaltered cortex
in
bilateral MSand cortical
globus pallidus,
inferior (frontal,
parietal cortexparietal,
anterior and and Alteration⬇
⬆ in FC
[81]
[83]
[78,79]
[86]
[84]
[76]
[88] Insula
Left
Right
Medial
Superior and the
hippocampus
sensory-motor
left
prefrontal
ventral dACC and
cerebellar
and
striatumto
and
Table the
cortical
areas
frontal
thalamic striatum
premotor
2. regions
Regions
pole
andconnectivity
posterior cortex,
with
regions
functional and
cingulate anterior
functional
connectivity cortex cingulate
[73]. connectivity gyrusin
Frontoparietal and MS.
andoccipital brainAlteration
regions ⬆
⬆
[80]
[82]
[85]
Papers
[87]
[82]
[74]
[78,79]
Right
temporal)
Regions
posteriormedial
Subcortical
[72] [87] Intra-
Fusiform and
Cerebellum,
Sensorimotor
Intra-
Bilateral
Right
and
areas
with
andinferior
Left
thalamic
Altered
thalamus,
thalamus,
cerebellum
inter-thalamic
sensory-motor
the
parietal
anterior and
nuclei
default-mode
inter-thalamic
gyrus with right
Functional
subthalamic
cingulum,
with
thalamic
Table premotor
networks
connectivity
lateral
cerebellar,
connectivity
cortex,
occipital
Connectivity
nucleus,
and
posterior
nuclei
2. Regions and
cortex,
with
withcortex
motor
prefrontal
thalamic,
bilateral
cingulate,
anterior in MS
network
cortexand
medial
cingulate
and anterior
altered functional
caudate/thalamus
components
cortical (frontal,
prefrontal
cortex,
cingulate
connectivity gyrus
left
parietal, and
incortex
bilaterallyMS. ⬇ have
⬇
⬆
⬇
⬆ in FC been
[72]
[86]
[82]
[84]
[80] Bilateral
Thalamus
Medial
cerebellar
Subcortical hippocampal
and
prefrontal
areas
and several
andthe and
reported
cortical
frontal
default-mode dorsal-frontal
to show
regions
pole
networks regions components
changes in parallel to thalamic connectivity in patients with ⬆
⬆
⬇MS [72].
[85]
Papers
[89]
[86]
[77] Fusiform
Regions
DMN
[81] [88] Left
[74]
[83] Insula
Bilateral
temporal)in
Sensorimotor
Prefrontaland gyrus
with
thethe
inferior
areas andwith
Altered
posterior
cerebellum
dACC
Superior
cortices,
hippocampus
right
Functional
cingulate
somatosensory
parietalto
ventral
anterior
and with
the lateral
striatum
cortex,
striatum
and
cortical cortex
cerebellar,
insular occipital
Connectivity
andthalamic,
and areas
association
posterior
regions
cortex
cingulate,
posterior in MS
bilateral
cingulate
cingulate inferior
and
medialcortical
cortex
cortices, parietal
prefrontal
anterior cortex
(frontal,
and parietal,
middle and
cortex Alteration⬆ in FC
⬇
⬆
[86]
[83]
[75]
[80]
[33]
Papers
[72] Left hippocampus
Caudate
Subcortical
Regions
Cerebellum, nucleus
withand Altered
thalamus, and
and cortical
motor
default-mode
Functional
cingulum,cortexregions
networksConnectivity
and prefrontal in MS
cortex components Alteration⬆
⬇
⬇ in FC
⬆
[87]
[82]
[85]
[74] Left
Intra-
Insulaanterior
Sensorimotor
Fusiform
[81] [89] Bilateral
temporal)
temporal
Right and
and thethalamic
areas
inferior
DMN cerebellum
inter-thalamic
gyrus with
dACC
cortices,
medial thethe
parietal nuclei
to
ininferior with
the
posterior and
connectivity
rightstriatum
cortex,
parietal anterior
cerebellar,
lateral occipital
posterior
cingulate
cortex, cingulate
thalamic,
cortex
cingulate,
cortex
and and cortex,
and
medial
bilateral
thalamus bilaterally
cortical (frontal,
prefrontal
inferior parietal parietal,
cortex
cortex leftand ⬇
⬆
⬆
⬇
[72]
[86]
[78,79]
[82]
[75]
[84]
[87]
Bilateral
Sensorimotor
Right
Thalamus
Caudate
Medial
Anterior andthalamic
hippocampal
nucleus
prefrontal
and
cerebellum
sensory-motorseveral
middleand
and andnuclei
and
Table with
cortical
motor
frontal
parts of
connectivity
dorsal-frontal
premotor
2.cortexinsular
Regions
regions
pole
the regions
putamen,
areas
cortex,
with with
components
and
altered bilateral
anterior
adjacentfunctional
globus
caudate/thalamus
cingulate
connectivity
pallidus, gyrusin MS.and
anterior and ⬆
⬇
[84]
[81]
[74] Medial
Insula
temporal)
[72] Bilateral
Prefrontal prefrontal
and the
areas
inferior dACC
cortices,
Bilateral and
parietaltofrontal
anterior the
hippocampalcortex,
and pole
striatum regions
posterior
and cingulate,
cingulate
dorsal-frontal medial
cortices,
components prefrontal
anterior andcortex
middle and ⬆
⬆
⬇
[88]
[86]
[76]
[83]
[82]
[75]
[33] Superior
Sensorimotor
cerebellar
Left
Thalamus
Caudate
Right
[72] [72] Intra-
Cerebellum,
ventral
areas
hippocampus
and
nucleus
medial striatum
cerebellum
and
several
and
thalamic
thalamus,
and
with
cortical
cortical
motor
nuclei posterior
cerebellar,
insular
regions
regions
cortex
of connectivity
cingulum, and
cingulate
areas thalamic,
with
prefrontal
cortex
and
bilateral
cortex
cortical (frontal,
caudate/thalamus
components
parietal,
andand left ⬇
⬆
⬇ in FC
[86]
[80]
[82]
[85]
Papers
[87] Anterior
posterior
Subcortical
Fusiform
Regions
temporal and
andwith and
gyrus middle
thalamus, with
Cerebellum,
Altered
cortices, parts
subthalamic
default-mode
inter-thalamic the
inferior right
thalamus,
Functional the putamen,
nucleus,
networks
connectivity
lateral
parietal cingulum,occipital
Connectivity
cortex, adjacent
motor
and
and network
cortex
prefrontal
ina MS
thalamus globus
cortex pallidus,
incomponents
anterior Alteration⬆
⬇
⬇
[86]
[76]
[85]
[82]
[75]
[87] Sensorimotor
Fusiform
temporal)
Thalamus
Caudate
Right
Left gyrus
areas
and
nucleus
medial
anterior
cerebellar
cerebellum
with
several
and
thalamic
thalamic
areas the with
The
right
cortical
motor
nuclei
nuclei and insular
hippocampus
lateral
regions
cortex
connectivity
anterior areas
occipital withhas
cortex
cingulate key
bilateral
cortex,role memory. Previous
caudate/thalamus
bilaterally and left studies have ⬇
⬆
suggested
⬆
that
[89]
[84]
[82] DMN
Anterior
posterior
Medial
Intra- in
and
Prefrontal
[87] [33] Left
[77]
the
and posterior
middle
thalamus,
prefrontal
Prefrontal
cortices,
and and
inter-thalamic cingulate
parts
subthalamic
frontal
anterior
somatosensory
of
and the
pole
connectivity
cortices, cortex
anterior putamen,
nucleus,
regionsand bilateral
adjacent
motor
and posterior
posterior
association cingulate networkinferior
globus
cingulate
cortices, parietal
pallidus,
cortices,
anterior cortex
anterior
anterior
and and and
middle
middle ⬆
⬇
[76]
[81]
[74]
[83]
[33] Sensorimotor
Insula
Bilateral
Right and the
inferior
hippocampus
medial cerebellum
dACC
parietal
thalamicand to with
hippocampal
the
cortical
nuclei cerebellar,
striatum
cortex, connectivity
posterior
regions
connectivity thalamic,is
cingulate,
with alsoand
bilateralmedialcortical
associated (frontal,
with
prefrontal
caudate/thalamus parietal,
disease
cortex
andand and
severity
leftand and loss of ⬆
⬆
hippocampal
⬇
[86]
[82]
[87]
[88] Sensorimotor
cerebellar
Anterior
posterior
Intra-
Left anterior
Superior areas
and cerebellum
middle
temporal
thalamus,
andhippocampal
inter-thalamic
thalamic
ventral parts
cortices, with
subthalamic
striatum thecerebellar,
insular
ofinferior
connectivity
nucleiand and putamen,
nucleus,
anterior
posterior areas
parietal thalamic,
adjacent
cortex,
motor
cingulate
cingulate and
networkand
globuscortical
thalamus
cortex, (frontal,
pallidus,
bilaterally parietal,
anterior ⬆
⬆
⬇ activation
⬆
[77]
[72]
[86]
[76]
[85]
[83]
[78,79]
temporal
Sensorimotor
Bilateral
Fusiform
Left
Right
cortices,
gyrus
hippocampus
temporal) areas and
sensory-motor
inferior
somatosensory
withand the
and
and parietal
dorsal-frontal
The
right
cortical
volume, premotorlateral cortex,
association
hippocampus
regions
resulting occipital
cortex, in and
components
has acortex
thalamus
cortex
verbal
and key
memory
anterior role in memory.
impairment
cingulate gyrus Previous studies
[48,90,91]. As hippocampal ⬇
⬆
have suggested
⬆ that
[82]
[75]
[84]
[87]
[77]
cerebellar
temporal)
Thalamus
Caudate
Medial
posterior
Right
Left medial
anterior
Sensorimotor
areas
and
nucleus
prefrontal several
thalamus, and
and
thalamic
thalamic
and cortical
motor
frontal
subthalamic
nuclei
nuclei
somatosensory andregions
cortex
pole regionsmotor
nucleus,
connectivity
anterior
association cingulate network
with bilateral cortex, caudate/thalamus
bilaterally andseverity
left ⬇
⬆
⬇
[83]
[88]
[87]
[89]
[78,79] Left hippocampus
Superior ventral
DMN sensory-motor
Right inprefrontal
the posterior and hippocampal
striatum cortical
and pole
decreases,
cingulate
and premotor regions
posterior
cortexconnectivity
connectivity
and
cortex,
cerebellar, cingulate is
bilateral
and also
cortex
increases
anterior
thalamic, associated
incomponents
inferior
and theparietal
cingulate
cortical brain with disease
network
cortex
gyrus
(frontal, [92]. and
parietal, and loss of ⬆
hippocampal
⬆
⬇
[72]
[86]
[84]
[87]
[86]
[80]
Cerebellum,
Sensorimotor
Medial
Left anterior
Sensorimotor
cerebellar
Subcortical
thalamus,
cerebellum
thalamic
areas
and and
cerebellum cingulum,
nuclei
default-mode
with
frontalofand
with and
insularregions
anterior
insular
networks
prefrontal
areas
areas cingulate cortexcortex, bilaterally ⬆
⬇ activation
[77]
[82]
[85]
[88]
[78,79]
[76]
Anterior
Intra-
Fusiform
Superior
Right andand middle
ventraland
inter-thalamic
gyrus
sensory-motor with parts
somatosensory
the
volume,
striatum
and The
and the
connectivity
right
premotor
putamen,
lateral association
hippocampus
resulting
posterior
