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Functional Network Connectivity Reveals the Brain Functional Alterations in Breast Cancer Survivors

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Different neurological and psychiatric disorders such as vertebrobasilar insufficiency, chronic pain syndrome, anxiety, and depression are observed in more than 90% of patients after treatment for breast cancer and may cause alterations in the functional connectivity of the default mode network. The purpose of the present study is to assess changes in the functional connectivity of the default mode network in patients after breast cancer treatment using resting state functional magnetic resonance imaging (rs-fMRI). Rs-fMRI was performed using a 3.0T MR-scanner on patients (N = 46, women) with neurological disorders (chronic pain, dizziness, headaches, and/or tinnitus) in the late postoperative period (>12 months) after Patey radical mastectomy for breast cancer. According to the intergroup statistical analysis, there were differences in the functional connectivity of the default mode network in all 46 patients after breast cancer treatment compared to the control group (p < 0.01). The use of rs-fMRI in in breast cancer survivors allowed us to identify changes in the functional connectivity in the brain caused by neurological disorders, which correlated with a decreased quality of life in these patients. The results indicate the necessity to improve treatment and rehabilitation methods in this group of patients.
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Citation: Bukkieva, T.; Pospelova, M.;
Efimtsev, A.; Fionik, O.; Alekseeva, T.;
Samochernych, K.; Gorbunova, E.;
Krasnikova, V.; Makhanova, A.;
Levchuk, A.; et al. Functional
Network Connectivity Reveals the
Brain Functional Alterations in Breast
Cancer Survivors. J. Clin. Med. 2022,
11, 617. https://doi.org/10.3390/
jcm11030617
Academic Editors:
Massimiliano Berretta and
Nicola Avenia
Received: 2 November 2021
Accepted: 10 January 2022
Published: 26 January 2022
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4.0/).
Journal of
Clinical Medicine
Article
Functional Network Connectivity Reveals the Brain Functional
Alterations in Breast Cancer Survivors
Tatyana Bukkieva 1, Maria Pospelova 1, Aleksandr Efimtsev 1, Olga Fionik 1, Tatyana Alekseeva 1,
Konstantin Samochernych 1, Elena Gorbunova 1, Varvara Krasnikova 1, Albina Makhanova 1,
Anatoliy Levchuk 1, Gennadiy Trufanov 1, Stephanie Combs 2and Maxim Shevtsov 1,2,3,*
1Personalized Medicine Centre, Almazov National Medical Research Centre, 2 Akkuratova Str.,
197341 Saint Petersburg, Russia; tanya-book25@mail.ru (T.B.); pospelovaml@mail.ru (M.P.);
atralf@mail.ru (A.E.); fvolga@mail.ru (O.F.); atmspb@mail.ru (T.A.); neurobaby12@gmail.com (K.S.);
lenagorbunova-124@yandex.ru (E.G.); varya.krasnikova.93@mail.ru (V.K.); a.mahanova.a@mail.ru (A.M.);
feuerlag999@yandex.ru (A.L.); trufanovge@mail.ru (G.T.)
2Department of Radiation Oncology, Technishe Universität München (TUM), Klinikum rechts der Isar,
Ismaningerstr. 22, 81675 Munich, Germany; stephanie.combs@tum.de
3
Laboratory of Biomedical Nanotechnologies, Institute of Cytology of the Russian Academy of Sciences (RAS),
Tikhoretsky Ave. 4, 194064 Saint Petersburg, Russia
*Correspondence: shevtsov-max@mail.ru; Tel.: +7-981-829-4848
Abstract:
Different neurological and psychiatric disorders such as vertebrobasilar insufficiency,
chronic pain syndrome, anxiety, and depression are observed in more than 90% of patients after
treatment for breast cancer and may cause alterations in the functional connectivity of the default
mode network. The purpose of the present study is to assess changes in the functional connectivity
of the default mode network in patients after breast cancer treatment using resting state functional
magnetic resonance imaging (rs-fMRI). Rs-fMRI was performed using a 3.0T MR-scanner on patients
(N = 46, women) with neurological disorders (chronic pain, dizziness, headaches, and/or tinnitus)
in the late postoperative period (>12 months) after Patey radical mastectomy for breast cancer.
According to the intergroup statistical analysis, there were differences in the functional connectivity
of the default mode network in all 46 patients after breast cancer treatment compared to the control
group (p< 0.01). The use of rs-fMRI in in breast cancer survivors allowed us to identify changes in
the functional connectivity in the brain caused by neurological disorders, which correlated with a
decreased quality of life in these patients. The results indicate the necessity to improve treatment and
rehabilitation methods in this group of patients.
Keywords:
breast cancer; breast cancer treatment; post-mastectomy pain syndrome; functional MRI;
connectome; default mode network
1. Introduction
Currently, breast cancer is the most common cancer among women worldwide—
according to GLOBOCAN, 2.26 million new cases of breast cancer were detected in 2020,
which accounted for 11.7% of all cancers [
1
]. In Russia, breast cancer also occupies the
first place in the structure of cancer incidence in women, accounting for about 20.9% of
cases [
2
]. In most cases, breast cancer treatment is complex and usually includes surgical
treatment, chemotherapy, and/or radiation therapy. As a rule, it is carried out in three
stages: preoperative (induction) chemotherapy, local (surgery
±
radiation therapy), and
postoperative treatment (adjuvant therapy). One of the most common methods for the
surgical treatment of breast cancer is Patey radical mastectomy, which consists of removing
the breast, the surrounding fat and lymph nodes, the small pectoral muscle.