The occipital
hippocampus
cortex,
adjacent
in and has
cingulate cortex
verbal has globus
acortex
key
memory
anterior a keyrole pallidus,
in memory.
impairment
role
cingulate in anterior
memory.
gyrus
and studies
Previous
[48,90,91].
Previous Asstudies have
hippocampal
have ⬆
⬇
suggested
suggested
⬆
thatthat
[84]
[89]
[72]
[80] temporal)
Medial
DMN
Right
Bilateralin
Prefrontal
medial
Subcortical areas
prefrontal
the posterior
cortices, and
thalamic
hippocampal
and frontal
cingulate
anterior
nuclei
and
default-mode and pole regions
cortex
posterior
connectivity
dorsal-frontal
networks and bilateral
cingulate
with
components inferior
cortices,
bilateral parietal
anterior
caudate/thalamus cortex
and middle
and left ⬆
⬇
⬇
[85]
[87]
[88] posterior
Fusiform
Right
Left anterior
Superior thalamus,
gyrus
medial with
thalamic
thalamic
ventral subthalamic
the
striatum right
hippocampal
nuclei
nucleiand
decreases, and nucleus,
lateral
connectivity occipital
connectivity
anterior
posterior
hippocampal connectivity motor
with
cingulate
cingulate
connectivity network
cortex
is also
bilateral associated
cortex,
cortex
increases isand bilaterally
incingulate
also the brain
associated with
caudate/thalamus disease
network and severity
left
[92]. severity
withparietal,
disease and loss of
and loss of ⬆
hippocampal
⬇
⬆
[33]
[81]
[78,79]
[83]
[89]
[87]
[86]
[80]
Insula
Right
Left
DMN
temporal
and
Sensorimotor
in
Sensorimotor
cerebellar
Subcortical thethe
sensory-motor
hippocampus dACC
cerebellum
posterior
areas
and and
cerebellum
cortices,
4.3.
to
and
inferior
default-mode
Brain
the
with
premotor
cortical
cingulate
with
parietal
Functional
striatum
cerebellar,
regions
cortex
insular
networks cortex,andConnectivity
cortex,
areas
thalamic,
and anterior
bilateral
and thalamus
in
inferiorMS
cortical (frontal,
parietal gyrus
cortex and ⬆ hippocampal
⬇
⬇
⬆
⬇
[85]
[72]
[77]
[81] Fusiform
Bilateral
Cerebellum,
cerebellar
Sensorimotor
Insula and gyrus
hippocampal
areas
the andwith
thalamus,
dACC the
volume,
and right
somatosensory
cerebellum to volume,
the
with lateral
resulting
dorsal-frontal
cingulum,
striatum and occipital
prefrontal
association
resulting
cerebellar, in cortex
incomponents
verbal
verbal
thalamic, memory
cortex memory
and impairment
components
cortical impairment
(frontal, [48,90,91].
[48,90,91].
parietal, andAs Ashippocampal
hippocampal ⬆ activation
⬇ activation
[88]
[89]
[82]
[80]
[86]
temporal)
Superior
Thalamus
Subcortical areas
ventral
DMN inprefrontal
the
and striatum
posterior
and several and
In MS
cingulate
cortical
default-mode posterior
studies,
cortex
regions
networks andcingulate
model-free
bilateral cortex
and model-based
inferior parietal cortexfunctional connectivity were ⬇ ⬆broadly
⬆ ap-
[84]
[72]
[87]
[81] Medial
Right
Bilateral
Left
Insula
temporal)medial
Prefrontaland
Sensorimotor
Left anteriorhippocampal
anterior thethalamic
areas dACC anddecreases,
thalamic
cerebellum
cortices,
thalamic tofrontal
nuclei
and
nuclei
4.3.
anterior the
nuclei
pole
dorsal-frontal
Brain and
striatum
decreases,
with
andand
regions
connectivity
anterior
connectivity
Functional
connectivity
cerebellar,
posterior
anterior
with
components
cingulate
thalamic,
cingulate
bilateral
increases
Connectivity cortex,
increases
and in
in caudate/thalamus
the
MSinbilaterally
cortical
cortices,
cortex, brain
the brainnetwork
network
(frontal,
anterior
bilaterally
and
[92].
parietal, leftand
[92].
and middle method in several⬇ ⬆
⬆
⬆MS studies
[72]
[87]
[78,79]
[86]
[82] Cerebellum,
Right
Sensorimotor
Thalamus andthalamus,
sensory-motor
cerebellum
several and cingulum,
plied. The
premotor
with
cortical
The and
correlation
insular
regions prefrontal
cortex,
hippocampus areas and cortex
coefficient
anterior
has a key wascomponents
used
cingulate
role parietalas a model-based
gyrus
in memory. Previous studies have suggested ⬆
⬆ that
were ⬆
[89]
[33]
[72]
[82]
[81] DMN
Bilateralin
cerebellar
Intra-
Insula and
andthe posterior
hippocampal
areas
inter-thalamic
the dACC cingulate
toandthe cortexoccipital
dorsal-frontal
connectivity
striatum andcomponents
bilateral inferior cortex ⬇
[85]
[72]
[88]
[86]
[82]
[88]
Fusiform
temporal)
Cerebellum,
Superior
temporal
Sensorimotor
Thalamus
Prefrontal
Superior
gyrus
areas
and
ventral
with
thalamus,
ventral
cortices,
cerebellum
several
cortices,
the
striatum
inferior
(Figure
striatum
right
In
cingulum,
and
with
cortical
anterior andand 4)lateral
MS studies,
and
posterior
parietal [93].
insular
regions cortex, and cortex
model-free
prefrontal
cingulate
Correlations
posterior
posterior areas cortex
thalamus
cingulate
cingulate andcomponents
cortex
between model-based
cortices,
cortex the brain
anterior functional
network
and middle and connectivity
cognitive ⬆
⬇broadly
impairment
⬆ ap-
illus-
[80]
[82]
[33] Right
Intra-
Left
medial
Subcortical
anterior andthalamic
andhippocampal hippocampal
nuclei
default-mode
inter-thalamic
thalamic 4.3.
nuclei
connectivity
networks
connectivity
Brain and
connectivity
Functional
anterior
with is
Connectivity
cingulate
also
bilateral associated
incomponents
cortex, MS bilaterally
with
caudate/thalamus disease
and severity
left and loss of ⬇
hippocampal
⬆
⬆
⬇
[72]
[87]
[83]
[86]
[82]
[89]
Bilateral
Cerebellum,
Left hippocampus
Sensorimotor
Thalamus
Prefrontal
temporal
Right
DMN medial
in andthalamus,
cortices,
cortices,
the thalamic
posterior and
cerebellum
several and
plied.
anterior
inferiornuclei
dorsal-frontal
cingulum,
cingulate
volume,
The
cortical
with
cortical
trate the
and
parietal
and
correlation
regions
cerebellar,
insular
regions
disease
posterior
cortex,
connectivity
cortex
resulting areascomponents
prefrontal
course
and thalamic,
and
withor
incingulate
cortex
coefficient and
progression.
thalamus was
cortices,
bilateral
bilateral
verbal inferior
memory
used
cortical As as a model-based
(frontal,
depicted
anteriorcortex
caudate/thalamus
parietal
impairment parietal,
in Figure
and[48,90,91].
middle method
and 5, The in
and left As hippocampal⬆
several
severity ⬆
⬇
of
⬆MS studies
cognitive
activation
[82]
[86] cerebellar
Intra- and areas
inter-thalamic connectivity ⬆broadly
[33]
[89]
[87]
[81]
[83]
[88]
[72]
DMN
Insula
Left
temporal)in
Prefrontal
Superior and
Cerebellum,
temporal
the posterior
the
hippocampus
areas dACC
cortices,
ventral and cingulate
to the
(Figure In
cortical
The
impairment
anterior
striatum
thalamus,
cortices, inferior andand
cingulum,
MS
striatum
parietal
cortex
studies,
4)posterior
[93].
regions
hippocampus
caused
posterior
and
cortex,
and bybilateral
model-free
Correlations has
MS
cingulate
cingulate
prefrontal
and isa inferior
androle
between
key
reflected
cortex
thalamus cortices,
cortex
parietal
model-based
the
in
by brain
memory.
a
anterior
components
cortex
functional
network
significant
and Previousand
increase
middle connectivity
cognitive
studies
in have were
functional ⬇
⬆
impairment
⬆
suggested
⬇
connectivity ap-
illus-
that
[84]
[82]
[33] Right
Intra- medial
cerebellar
Medial areasthalamic
prefrontal
and
Left anterior inter-thalamic
thalamic
nuclei
anddecreases,
frontal
nuclei
connectivity
pole
connectivity
and connectivity with
regionscomponents
anterior cingulate
bilateral
increases cortex,
caudate/thalamus
in the brain network [92].
bilaterally
and left ⬆
⬆
⬇
[72]
[87]
[83]
[72] Bilateral
Left
Bilateral hippocampal
hippocampus
hippocampal and and
plied. dorsal-frontal
hippocampal
incortical
the
and The
cortical
trate the correlation
regions
disease
default-node
dorsal-frontal course
connectivity coefficient
or
network
componentsprogression.
isa[74].
also was used
associated
Therefore, As as a model-based
depicted
with
functional in
disease Figure method
severity
connectivity5, The in several
severity
andinhave
loss
MSof ⬆
ofMS studies
⬆ the that
cognitive
hippocampal
reflects dis-
[86]
[82]
[84]
[89]
temporal
Sensorimotor
Thalamus
cerebellar
Medial
Prefrontal
DMN
cortices,
and
areas
inprefrontal
cortices,
the posterior
inferior
cerebellum
several
and
anterior parietal
with
The
frontal
cingulateand insular
regions cortex,
hippocampus
pole regions
posterior
cortex areas
andby
andhas thalamus
cingulate
bilateral key rolebilaterally
cortices,
inferior in memory.
anterior
parietal and
cortex Previous
middle studies ⬇
⬆
suggested
⬆
[87]
[85]
[83]
[33]
[88]
Left
Left anterior
Fusiform
Superior gyrus
hippocampus thalamic
ventral withand nuclei
the
(Figureright
cortical
impairment
volume,
striatum
ease and
and
course.
anterior
4)lateral
[93].
regions occipital
caused
resulting
posterior
Other in
cingulate
Correlations MScortex
verbal
cingulate
findings is cortex,
between
reflected
memory
cortex
revealed the
by
that, brain
a network
significant
impairment
although an and cognitive
increase
[48,90,91]. As in functional
hippocampal ⬇
⬆
impairment
⬆
⬇ illus-
activation
connectivity
[72]
[84] Cerebellum, thalamus,
Medial prefrontal andhippocampal cingulum,
Thepole
frontal
4.3. Brain and
hippocampus
regions
Functional prefrontal
connectivity cortex
hasisaalso
Connectivity keyin components
role
MS in memory.
associated Previous
with disease studies
severity and have ⬆
loss ofsuggested
hippocampal that
Brain Sci. 2023, 13, 246 10 of 23

4.3. Brain Functional Connectivity in MS

In MS studies, model-free and model-based functional connectivity were broadly ap-
plied. The correlation coefficient was used as a model-based method in several MS studies
(Figure 4) [93]. Correlations between the brain network and cognitive impairment illus-
trate the disease course or progression. As depicted in Figure 5, The severity of cognitive
impairment caused by MS is reflected by a significant increase in functional connectivity in
the default-node network [74]. Therefore, functional connectivity in MS reflects the disease
Brain Sci. 2023, 13, x FOR PEER REVIEW 10 of 24
course. Other findings revealed that, although an increase in functional connectivity was
expected in the early stages of MS, functional connectivity enhancement decreases with
disease progression [33]. In studies of fatigue in MS, functional connectivity was found to
was expected in the early stages of MS, functional connectivity enhancement decreases
increase in the caudate nucleus
with diseaseand the motor
progression [33].cortex under
In studies fatigue
of fatigue in conditions [75].
MS, functional Anotherwas
connectivity
study revealed sex-specific found toalterations incaudate
increase in the functional connectivity
nucleus and the motor incortex
MS [94].
under fatigue conditions
[75]. Another study revealed sex-specific alterations in functional connectivity in MS [94].

Faivre et al., 2016

Bivariate Correlation
Functional Connectivity in MS studies

Rocca et al., 2014

Flippi et al., 2014
Model-based Pearson Correlation

Baijot et al., 2021,

Shu et al., 2016,

Intraclass Correlation
Tewarie et al., 2015,
Coefficient
Liu et al., 2017,

Welton et al., 2020

Hierarchial Clustering
Model free Analysis Eijlers et al., 2017

Brain Sci. 2023, 13, x FOR PEER REVIEW 11 of 24

Dobryakova et al., 2016

Causal Bayesian Network
(CBN) Analysis Fleischer et al., 2020
Effective Connectivity in MS

Structural Equation Duong et al., 2005

Modeling (SEM)
Studies

Time Resolved Partial Fleischer et al., 2020

Directed Coherence
Analysis

Leavitt et al., 2012

Granger Casualty (GC)
Analysis

Dynamic Causal Modeling Mansoory et al., 2020

(DCM)

Figure 4. Literature on functional

Figure and effective
4. Literature connectivity
on functional andin MS studies.connectivity
effective [2,30,33,36,38,42,47,66,95–100].
in MS studies.
[2,30,33,36,38,42,47,66,95–100].

Gender
 (DCM)

Brain Sci. 2023, 13, 246

Figure 4. Literature on functional and effective connectivity
11 of 23
in
[2,30,33,36,38,42,47,66,95–100].

Gender

Memory
deficit/ Fatigue
rehabilitaion
Functional
Connectivity
for MS
Patients

Cognitive/
Disease physical
Course
Impairment

Figure 5. Clinical factors impacting the functional connectivity.

Figure 5. Clinical factors impacting the functional connectivity.
4.4. Brain Effective Connectivity in MS Studies
Effective connectivity provides insight into how a given region in the brain affects
4.4.other
Brain Effective Connectivity in MS Studies
brain regions (Figure 4). In MS studies, any abnormalities in the connections between
regions can be inferred
Effective as cognitive
connectivity and physical
provides impairments
insight into[97].
howIn studies on patients
a given region in
with MS, effective connectivity showed that the frontal cortices have high connectivity with
other brain
multiple regions
regions (Figure
[99]. Few 4).theInMSMS
studies in fieldstudies, any connectivity
applied effective abnormalitiesto studyin the
tween
brainregions
networks. can be inferred
The limited number ofas cognitive
articles using ECand physical
may result impairments
from the limitations [9
of EC in previous articles, such as the existence of a priori assumptions regarding the
patients with
interaction MS,two
between effective connectivity showed that the frontal cortices
regions [97].
nectivity with multiple regions [99]. Few studies in the MS field applied e
4.5. Graph Theory in Studying Brain Connectivity
tivity to study brain networks. The limited number of articles using EC
Graph theory is a mathematical approach to studying network connectivity. In neuro-
science, it is widely applied to study interactions between regions. In this model, nodes
represent regions, and edges represent the interactions between regions (Figure 6).

1 1
Eglob (G) =
N (N − 1) ∑i6=jG Lij (1)

1
N ∑iG
Eloc(G) = Eglob (Gi) (2)
 regarding the interaction between two regions [97].

4.5. Graph Theory in Studying Brain Connectivity

Graph theory is a mathematical approach to studying network connectivity. In neu-
roscience, it is widely applied to study interactions between regions. In this model, nodes
Brain Sci. 2023, 13, 246 12 of 23
represent regions, and edges represent the interactions between regions (Figure 6).

B: Graph theory analysis

Figure 6.
Figure 6. (A)
(A)Graph
Graphtheory
theoryelements.
elements. (B)(B)
Graph
Graph theory analysis
theory Clustering
analysis Clusteringcoefficients: TheseThese
coefficients: coef-
ficients measure segregation in the network and the capability of interconnections for a specific
coefficients measure segregation in the network and the capability of interconnections for a specific
node. Transitivity: Transitivity is the proportion of the number of the triangles in a specific region
node. Transitivity: Transitivity is the proportion of the number of the triangles in a specific region
and the total number of triangles [101]. Global efficiency: Global efficiency is a parameter to measure
and the total and
segregation number of triangles
integration [101].
of the brainGlobal efficiency:
network Global efficiency
[96]. Equation (2) is usedis atoparameter
calculate to measure
global effi-
segregation and integration of the brain network [96]. Equation (2) is used to calculate
ciency in a brain network, where Lij is the shortest path between node i and node j [65]. (Equation global efficiency
in
(1),a brain
globalnetwork, where
efficiency). Lij is
Local the shortest
efficiency: path
Local between calculates
efficiency node i andshort
node distance
j [65]. (Equation (1), global
connectivity [33].
(Equation (2),
efficiency). global
Local efficiency).
efficiency: LocalSmall-world network:
efficiency calculates Thisdistance
short networkconnectivity
is named according to its ori-
[33]. (Equation (2),
gins inefficiency).
global the social sciences. The randomness
Small-world network: This of anetwork
networkisisnamed
assessed with thetosmall-world
according its origins inparameter,
the social
which reflects
sciences. the effectiveness
The randomness of the transformation
of a network is assessed with of information
the small-worldwithin the network.
parameter, whichStudies
reflectsin
MS effectiveness
the have shown of that
thesmall-world
transformation efficiency is significantly
of information diminished
within the in patients
network. Studies with
in MS haveMSshown
com-
pared with control individuals [28,65].
that small-world efficiency is significantly diminished in patients with MS compared with control
individuals [28,65].
Eglob (G)= ∑ (1)
4.6. Graph Theory in MS ( )

In this study, our focus was on Eloc(G) = ∑ Eglobof(Gi)

the application graph theory to fMRI data from (2)
patients with MS (Figure 7). Blood oxygen level-dependent fluctuations in resting-state
fMRI provide insights into brain connectivity in the entire brain [33]. Graph theory anal-
4.6. Graph Theory in MS
ysis identifies patterns in brain connections and investigates structural and functional
In this
systems [71].study, our focus was may
Any dysconnectivity on the application
reveal the brainofnetwork
graph theory to fMRI
for particular data from
neurological
patients with
disorders suchMS (Figure
as MS. 7). Blood can
Abnormalities oxygen level-dependent
be demonstrated fluctuations
through in resting-state
graph theory in patients
fMRIMS
with provide
[71]. insights into brain connectivity
Several parameters in thetoentire
have been used studybrain
early[33].
MSGraph theory anal-
impairments with
ysis identifies patterns in brain connections and investigates structural and functional
graph theory parameters, such as centrality, segregation, and integration [48]. Functional sys-
temsstructural
and [71]. Any connectivity
dysconnectivity
wasmay reveal
applied to the
studybrain network
changes for particular
in whole-brain neurological
networks [93].
Moreover, serotonergic, noradrenergic, cholinergic, and dopaminergic systems may be
examined to investigate fluctuations in functional connectivity [41]. One benefit of func-
tional connectivity is helping researchers define specific biomarkers to classify disease
impairments and severity [39]. In contrast, the graph–theoretical approach is used to detect
cognitive dysfunction by classifying task-based brain functions [102]. Node-based graph
theory also helps researchers detect specific regions and functions in patients and healthy
controls [37,64]. Brain connectivity, along with the nodal degree between and within differ-
ent regions, was studied to determine the sources of impairment in patients with MS [34].
Functional connectivity in working memory studies using fMRI has resulted in identifying
a biomarker for detecting early-stage MS [29].
 detect cognitive dysfunction by classifying task-based brain functions [102]. Node-based
graph theory also helps researchers detect specific regions and functions in patients and
healthy controls [37,64]. Brain connectivity, along with the nodal degree between and
within different regions, was studied to determine the sources of impairment in patients
Brain Sci. 2023, 13, 246 with MS [34]. Functional connectivity in working memory studies using fMRI has resulted
13 of 23
in identifying a biomarker for detecting early-stage MS [29].

A B C D

Construct Binary
Adjacency Matrix

H G F F E
Pipeline
Figure7.7.Pipeline
Figure ofof theoretical
theoretical analysis
analysis using
using fMRI
fMRI data.
data. After
After collection
collection of of data
data with
with fMRI
fMRI (A),
(A),
brain
brain imagepreprocessing
image preprocessing(B) (B)should
shouldbebeperformed
performed byby applying
applying motion correction,
correction,spatial
spatialsmoothing,
smooth-
ing,
andand high-pass
high-pass temporal
temporal filtering.
filtering. An atlas
An atlas should
should be selected
be selected for dividing
for dividing the entire
the entire brain brain into
into parcels
parcels (C). courses
(C). Time Time courses are extracted
are extracted in thein thelevel
next next (D).
levelThe
(D).functional
The functional connectivity
connectivity matrix
matrix and
and binary
binary
matrixmatrix areconstructed
are then then constructed (E,F).construction
(E,F). After After construction of the
of the brain brain network,
network, local andlocal and
global globalof
features
features of the network can be calculated (G,H).
the network can be calculated (G,H).

Properties
Propertiesfor
forGraph
GraphTheory
TheoryUsing
UsingMS
MSData
DataBased
Basedon
onfMRI
fMRI
Global
Globaland
andlocal
localnetworks
networkswere wereapplied
appliedtotoinvestigate
investigate the
the effects
effects of
of brain connectiv-
connectivity
ityororimpairments.
impairments.TheThe results
results of of previous studies
studies suggested
suggestedaalower
lowerglobal
globalefficiency
efficiencyinin
patientswith
patients withMSMSthan
thanhealthy
healthycontrol
controlindividuals
individuals[32,47].
[32,47].One
One graph
graph property
property is is small-
small-
worldness,which
worldness, whichrefers
referstotoa acondition
conditionininwhich
whichnodes
nodesare
areneighbors
neighborstotoeach
eachother
otherbut butare
are
still connected through other nodes with a number of edges and nodes [103]. Small-world
efficiency is used for structural and topological characterization [65]. This property was
suggested to provide an economic brain functional network [104]. Figure 7 shows the
overall concepts and applications of node-based analysis. Figure 6 depicts the application
of each graph theory property in MS studies. Global efficiency, local efficiency, network
modularity, clustering coefficients, and centrality are frequently used in the MS field.

4.7. Other Computational Approaches in MS Studies Using fMRI

With the advent of computer-aided diagnosis (CAD), several computational methods
have been applied in fields as diverse as disease detection and patient classification. Among
all computational approaches, graph theory, machine learning, deep learning, and Bayesian
modeling have been extensively applied to MS data. Machine learning is among the best tools
applied to diagnose the early stages of MS [22,105]. In this respect, several algorithms have been
used, such as Random Forest, Support Vector Machine (SVM), General Linear Model, partial least
squares, neural network, naïve-Bayes, and K-nearest-neighbor [22,106–108]. These algorithms
have been applied in classifying biomarkers and predicting the disease course. Deep learning
Brain Sci. 2023, 13, 246 14 of 23

approaches in MS have been applied to classification, segmentation, and detection [109–112].

According to the McDonald criteria, deep learning is also used to find the exact locations of
brain lesions. DL is a CAD approach for patients with MS [23]. The Bayesian model has been
used as a computational model incorporating the basics of probability studies. Studying risk
factors, including sex and the environment, are examples of applying the Bayesian model in
MS studies [113]. We did not find any specific articles after adding “fMRI” to the keywords
in our search for the Bayesian model, we did not find any specific articles. The nature of the
Bayesian model helps researchers study underlying causes and probabilities of the disease course
or disease progression. Therefore, MRI studies usually do not apply the Bayesian model to study
brain networks.

Graph Theory Combined with Machine Learning in MS Studies

Mathematical and statistical approaches are inseparable methods used in analyzing
brain connectivity. General linear model is a mathematical method applied in graph-
theoretical studies in MS to detect brain activation [102,114]. Some articles in recent years
have applied a combination of graph theory and machine learning. Various machine
learning classifiers such as SVM have been used to distinguish patients with graph metrics
from healthy individuals. SVM is a supervised machine learning approach for classifications
that aims to find the best algorithms for classifying classes or groups of specific data.
Moreover, the use of SVM on graph-based measures has enabled the investigation of
biomarkers to distinguish people in early disease stages from healthy controls [49]. The
use of SVM can avoid or decrease the effects of overfitting of the results and consequently
the introduction of bias [115,116]. Previous studies have shown that SVM increases model
accuracy and can be applied to MS data-driven graph parameters. Moreover, the combi-
nation of graph theory and SVM enables the identification of more sensitive biomarkers
that can distinguish different types of MS, such as RRMS and PPMS [101]. Because the
graph properties are sensitive, and SVM classification is accurate, this method may provide
a valuable tool for disease detection in patients with MS.

4.8. Disease Detection and Prediction in MS Studies with Graph Theory

No cure exists for MS, although the disease can be controlled. Therefore, identifying
the disease in the earliest possible stages is essential. Most articles in this review included
healthy control individuals in their experiments to enable fMRI image comparison. How-
ever, network properties could also be used as an indicator in disease detection and the
prediction of disease progression, as illustrated by the modularity values in the network
for patients with MS. Higher modularity can be inferred as an indicator of MS in the brain
network [29,34]. In parallel, a decrease in centrality is seen in the ventral stream and
sensorimotor regions in the entire brain network in patients with MS [31]. DMN centrality
was suggested to be greater in patients with MS [36]. Local connectivity is more significant
in patients with MS than in the HC network. However, the strength of the connections
is lower in the early stages of MS [34,39]. Another approach to identify the early stages
of the disease involve cognitive tasks. Dual tasking experiments and fatigue in patients
with MS cause alterations in the network [28,30]. Different network hub formations in the
cerebellum and left temporal region were reported in the networks of patients with MS in
early stages [32].

4.8.1. Network Abnormalities in Patients with MS

Abnormalities in the global and local networks are found in patients with MS [32]. A
significant abnormality is a reduction in default-mode, frontoparietal, and visual networks
dynamics in patients with MS [117]. Moreover, the neuro-modularity network shows
abnormalities in functional connectivity in patients with MS, and centrality is decreased in
the brainstem for the serotonergic–noradrenergic network but increased in the cerebellum
for the same network [41].
Brain Sci. 2023, 13, 246 15 of 23

4.8.2. Cognitive Impairment and Network Efficiency in MS

The focus of this section is to explore the effects of cognitive impairment in patients
with MS on network efficiency. Studies have suggested that cognitive impairment con-
tributes to a decrease in the nodal degree (i.e., the number of edges neighboring a given
node) in the bilateral caudate nucleus and right cerebellum in MS [101]. The increase in
thalamic connectivity, in contrast, is correlated with cognitive impairment [72]. Alterations
in DMN are critical to evaluate the efficiency of the network. The results of previous studies
shed light on these reduction dynamics in DMN and indicated that the frontoparietal and
visual networks are associated with cognitive impairments in MS [36,95,118]. The robust
evidence indicating the role of cognitive impairment in this alteration is the increase in
connectivity in DMN in patients with CIS who are not cognitively impaired [119]. Notably,
decreases in network efficiency and small-worldness were identified in patients with MS
with cognitive dysfunction [42].

4.9. Graph Theory Analysis of Disease Progression in MS

Studying brain networks in MS provides insight into cognitive and physical functions
that may optimize disease progression evaluation. Recent studies revealed that disease
progression may decrease the connectivity in the brain network in patients with MS [33].
• Hubs (High-Degree Nodes)
According to previous studies, hubs are assumed to reveal important information
regarding the effects of neurological disorders on brain functional connectivity. This
finding was suggested to be rooted in a decrease in inhibitory activity in the brain network,
particularly in hubs [64,96]. Although hubs are not a reliable source for studying the very
early stages of MS, hubs as core regions are sensitive to MS progression [96]. Functional
connections are negatively affected during disease progression. In contrast, lost hubs
have been reported in the thalamus, left frontal lobes, superior frontal gyrus, precuneus,
and anterior cingulum in the left hemisphere in patients with MS [7,32]. In addition,
cognitive impairment was revealed in hub analysis of MS progression [7]. The rich club
is another term that has been used in MS studies using graph theory. It is defined by
high degree/strongest nodes [37]. A decrease in rich club connections was observed in
patients with PPMS [37]. In patients with MS, higher physical disability is associated with
lower connections in rich-clubs, and cognitive impairment is associated with loss of rich
hubs [37,64].
• White Matter Lesions
Changes in white matter lesions in patients with MS affect high-degree regional
connections. Some studies divided patients into subgroups based on white matter lesion
load [28]. A disruption in small-worldness is associated with white matter lesions [28].
White matter and grey matter changes are used as biomarkers in the detection process and
in identifying disease progression. White matter lesion accumulation has a substantial role
in disease progression, which could be addressed in changes in functional connectivity in
patients with MS [33].

4.10. Toolboxes for Statistical Analysis in MS Studies Using fMRI

The Brain Connectivity Toolbox (brain-connectivity-toolbox.net) was implemented
in some studies to measure network properties and detect modularity maximiza-
tion [29,32,39,42,45,46,48–50]. The CONN toolbox is commonly used in MS studies
applying graph theory to study functional connectivity [34,41]. Brainwaver is another
toolbox that allows researchers to measure brain connectivity [33]. GAT and GRETNA
are utilized to analyze brain connectomes and measure network properties [34,44].
DPARS (Data Processing Assistant for Resting-State fMRI) is an SPM-based toolbox for
investigating functional connectivity and network measures in MS studies [40,120].
Brain Sci. 2023, 13, 246 16 of 23

4.11. Limitation and Future Directions in MS Studies Using Graph Theory

• Experiment Design:
PASAT is used in working memory and attention studies of MS, and the Stroop task is
designed to trace the sensorimotor cortex [2,7,29,38,55,72]. Although many studies applying
fMRI have utilized PASAT, this experiment is more applicable to working memory studies
and cannot directly indicate neuropsychological function. Applying multiple experiments
in future studies may lead to a comprehensive understanding of all neuropsychological
functionalities for MS patients.
• Sample Size
Small sample sizes pose another limitation in MS studies, given the difficulties involved
in conducting experiments with all considerations for patients with MS [10,22,44,115,121].
Small sample sizes may affect the results of studies, and increasing the number of participants
will improve analyses in graph theory. This is a potential direction for future studies in MS.
• Graph-Theory-Related Limitations in MS Studies
In graph theory, Pearson’s correlation is a linear bivariate model. Therefore, this model
cannot fully reveal the complex connectivity in the MS brain network [10,47]. In addition,
in prior studies, researchers selected the voxel size and parcellation methods without any
optimum modeling reflecting the thickness and convolutions [10,40,46,115]. In future work,
the voxel size could be optimized to improve the analytic results.
• Network Reliability Limitations
There are many factors that may affect the reliability of the network, including, but
not limited to, test–retest data set, different atlases, thresholding, and parcellations. As
mentioned, one side of the reliability goes back to the data collection of different sessions
that may lead to different network measures [42]. In addition to that, Different atlases,
parcellation approaches, and thresholding should be considered in measuring the reliability
of the network [122].
• Study Design Limitations
Experimental designs in MS studies have several limitations. Functional metrics in
cross-sectional design should be considered when studying patients with MS with different
disease courses [10,33,50]. As another limitation of the cross-sectional design, some features
cannot correctly demonstrate functional abnormalities [32]. Temporal dynamics and related
cognitive impairments are missing in cross-sectional designs. To tackle this issue, cognitive
test monitoring would be useful in future studies. Moreover, the reverse inference approach
was previously proposed to address these missing components for interpretations and
analyses of cognitive process [123]. As suggested in this approach, evidence is needed
to link changes in interactions of specific regions to cognitive impairment. This evidence
might be provided by cognitive tests.
• Disease Classification
A lack of study participation among patients in very severe stages of disease presents
another limitation in MS studies [44]. Most participants have a low or moderate disability,
resulting in a gap in the network [107]. Moreover, the data cannot be validated because of
a lack of longitudinal data [40,96]. In future studies, including MS patients from various
EDSSs, ranging from low to high, could give researchers greater insight into the physical
and cognitive impairments caused by MS. Such information would help in identifying
accurate biomarkers for diagnosing MS progression.
• Overlapping in the Network
In contrast to the neuro-modulatory network in MS studies, overlapping in the non-
modulatory network may show functional connectivity alterations among other regions. How-
ever, such overlaps do not necessarily depict alternations in functional connectivity [10,41].
Brain Sci. 2023, 13, 246 17 of 23

Region of interest (ROI) selection might be a good approach for reducing overlaps in brain
regions in the neuro-modulatory network [41]. Thus, overlapping in the modulatory network is
a limitation in MS studies that could be addressed in future works.
• Suggestions and Future Work
MS is a neurological disorder that negatively affects the longest (or more expensive)
connections or edges in the entire system based on the economic connectivity frame-
work [104]. However, in the MS field, edges have not been used for analysis, although
they have been considered in other fields such as autism [25,96,124]. Studying edges plus
nodes as the main elements of the network could provide more information on functional
connectivity in the brain networks affected by MS.
Another appealing idea for a future paper in the MS field would be meta-analysis
approaches for graph theory metrics on MS data. Previously, it was applied for brain injury
data, depression, and other neurological disorders [125,126].
Recently, the multi-model network was extensively used to study neurological dis-
orders. This approach may give researchers a comprehensive view of the whole network
when neuroimaging data and analysis is combined with cognitive tests and data or ques-
tionaries collected from patients [42,127]. More multi-model studies are needed in the field
of MS to grasp a better insight into network alterations.
In recent years, a notable approach to classifying data from fMRI is graph neural
networks. This approach was first developed to graph convolutional neural networks
between 2009 and 2016 [128,129]. It has since been used in many neurological disorders;
however, few studies have used graph neural networks in the MS field [130,131].

5. Conclusions
In this systematic review, we discussed the role of graph theory in detecting MS and
disease progression, including the effects of cognitive impairment on network efficiency
in MS. This knowledge should help researchers model disease progression in patients
with MS because brain network connectivity may reflect the brain’s cognitive performance.
Global and local efficiency are frequently applied to evaluate brain networks in patients
with MS. However, graph theory has several limitations that stem from the sample size,
experimental design, and the challenges of overlap in the brain network. Our review of
previous studies highlighted the importance of alterations in networks such as the thalamus
and DMN. Increasing the sample size and applying combined computational approaches
might provide more accurate network modeling results in future studies for patients with
MS. To conclude, our review of applying graph theory in MS studies revealed that graph
theory as a computational method helps researchers better understand brain connectivity
changes in patients with multiple sclerosis.

Author Contributions: S.H. performed the literature search and wrote the first draft. W.K. supervised
all steps of selection, editing and revision. S.H. and W.K. were both involved in creating intellectual
content. F.V.F. contributed to study conception, editing, and final intellectual content. T.M. and P.A.H.
were involved in editing and adding intellectual content. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Apostolopoulos, V.; Matsoukas, J. Advances in Multiple Sclerosis Research–Series I. Brain Sci. 2020, 10, 795. [CrossRef]
2. Fleischer, V.; Muthuraman, M.; Anwar, A.R.; Gonzalez-Escamilla, G.; Radetz, A.; Gracien, R.-M.; Bittner, S.; Luessi, F.; Meuth,
S.G.; Zipp, F.; et al. Continuous reorganization of cortical information flow in multiple sclerosis: A longitudinal fMRI effective
connectivity study. Sci. Rep. 2020, 10, 806. [CrossRef]
Brain Sci. 2023, 13, 246 18 of 23

3. Macaron, G.; Ontaneda, D. Diagnosis and Management of Progressive Multiple Sclerosis. Biomedicines 2019, 7, 56. [CrossRef]
4. Siegert, R.J.; Abernethy, D.A. Depression in multiple sclerosis: A review. J. Neurol. Neurosurg. Psychiatry 2005, 76, 469–475.
[CrossRef]
5. Grossman, P.; Kappos, L.; Gensicke, H.; D’Souza, M.; Mohr, D.C.; Penner, I.K.; Steiner, C. MS quality of life, depression, and
fatigue improve after mindfulness training: A randomized trial. Neurology 2010, 75, 1141–1149. [CrossRef]
6. Sauder, T.; Keune, P.M.; Müller, R.; Schenk, T.; Oschmann, P.; Hansen, S. Trait mindfulness is primarily associated with depression
and not with fatigue in multiple sclerosis (MS): Implications for mindfulness-based interventions. BMC Neurol. 2021, 21, 115.
[CrossRef]
7. Rocca, M.A.; De Meo, E.; Filippi, M. Functional MRI in investigating cognitive impairment in multiple sclerosis. Acta Neurol.
Scand. 2016, 134, 39–46. [CrossRef]
8. Kurtzke, J.F. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 1983, 33,
1444–1452. [CrossRef]
9. World Health Organization. Atlas: Multiple Sclerosis Resources in the World 2008; World Health Organization: Geneva, Switzerland, 2008.
10. MS Classifications Revised. Available online: https://momentummagazineonline.com/ms-classifications-revised/ (accessed on
5 December 2022).
11. Walton, C.; King, R.; Rechtman, L.; Kaye, W.; Leray, E.; Marrie, R.A.; Robertson, N.; La Rocca, N.; Uitdehaag, B.; Van Der Mei,
I.; et al. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult. Scler. J. 2020, 26,
1816–1821. [CrossRef]
12. Sintzel, M.B.; Rametta, M.; Reder, A.T. Vitamin D and Multiple Sclerosis: A Comprehensive Review. Neurol. Ther. 2017, 7, 59–85.
[CrossRef]
13. Bjornevik, K.; Cortese, M.; Healy, B.C.; Kuhle, J.; Mina, M.J.; Leng, Y.; Elledge, S.J.; Niebuhr, D.W.; Scher, A.I.; Munger, K.L.; et al.
Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science 2022, 375, 296–301.
[CrossRef]
14. Lublin, F.D.; Reingold, S.C.; Cohen, J.A.; Cutter, G.R.; Sørensen, P.S.; Thompson, A.J.; Wolinsky, J.S.; Balcer, L.J.; Banwell, B.;
Barkhof, F. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014, 83, 278–286. [CrossRef]
15. McDonald, W.I.; Compston, A.; Edan, G.; Goodkin, D.; Hartung, H.P.; Lublin, F.D.; McFarland, H.F.; Paty, D.W.; Polman, C.H.;
Reingold, S.C. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis
of multiple sclerosis. Ann. Neurol. 2001, 50, 121–127. [CrossRef]
16. Polman, C.H.; Wolinsky, J.S.; Reingold, S.C. Multiple sclerosis diagnostic criteria: Three years later. Mult. Scler. J. 2005, 11, 5–12.
[CrossRef]
17. Politis, M. Neuroimaging in Parkinson disease: From research setting to clinical practice. Nat. Rev. Neurol. 2014, 10, 708–722.
[CrossRef]
18. Jameen, A.; Ribbons, K.; Lechner-Scott, J.; Ramadan, S. Evaluation of MS related central fatigue using MR neuroimaging methods:
Scoping review. J. Neurol. Sci. 2019, 400, 52–71.
19. Filippi, M.; A Rocca, M. Present and future of fMRI in multiple sclerosis. Expert Rev. Neurother. 2013, 13, 27–31. [CrossRef]
20. Kose, U.; Alzubi, J. Deep Learning for Cancer Diagnosis; Springer: Singapore, 2021.
21. Zeng, L.-L.; Wang, H.; Hu, P.; Yang, B.; Pu, W.; Shen, H.; Chen, X.; Liu, Z.; Yin, H.; Tan, Q.; et al. Multi-Site Diagnostic Classification
of Schizophrenia Using Discriminant Deep Learning with Functional Connectivity MRI. Ebiomedicine 2018, 30, 74–85. [CrossRef]
22. Saccà, V.; Sarica, A.; Novellino, F.; Barone, S.; Tallarico, T.; Filippelli, E.; Granata, A.; Chiriaco, C.; Bossio, R.B.; Valentino, P.; et al.
Evaluation of machine learning algorithms performance for the prediction of early multiple sclerosis from resting-state FMRI
connectivity data. Brain Imaging Behav. 2018, 13, 1103–1114. [CrossRef]
23. Shoeibi, A.; Khodatars, M.; Jafari, M.; Moridian, P.; Rezaei, M.; Alizadehsani, R.; Khozeimeh, F.; Gorriz, J.M.; Heras, J.; Panahiazar,
M. Applications of Deep Learning Techniques for Automated Multiple Sclerosis Detection Using Magnetic Resonance Imaging: A
Review. arXiv 2021, arXiv:2105.04881. [CrossRef]
24. Fleischer, V.; Radetz, A.; Ciolac, D.; Muthuraman, M.; Gonzalez-Escamilla, G.; Zipp, F.; Groppa, S. Graph Theoretical Framework
of Brain Networks in Multiple Sclerosis: A Review of Concepts. Neuroscience 2017, 403, 35–53. [CrossRef]
25. Bullmore, E.; Sporns, O. The economy of brain network organization. Nat. Rev. Neurosci. 2012, 13, 336–349. [CrossRef]
26. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; PRISMA Group. Preferred reporting items for systematic reviews and
meta-analyses: The PRISMA statement. PLoS Med. 2009, 6, e1000097. [CrossRef]
27. Whiting, P.; Savović, J.; Higgins, J.P.; Caldwell, D.M.; Reeves, B.C.; Shea, B.; Davies, P.; Kleijnen, J.; Churchill, R. ROBIS: A new
tool to assess risk of bias in systematic reviews was developed. J. Clin. Epidemiol. 2016, 69, 225–234. [CrossRef]
28. He, Y.; Dagher, A.; Chen, Z.; Charil, A.; Zijdenbos, A.; Worsley, K.; Evans, A. Impaired small-world efficiency in structural cortical
networks in multiple sclerosis associated with white matter lesion load. Brain 2009, 132, 3366–3379. [CrossRef]
29. Gamboa, O.; Tagliazucchi, E.; von Wegner, F.; Jurcoane, A.; Wahl, M.; Laufs, H.; Ziemann, U. Working memory performance of
early MS patients correlates inversely with modularity increases in resting state functional connectivity networks. Neuroimage
2014, 94, 385–395. [CrossRef]
30. Filippi, M.; Valsasina, P.; Bisecco, A.; Meani, A.; Parisi, L.; Messina, M.J.; Colombo, B.; Falini, A.; Comi, G.; Rocca, M. Thalamic
dysfunction is associated with fatigue in patients with multiple sclerosis: A graph theory study (S13.003). Neurology 2014, 82, S13.003.
Brain Sci. 2023, 13, 246 19 of 23

31. Schoonheim, M.M.; Geurts, J.J.G.; Wiebenga, O.T.; De Munck, J.C.; Polman, C.H.; Stam, C.J.; Barkhof, F.; Wink, A.M. Changes in
functional network centrality underlie cognitive dysfunction and physical disability in multiple sclerosis. Mult. Scler. J. 2013, 20,
1058–1065. [CrossRef]
32. Rocca, M.A.; Valsasina, P.; Meani, A.; Falini, A.; Comi, G.; Filippi, M. Impaired functional integration in multiple sclerosis: A
graph theory study. Anat. Embryol. 2014, 221, 115–131. [CrossRef]
33. Faivre, A.; Robinet, E.; Guye, M.; Rousseau, C.; Maarouf, A.; Le Troter, A.; Zaaraoui, W.; Rico, A.; Crespy, L.; Soulier, E.; et al.
Depletion of brain functional connectivity enhancement leads to disability progression in multiple sclerosis: A longitudinal
resting-state fMRI study. Mult. Scler. J. 2016, 22, 1695–1708. [CrossRef]
34. Chirumamilla, V.C.; Fleischer, V.; Droby, A.; Anjum, T.; Muthuraman, M.; Zipp, F.; Groppa, S. Functional connectivity analysis
using whole brain and regional network metrics in MS patients. In Proceedings of the 2016 38th Annual International Conference
of the IEEE Engineering in Medicine and Biology Society (EMBC), Orlando, FL, USA, 16–20 August 2016; pp. 4039–4042.
35. Eqlimi, E.; Shalchy, M.A.; Karami, E.; Shojaei, A.; Aarabi, M.H.; Safabakhsh, H.; Alam, N.R. Modular Organization of Resting
State Functional Networks in Patients with Multiple Sclerosis. In Proceedings of the 37th Annual International Conference of the
IEEE Engineering in Medicine and Biology Society (EMBC 2015), Milan, Italy, 25–29 August 2015.
36. Eijlers, A.J.; Meijer, K.A.; Wassenaar, T.M.; Steenwijk, M.D.; Uitdehaag, B.M.; Barkhof, F.; Wink, A.M.; Geurts, J.J.; Schoonheim,
M.M. Increased default-mode network centrality in cognitively impaired multiple sclerosis patients. Neurology 2017, 88, 952–960.
[CrossRef]
37. Stellmann, J.-P.; Hodecker, S.; Cheng, B.; Wanke, N.; Young, K.L.; Hilgetag, C.; Gerloff, C.; Heesen, C.; Thomalla, G.; Siemonsen, S.
Reduced rich-club connectivity is related to disability in primary progressive MS. Neurol.—Neuroimmunol. Neuroinflamm. 2017, 4, e375.
[CrossRef]
38. Liu, Y.; Wang, H.; Duan, Y.; Huang, J.; Ren, Z.; Ye, J.; Dong, H.; Shi, F.; Li, K.; Wang, J. Functional Brain Network Alterations in
Clinically Isolated Syndrome and Multiple Sclerosis: A Graph-based Connectome Study. Radiology 2017, 282, 534–541. [CrossRef]
39. Lin, S.-J.; Vavasour, I.; Kosaka, B.; Li, D.K.B.; Traboulsee, A.; Mackay, A.; McKeown, M.J. Education, and the balance between
dynamic and stationary functional connectivity jointly support executive functions in relapsing–remitting multiple sclerosis.
Hum. Brain Mapp. 2018, 39, 5039–5049. [CrossRef]
40. Liu, Y.; Duan, Y.; Dong, H.; Barkhof, F.; Li, K.; Shu, N. Disrupted Module Efficiency of Structural and Functional Brain
Connectomes in Clinically Isolated Syndrome and Multiple Sclerosis. Front. Hum. Neurosci. 2018, 12, 138. [CrossRef]
41. Carotenuto, A.; Wilson, H.; Giordano, B.; Caminiti, S.P.; Chappell, Z.; Williams, S.C.R.; Hammers, A.; Silber, E.; Brex, P.; Politis,
M. Impaired connectivity within neuromodulatory networks in multiple sclerosis and clinical implications. J. Neurol. 2020, 267,
2042–2053. [CrossRef]
42. Welton, T.; Constantinescu, C.S.; Auer, D.P.; A Dineen, R. Graph Theoretic Analysis of Brain Connectomics in Multiple Sclerosis:
Reliability and Relationship with Cognition. Brain Connect. 2020, 10, 95–104. [CrossRef]
43. Silemek, A.C.H.; Fischer, L.; Pöttgen, J.; Penner, I.-K.; Engel, A.K.; Heesen, C.; Gold, S.M.; Stellmann, J.-P. Functional and structural
connectivity substrates of cognitive performance in relapsing remitting multiple sclerosis with mild disability. NeuroImage Clin.
2020, 25, 102177. [CrossRef]
44. Tommasin, S.; De Giglio, L.; Ruggieri, S.; Petsas, N.; Giannì, C.; Pozzilli, C.; Pantano, P. Multi-scale resting state functional
reorganization in response to multiple sclerosis damage. Neuroradiology 2020, 62, 693–704. [CrossRef]
45. Koubiyr, I.; Deloire, M.; Besson, P.; Coupé, P.; Dulau, C.; Pelletier, J.; Tourdias, T.; Audoin, B.; Brochet, B.; Ranjeva, J.-P.; et al.
Longitudinal study of functional brain network reorganization in clinically isolated syndrome. Mult. Scler. J. 2018, 26, 188–200.
[CrossRef]
46. Hawkins, R.; Shatil, A.; Lee, L.; Sengupta, A.; Zhang, L.; Morrow, S.; Aviv, R. Reduced Global Efficiency and Random Network
Features in Patients with Relapsing-Remitting Multiple Sclerosis with Cognitive Impairment. Am. J. Neuroradiol. 2020, 41, 449–455.
[CrossRef] [PubMed]
47. Baijot, J.; Denissen, S.; Costers, L.; Gielen, J.; Cambron, M.; D’Haeseleer, M.; D’Hooghe, M.B.; Vanbinst, A.-M.; De Mey, J.; Nagels,
G.; et al. Signal quality as Achilles’ heel of graph theory in functional magnetic resonance imaging in multiple sclerosis. Sci. Rep.
2021, 11, 7376. [CrossRef] [PubMed]
48. Koubiyr, I.; Deloire, M.; Brochet, B.; Besson, P.; Charré-Morin, J.; Saubusse, A.; Tourdias, T.; Ruet, A. Structural constraints of
functional connectivity drive cognitive impairment in the early stages of multiple sclerosis. Mult. Scler. J. 2020, 27, 559–567.
[CrossRef]
49. Ashtiani, S.N.M.; Behnam, H.; Daliri, M.R. Diagnosis of Multiple Sclerosis Using Graph-Theoretic Measures of Cognitive-Task-
Based Functional Connectivity Networks. IEEE Trans. Cogn. Dev. Syst. 2021, 14, 926–934. [CrossRef]
50. Boscheron, J.; Ruet, A.; Deloire, M.; Charré-Morin, J.; Saubusse, A.; Brochet, B.; Tourdias, T.; Koubiyr, I. Insights on the Relationship
Between Hippocampal Connectivity and Memory Performances at the Early Stage of Multiple Sclerosis. Front. Neurol. 2021, 12, 752.
[CrossRef]
51. Saadat, N.; Mayo, C.D.; Lacey, C.; Gawryluk, J.R. Functional connectivity pre-post exercise intervention in individuals with
relapsing-remitting multiple sclerosis. Neuroreport 2021, 32, 1100–1105. [CrossRef]
52. Backner, Y.; Zamir, S.; Petrou, P.; Paul, F.; Karussis, D.; Levin, N. Anatomical and functional visual network patterns in progressive
multiple sclerosis. Hum. Brain Mapp. 2021, 43, 1590–1597. [CrossRef]
Brain Sci. 2023, 13, 246 20 of 23

53. Chiaravalloti, N.D.; Wylie, G.; Leavitt, V.; DeLuca, J. Increased cerebral activation after behavioral treatment for memory deficits
in MS. J. Neurol. 2012, 259, 1337–1346. [CrossRef]
54. Azarmi, F.; Ashtiani, S.N.M.; Shalbaf, A.; Behnam, H.; Daliri, M.R. Granger causality analysis in combination with directed network
measures for classification of MS patients and healthy controls using task-related fMRI. Comput. Biol. Med. 2019, 115, 103495.
[CrossRef]
55. Stellmann, J.-P.; Wanke, N.; Maarouf, A.; Gellißen, S.; Heesen, C.; Audoin, B.; Gold, S.M.; Zaaraoui, W.; Poettgen, J. Cognitive performance
shows domain specific associations with regional cortical thickness in multiple sclerosis. NeuroImage Clin. 2021, 30, 102606. [CrossRef]
56. Schega, L.; Hamacher, D.; Sailer, M.; Broscheid, K.-C. Reliability of the Hemodynamic Response During Walking in People With
Multiple Sclerosis: An fNIRS Study. Arch. Phys. Med. Rehabil. 2019, 100, e115. [CrossRef]
57. Kasser, S.; Belanger, B.; Purin, G.; Cannizzaro, M. Cognitive Motor Interference and Cortical Activation during Walking in
Individuals with Multiple Sclerosis. Arch. Phys. Med. Rehabil. 2019, 100, e53. [CrossRef]
58. Saleh, S.; Sandroff, B.M.; Vitiello, T.; Owoeye, O.; Hoxha, A.; Hake, P.; Goverover, Y.; Wylie, G.; Yue, G.; DeLuca, J. The Role of
Premotor Areas in Dual Tasking in Healthy Controls and Persons With Multiple Sclerosis: An fNIRS Imaging Study. Front. Behav.
Neurosci. 2018, 12, 296. [CrossRef] [PubMed]
59. Shirzadi, S.; Einalou, Z.; Dadgostar, M. Investigation of Functional Connectivity During Working Memory Task and Hemispheric
Lateralization in Left- and Right- Handers Measured by fNIRS. Optik 2020, 221, 165347. [CrossRef]
60. De Sanctis, P.; Malcolm, B.R.; Mabie, P.C.; Francisco, A.A.; Mowrey, W.B.; Joshi, S.; Molholm, S.; Foxe, J.J. Mobile Brain/Body
Imaging of cognitive-motor impairment in multiple sclerosis: Deriving EEG-based neuro-markers during a dual-task walking
study. Clin. Neurophysiol. 2020, 131, 1119–1128. [CrossRef]
61. Borragán, G.; Gilson, M.; Atas, A.; Slama, H.; Lysandropoulos, A.; De Schepper, M.; Peigneux, P. Cognitive Fatigue, Sleep and
Cortical Activity in Multiple Sclerosis Disease. A Behavioral, Polysomnographic and Functional Near-Infrared Spectroscopy
Investigation. Front. Hum. Neurosci. 2018, 12, 378. [CrossRef]
62. Bertoli, M.; Tecchio, F. Fatigue in multiple sclerosis: Does the functional or structural damage prevail? Mult. Scler. J. 2020, 26,
1809–1815. [CrossRef]
63. Buyukturkoglu, K.; Porcaro, C.; Cottone, C.; Cancelli, A.; Inglese, M.; Tecchio, F. Simple index of functional connectivity at rest in
Multiple Sclerosis fatigue. Clin. Neurophysiol. 2017, 128, 807–813. [CrossRef]
64. Meijer, K.A.; Eijlers, A.J.; Douw, L.; Uitdehaag, B.M.; Barkhof, F.; Geurts, J.J.; Schoonheim, M.M. Increased connectivity of hub
networks and cognitive impairment in multiple sclerosis. Neurology 2017, 88, 2107–2114. [CrossRef]
65. Shu, N.; Liu, Y.; Li, K.; Duan, Y.; Wang, J.; Yu, C.; Dong, H.; Ye, J.; He, Y. Diffusion tensor tractography reveals disrupted
topological efficiency in white matter structural networks in multiple sclerosis. Cereb. Cortex 2011, 21, 2565–2577. [CrossRef]
66. Tewarie, P.; Schoonheim, M.M.; Schouten, D.I.; Polman, C.H.; Balk, L.J.; Uitdehaag, B.M.; Geurts, J.J.; Hillebrand, A.; Barkhof, F.;
Stam, C.J. Functional brain networks: Linking thalamic atrophy to clinical disability in multiple sclerosis, a multimodal fMRI and
MEG Study. Hum. Brain Mapp. 2014, 36, 603–618. [CrossRef] [PubMed]
67. Stickland, R.; Allen, M.; Magazzini, L.; Singh, K.D.; Wise, R.G.; Tomassini, V. Neurovascular coupling during visual stimulation
in multiple sclerosis: A MEG-fMRI study. Neuroscience 2019, 403, 54–69. [CrossRef] [PubMed]
68. Tewarie, P.; Schoonheim, M.M.; Stam, C.J.; Van Der Meer, M.L.; Van Dijk, B.W.; Barkhof, F.; Polman, C.H.; Hillebrand, A. Cognitive and
Clinical Dysfunction, Altered MEG Resting-State Networks and Thalamic Atrophy in Multiple Sclerosis. PLoS ONE 2013, 8, e69318.
[CrossRef] [PubMed]
69. Schoonheim, M.M.; Geurts, J.J.; Landi, D.; Douw, L.; van der Meer, M.L.; Vrenken, H.; Polman, C.H.; Barkhof, F.; Stam, C.J.
Functional connectivity changes in multiple sclerosis patients: A graph analytical study of MEG resting state data. Hum. Brain
Mapp. 2011, 34, 52–61. [CrossRef] [PubMed]
70. Velásquez, J.; Suarez, X.; Aristizabal, I.; Ascencio, J.; Ochoa, J. Functional connectivity changes caused by multiple sclerosis. In
Proceedings of the 2013 Pan American Health Care Exchanges (PAHCE), Medellin, Colombia, 29 April 2013–4 May 2013; pp. 1–6.
[CrossRef]
71. Bullmore, E.; Sporns, O. Complex brain networks: Graph theoretical analysis of structural and functional systems. Nat. Rev.
Neurosci. 2009, 10, 186–198. [CrossRef]
72. Tona, F.; Petsas, N.; Sbardella, E.; Prosperini, L.; Carmellini, M.; Pozzilli, C.; Pantano, P. Multiple Sclerosis: Altered Thalamic
Resting-State Functional Connectivity and Its Effect on Cognitive Function. Radiology 2014, 271, 814–821. [CrossRef] [PubMed]
73. Schoonheim, M.M.; Pinter, D.; E Prouskas, S.; Broeders, T.A.; Pirpamer, L.; Khalil, M.; Ropele, S.; Uitdehaag, B.M.; Barkhof, F.;
Enzinger, C.; et al. Disability in multiple sclerosis is related to thalamic connectivity and cortical network atrophy. Mult. Scler. J.
2021, 28, 61–70. [CrossRef]
74. Hawellek, D.J.; Hipp, J.F.; Lewis, C.M.; Corbetta, M.; Engel, A.K. Increased functional connectivity indicates the severity of
cognitive impairment in multiple sclerosis. Proc. Natl. Acad. Sci. USA 2011, 108, 19066–19071. [CrossRef]
75. Finke, C.; Schlichting, J.; Papazoglou, S.; Scheel, M.; Freing, A.; Soemmer, C.; Pech, L.; Pajkert, A.; Pfüller, C.; Wuerfel, J.; et al.
Altered basal ganglia functional connectivity in multiple sclerosis patients with fatigue. Mult. Scler. J. 2014, 21, 925–934. [CrossRef]
76. Dogonowski, A.-M.; Siebner, H.R.; Sørensen, P.S.; Wu, X.; Biswal, B.; Paulson, O.B.; Dyrby, T.B.; Skimminge, A.; Blinkenberg,
M.; Madsen, K.H. Expanded functional coupling of subcortical nuclei with the motor resting-state network in multiple sclerosis.
Mult. Scler. J. 2013, 19, 559–566. [CrossRef]
Brain Sci. 2023, 13, 246 21 of 23

77. Zhong, J.; Nantes, J.C.; Holmes, S.A.; Gallant, S.; Narayanan, S.; Koski, L. Abnormal functional connectivity and cortical integrity
influence dominant hand motor disability in multiple sclerosis: A multimodal analysis. Hum. Brain Mapp. 2016, 37, 4262–4275.
[CrossRef] [PubMed]
78. Wu, L.; Zhang, Y.; Zhou, F.-Q.; Gao, L.; He, L.; Gong, H.; Zeng, X. Altered intra- and interregional synchronization in relapsing–
remitting multiple sclerosis: A resting-state fMRI study. Neuropsychiatr. Dis. Treat. 2016, 12, 853–862. [CrossRef] [PubMed]
79. Wu, G.F.; Brier, M.R.; Parks, C.A.-L.; Ances, B.M.; Van Stavern, G.P. An Eye on Brain Integrity: Acute Optic Neuritis Affects
Resting State Functional Connectivity. Investig. Ophthalmol. Vis. Sci. 2015, 56, 2541–2546. [CrossRef] [PubMed]
80. D’Ambrosio, A.; Valsasina, P.; Gallo, A.; De Stefano, N.; Pareto, D.; Barkhof, F.; Ciccarelli, O.; Enzinger, C.; Tedeschi, G.; Stromillo,
M.L.; et al. Reduced dynamics of functional connectivity and cognitive impairment in multiple sclerosis. Mult. Scler. J. 2019, 26,
476–488. [CrossRef] [PubMed]
81. Chen, M.H.; DeLuca, J.; Genova, H.M.; Yao, B.; Wylie, G.R. Cognitive Fatigue Is Associated with Altered Functional Connectivity
in Interoceptive and Reward Pathways in Multiple Sclerosis. Diagnostics 2020, 10, 930. [CrossRef] [PubMed]
82. Liu, Y.; Liang, P.; Duan, Y.; Huang, J.; Ren, Z.; Jia, X.; Dong, H.; Ye, J.; Shi, F.-D.; Butzkueven, H.; et al. Altered thalamic functional
connectivity in multiple sclerosis. Eur. J. Radiol. 2015, 84, 703–708. [CrossRef]
83. Leavitt, V.M.; Wylie, G.R.; Girgis, P.A.; DeLuca, J.; Chiaravalloti, N.D. Increased functional connectivity within memory networks
following memory rehabilitation in multiple sclerosis. Brain Imaging Behav. 2012, 8, 394–402. [CrossRef]
84. Wojtowicz, M.; Mazerolle, E.L.; Bhan, V.; Fisk, J.D. Altered functional connectivity and performance variability in relapsing–
remitting multiple sclerosis. Mult. Scler. J. 2014, 20, 1453–1463. [CrossRef]
85. Golde, S.; Heine, J.; Pottgen, J.; Mantwill, M.; Lau, S.; Wingenfeld, K.; Otte, C.; Penner, I.K.; Engel, A.K.; Heesen, C.; et al. Distinct
Functional Connectivity Signatures of Impaired Social Cognition in Multiple Sclerosis. Front. Neurol. 2020, 11, 507. [CrossRef]
86. Pasqua, G.; Tommasin, S.; Bharti, K.; Ruggieri, S.; Petsas, N.; Piervincenzi, C.; Pozzilli, C.; Pantano, P. Resting-state functional
connectivity of anterior and posterior cerebellar lobes is altered in multiple sclerosis. Mult. Scler. J. 2021, 27, 539–548. [CrossRef]
87. Lin, F.; Zivadinov, R.; Hagemeier, J.; Weinstock-Guttman, B.; Vaughn, C.; Gandhi, S.; Jakimovski, D.; Hulst, H.; Benedict, R.H.;
Bergsland, N.; et al. Altered nuclei-specific thalamic functional connectivity patterns in multiple sclerosis and their associations
with fatigue and cognition. Mult. Scler. J. 2018, 25, 1243–1254. [CrossRef] [PubMed]
88. Cui, F.; Zhou, L.; Wang, Z.; Lang, C.; Park, J.; Tan, Z.; Yu, Y.; Sun, C.; Gao, Y.; Kong, J. Altered Functional Connectivity of Striatal
Subregions in Patients with Multiple Sclerosis. Front. Neurol. 2017, 8, 129. [CrossRef]
89. Bonavita, S.; Sacco, R.; Della Corte, M.; Esposito, S.; Sparaco, M.; D’Ambrosio, A.; Docimo, R.; Bisecco, A.; Lavorgna, L.; Corbo,
D.; et al. Computer-aided cognitive rehabilitation improves cognitive performances and induces brain functional connectivity
changes in relapsing remitting multiple sclerosis patients: An exploratory study. J. Neurol. 2014, 262, 91–100. [CrossRef] [PubMed]
90. Colasanti, A.; Guo, Q.; Giannetti, P.; Wall, M.B.; Newbould, R.D.; Bishop, C.; Onega, M.; Nicholas, R.; Ciccarelli, O.; Muraro, P.A.
Hippocampal neuroinflammation, functional connectivity, and depressive symptoms in multiple sclerosis. Biol. Psychiatry 2016,
80, 62–72. [CrossRef]
91. Roosendaal, S.D.; Hulst, H.; Vrenken, H.; Feenstra, H.E.M.; Castelijns, J.A.; Pouwels, P.J.W.; Barkhof, F.; Geurts, J.J.G. Structural
and Functional Hippocampal Changes in Multiple Sclerosis Patients with Intact Memory Function. Radiology 2010, 255, 595–604.
[CrossRef] [PubMed]
92. Hulst, H.E.; Schoonheim, M.M.; Van Geest, Q.; Uitdehaag, B.M.; Barkhof, F.; Geurts, J.J. Memory impairment in multiple sclerosis:
Relevance of hippocampal activation and hippocampal connectivity. Mult. Scler. J. 2015, 21, 1705–1712. [CrossRef]
93. Farahani, F.V.; Karwowski, W.; Lighthall, N.R. Application of Graph Theory for Identifying Connectivity Patterns in Human
Brain Networks: A Systematic Review. Front. Neurosci. 2019, 13, 585. [CrossRef] [PubMed]
94. Schoonheim, M.M.; E Hulst, H.; Landi, D.; Ciccarelli, O.; Roosendaal, S.D.; Sanz-Arigita, E.J.; Vrenken, H.; Polman, C.H.; Stam,
C.J.; Barkhof, F.; et al. Gender-related differences in functional connectivity in multiple sclerosis. Mult. Scler. J. 2011, 18, 164–173.
[CrossRef]
95. Rocca, M.A.; Absinta, M.; Amato, M.P.; Moiola, L.; Ghezzi, A.; Veggiotti, P.; Capra, R.; Portaccio, E.; Fiorino, A.; Pippolo, L.; et al.
Posterior brain damage and cognitive impairment in pediatric multiple sclerosis. Neurology 2014, 82, 1314–1321. [CrossRef]
96. Shu, N.; Duan, Y.; Xia, M.; Schoonheim, M.M.; Huang, J.; Ren, Z.; Sun, Z.; Ye, J.; Dong, H.; Shi, F.-D.; et al. Disrupted topological
organization of structural and functional brain connectomes in clinically isolated syndrome and multiple sclerosis. Sci. Rep. 2016,
6, 29383. [CrossRef]
97. Dobryakova, E.; Rocca, M.A.; Valsasina, P.; Ghezzi, A.; Colombo, B.; Martinelli, V.; Comi, G.; DeLuca, J.; Filippi, M. Abnormalities
of the executive control network in multiple sclerosis phenotypes: An fMRI effective connectivity study. Hum. Brain Mapp. 2016,
37, 2293–2304. [CrossRef] [PubMed]
98. Duong, M.A.; Boulanouar, K.; Audoin, B.; Treseras, S.; Ibarrola, D.; Malikova, I.; Confort-Gouny, S.; Celsis, P.; Pelletier, J.; Cozzone,
P.; et al. Modulation of effective connectivity inside the working memory network in patients at the earliest stage of multiple
sclerosis. Neuroimage 2005, 24, 533–538. [CrossRef] [PubMed]
99. Leavitt, V.M.; Wylie, G.; Genova, H.M.; Chiaravalloti, N.D.; DeLuca, J. Altered effective connectivity during performance of an
information processing speed task in multiple sclerosis. Mult. Scler. J. 2011, 18, 409–417. [CrossRef] [PubMed]
100. Mansoory, M.S.; Chehreh, A.; Khoshgard, K.; Rashidi, I.; Ebrahiminia, A. Effective Connectivity within the Papez Circuit in the
Multiple Sclerosis Patients: A Comparative Study Using Resting-State fMRI. J. Biomed. Phys. Eng. 2022, 12, 149–160. [CrossRef]
Brain Sci. 2023, 13, 246 22 of 23

101. Stamile, C.; Kocevar, G.; Hannoun, S.; Durand-Dubief, F.; Sappey-Marinier, D. A Graph Based Classification Method for Multiple
Sclerosis Clinical Forms Using Support Vector Machine. In Machine Learning Meets Medical Imaging: First International Workshop,
MLMMI 2015, Held in Conjunction with ICML 2015, Lille, France, July 11, 2015, Revised Selected Papers 1; Springer International
Publishing: Cham, Switzerland, 2015; pp. 57–64. [CrossRef]
102. Ashtiani, S.N.M.; Daliri, M.R.; Behnam, H.; Hossein-Zadeh, G.-A.; Mehrpour, M.; Motamed, M.R.; Fadaie, F. Altered topological
properties of brain networks in the early MS patients revealed by cognitive task-related fMRI and graph theory. Biomed. Signal
Process. Control. 2018, 40, 385–395. [CrossRef]
103. Humphries, M.D.; Gurney, K. Network ‘Small-World-Ness’: A Quantitative Method for Determining Canonical Network
Equivalence. PLoS ONE 2008, 3, e0002051. [CrossRef]
104. Achard, S.; Bullmore, E. Efficiency and Cost of Economical Brain Functional Networks. PLoS Comput. Biol. 2007, 3, e17. [CrossRef]
105. Moazami, F.; Lefevre-Utile, A.; Papaloukas, C.; Soumelis, V. Machine Learning Approaches in Study of Multiple Sclerosis Disease
Through Magnetic Resonance Images. Front. Immunol. 2021, 12. [CrossRef]
106. Karmonik, C.; Boone, T.; Khavari, R. Data-driven machine-learning quantifies differences in the voiding initiation network in
neurogenic voiding dysfunction in women with multiple sclerosis. Int. Neurourol. J. 2019, 23, 195. [CrossRef]
107. Zurita, M.; Montalba, C.; Labbé, T.; Cruz, J.P.; da Rocha, J.D.; Tejos, C.; Ciampi, E.; Cárcamo, C.; Sitaram, R.; Uribe, S.
Characterization of relapsing-remitting multiple sclerosis patients using support vector machine classifications of functional and
diffusion MRI data. NeuroImage Clin. 2018, 20, 724–730. [CrossRef]
108. Al Zoubi, O.; Misaki, M.; Tsuchiyagaito, A.; Zotev, V.; White, E.; Paulus, M.; Bodurka, J. Machine Learning Evidence for
Sex Differences Consistently Influences Resting-State Functional Magnetic Resonance Imaging Fluctuations Across Multiple
Independently Acquired Data Sets. Brain Connect. 2022, 12, 348–361. [CrossRef] [PubMed]
109. Aslani, S.; Dayan, M.; Murino, V.; Sona, D. Deep 2D encoder-decoder convolutional neural network for multiple sclerosis lesion
segmentation in brain MRI. In Brainlesion: Glioma, Multiple Sclerosis, Stroke and Traumatic Brain Injuries: 4th International Workshop,
BrainLes 2018, Held in Conjunction with MICCAI 2018, Granada, Spain, September 16, 2018, Revised Selected Papers, Part I 4; Springer
International Publishing: Cham, Switzerland, 2019; pp. 132–141. [CrossRef]
110. Yoo, Y.; Tang, L.W.; Brosch, T.; Li, D.K.B.; Metz, L.; Traboulsee, A.; Tam, R. Deep Learning of Brain Lesion Patterns for Predicting
Future Disease Activity in Patients with Early Symptoms of Multiple Sclerosis. In Deep Learning and Data Labeling for Medical
Applications: First International Workshop, LABELS 2016, and Second International Workshop, DLMIA 2016, Held in Conjunction with
MICCAI 2016, Athens, Greece, October 21, 2016, Proceedings 1; Springer International Publishing: Cham, Switzerland, 2016; pp.
86–94. [CrossRef]
111. Yoo, Y.; Brosch, T.; Traboulsee, A.; Li, D.K.; Tam, R. Deep learning of image features from unlabeled data for multiple sclerosis
lesion segmentation. In Proceedings of the International Workshop on Machine Learning in Medical Imaging, Munich, Germany,
5 October 2015; pp. 117–124.
112. Ye, Z.; George, A.; Wu, A.T.; Niu, X.; Lin, J.; Adusumilli, G.; Naismith, R.T.; Cross, A.H.; Sun, P.; Song, S. Deep learning with
diffusion basis spectrum imaging for classification of multiple sclerosis lesions. Ann. Clin. Transl. Neurol. 2020, 7, 695–706.
[CrossRef]
113. Bergamaschi, R.; Berzuini, C.; Romani, A.; Cosi, V. Predicting secondary progression in relapsing–remitting multiple sclerosis: A
Bayesian analysis. J. Neurol. Sci. 2001, 189, 13–21. [CrossRef]
114. Abidin, A.Z.; Chockanathan, U.; Dsouza, A.M.; Inglese, M.; Wismüller, A. Using large-scale Granger causality to study changes in
brain network properties in the Clinically Isolated Syndrome (CIS) stage of multiple sclerosis. In Proceedings of the SPIE Medical
Imaging, Orlando, FL, USA, 11–16 February 2017; Volume 10137, p. 101371B. [CrossRef]
115. Kocevar, G.; Stamile, C.; Hannoun, S.; Cotton, F.; Vukusic, S.; Durand-Dubief, F.; Sappey-Marinier, D. Graph Theory-Based
Brain Connectivity for Automatic Classification of Multiple Sclerosis Clinical Courses. Front. Neurosci. 2016, 10, 478. [CrossRef]
[PubMed]
116. Cortes, C.; Vapnik, V. Support-vector networks. Mach. Learn. 1995, 20, 273–297. [CrossRef]
117. Eijlers, A.J.C.; Wink, A.M.; Meijer, K.A.; Douw, L.; Geurts, J.J.G.; Schoonheim, M.M. Reduced Network Dynamics on Functional
MRI Signals Cognitive Impairment in Multiple Sclerosis. Radiology 2019, 292, 449–457. [CrossRef]
118. Rocca, M.; Valsasina, P.; Absinta, M.; Riccitelli, G.; Rodegher, M.; Misci, P.; Rossi, P.; Falini, A.; Comi, G.; Filippi, M. Default-mode
network dysfunction and cognitive impairment in progressive MS. Neurology 2010, 74, 1252–1259. [CrossRef]
119. Schoonheim, M.M.; Meijer, K.A.; Geurts, J.J.G. Network Collapse and Cognitive Impairment in Multiple Sclerosis. Front. Neurol.
2015, 6, 82. [CrossRef]
120. Yan, C.; Zang, Y. DPARSF: A MATLAB toolbox for “pipeline” data analysis of resting-state fMRI. Front. Syst. Neurosci. 2010, 4, 13.
[CrossRef]
121. Droby, A.; Yuen, K.S.L.; Muthuraman, M.; Reitz, S.-C.; Fleischer, V.; Klein, J.; Gracien, R.-M.; Ziemann, U.; Deichmann, R.; Zipp, F.;
et al. Changes in brain functional connectivity patterns are driven by an individual lesion in MS: A resting-state fMRI study.
Brain Imaging Behav. 2015, 10, 1117–1126. [CrossRef]
122. Bottino, F.; Lucignani, M.; Pasquini, L.; Mastrogiovanni, M.; Gazzellini, S.; Ritrovato, M.; Longo, D.; Figà-Talamanca, L.; Rossi
Espagnet, M.C.; Napolitano, A. Spatial stability of functional networks: A measure to assess the robustness of graph-theoretical
metrics to spatial errors related to brain parcellation. Front. Neurosci. 2022, 15, 1909. [CrossRef] [PubMed]
Brain Sci. 2023, 13, 246 23 of 23

123. Poldrack, R.A. Can cognitive processes be inferred from neuroimaging data? Trends Cogn. Sci. 2006, 10, 59–63. [CrossRef]
[PubMed]
124. Faskowitz, J.; Betzel, R.F.; Sporns, O. Edges in brain networks: Contributions to models of structure and function. Netw. Neurosci.
2021, 6, 1–28. [CrossRef] [PubMed]
125. Imms, P.; Clemente, A.; Cook, M.; D’Souza, W.; Wilson, P.H.; Jones, D.K.; Caeyenberghs, K. The structural connectome in
traumatic brain injury: A meta-analysis of graph metrics. Neurosci. Biobehav. Rev. 2019, 99, 128–137. [CrossRef]
126. Kambeitz, J.; Kambeitz-Ilankovic, L.; Cabral, C.; Dwyer, D.B.; Calhoun, V.D.; Heuvel, M.P.V.D.; Falkai, P.; Koutsouleris, N.;
Malchow, B. Aberrant Functional Whole-Brain Network Architecture in Patients With Schizophrenia: A Meta-analysis. Schizophr.
Bull. 2016, 42, S13–S21. [CrossRef]
127. Rakhimberdina, Z.; Liu, X.; Murata, T. Population Graph-Based Multi-Model Ensemble Method for Diagnosing Autism Spectrum
Disorder. Sensors 2020, 20, 6001. [CrossRef]
128. SScarselli, F.; Gori, M.; Tsoi, A.C.; Hagenbuchner, M.; Monfardini, G. The graph neural network model. IEEE Trans. Neural Netw.
2008, 20, 61–80. [CrossRef]
129. Kipf, T.N.; Welling, M. Semi-supervised classification with graph convolutional networks. arXiv 2016, arXiv:1609.02907.
130. Marzullo, A.; Kocevar, G.; Stamile, C.; Durand-Dubief, F.; Terracina, G.; Calimeri, F.; Sappey-Marinier, D. Classification of multiple
sclerosis clinical profiles via graph convolutional neural networks. Front. Neurosci. 2019, 13, 594. [CrossRef]
131. Barile, B.; Marzullo, A.; Stamile, C.; Durand-Dubief, F.; Sappey-Marinier, D. Data augmentation using generative adversarial
neural networks on brain structural connectivity in multiple sclerosis. Comput. Methods Programs Biomed. 2021, 206, 106113.
[CrossRef]

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.