After treatment for breast cancer, a complex of symptoms occurs, including disorders
of the lymphatic, cardiovascular, musculoskeletal, and nervous systems [
3
,
4
]. Currently,
J. Clin. Med. 2022,11, 617. https://doi.org/10.3390/jcm11030617 https://www.mdpi.com/journal/jcm
J. Clin. Med. 2022,11, 617 2 of 13
special attention is being paid to neuropsychiatric disorders after breast cancer treatment,
which present in the form of changes in both the peripheral and central nervous systems.
Peripheral neurological disorders after breast cancer treatment are associated with persis-
tent pain syndrome and impaired sensitivity and muscle strength of the upper limb on the
side of surgical treatment [
5
,
6
]. These changes are primarily caused by disorders of the
peripheral nervous system due to local fibrous-atrophic postoperative and post-radiation
changes [
7
,
8
]. However, at later stages, the “centralization” of chronic pain syndrome
occurs with the involvement of structural and functional elements of the “pain connectome”
of the brain [
9
]. In the late postoperative period, patients also suffer from so-called thoracic
outlet syndrome [
10
], which is caused by the compression of the vertebral artery on the side
of surgical treatment with hypertrophic scalenus muscles, which leads to vertebral-basilar
insufficiency [
11
,
12
]. According to recent data, mental disorders including the development
of severe depression occur in about 25% of women after breast cancer treatment [
13
,
14
].
All of the above changes can lead to structural and functional changes in the brain, which
worsens the long-term prognosis of rehabilitation and the quality of life of patients [15].
A modern promising method for assessing functional changes in the brain in breast
cancer survivors is functional MRI (fMRI) and is based on the BOLD effect (blood oxy-
genation level dependent), which allows the activation of various areas of the brain to
be determined on the basis of the hemodynamic changes that occur in response to the
presentation of a particular stimulus or at rest [
16
]. The most common variant of fMRI
is resting state fMRI (rs-fMRI), which evaluates the functional connectivity between the
areas of the brain that make up the so-called resting state networks [
17
,
18
]. One of the
most important and well-studied resting state networks is the default mode network,
which includes extensive areas of the medial prefrontal cortex (MPFC), posterior cingulate
cortex, and precuneus [
19
,
20
]. DMN is involved in the cognitive processes of memory,
attention, and emotion regulation; the role of its functional disorders in the pathogenesis
of many neurological and mental diseases, including in chronic pain syndrome, has been
proven [2125].
In the current study, rs-fMRI was employed to allow us to evaluate the changes in the
brain connectome—the totality of all of the functional networks of the brain that play a key
role in the organization of the central nervous system.
2. Materials and Methods
2.1. Participants
An open single-center controlled study of the functional connectivity of the default
mode network in patients following breast cancer treatment was conducted.
The study enrolled 46 patients (women) aged 35 to 50 years old after breast cancer
treatment: surgical treatment (unilateral or bilateral Patey radical mastectomy), a combina-
tion of surgical treatment and radiation therapy (local therapy), a combination of surgical
treatment and systemic therapy, or complex treatment (combination of surgery, radiation
therapy, and chemotherapy), who developed various post-treatment symptoms associated
with treatment but not with the primary cancer disease. All of the patients were in the
late postoperative period (>12 months) after Patey radical mastectomy. The control group
enrolled 20 healthy female volunteers from the same age category.
2.2. Exclusion Criteria
The exclusion criteria included signs of main oncological disease progression; the
presence of distant breast cancer metastases, including brain metastases, brain tumors,
demyelination diseases, brain development anomalies, traumatic brain injury, and other
relevant brain pathologies; the presence of hemodynamically significant atherosclerotic
stenoses of the main arteries in the head and neck; acute infectious and mental diseases;
pregnancy; decompensated somatic pathology; and contraindications to MRI.
All of the patients participating in the study were examined by a neurologist, and
the exmination included collecting anamnesis (date of surgery, presence of chemotherapy,
J. Clin. Med. 2022,11, 617 3 of 13
radiation therapy) and complaints (for edema of the upper limb on the side of surgical
treatment, sensitivity disorders of the upper limb, paresthesia, muscle weakness, restriction
of movement in the shoulder joint, pain in the upper limb and upper arm, headaches,
dizziness, sleep disorders). During the examination, the mobility in the shoulder joint was
assessed, the Adson test was used to assess the thoracic outlet syndrome (which consists of
pulsing palpitations on the right and left radial artery when turning the head to the right
and left with simultaneous deep breathing), and hand dynamometry to assess the strength
of the hands on both sides. A comparative measurement of the circumference of the hands
was performed at five points to assess the edema. All patients were tested using scales and
questionnaires to assess the level of their pain syndrome (VAS scale, McGill questionnaire),
the presence of anxiety and depressive disorders (Zung depression scale, STAI anxiety
scale), and quality of life assessment (SF-36 questionnaire).
The study was approved by the ethics committee of Almazov National Medical
Research Centre (Protocol number 05112019 from 11 November 2019) and was performed
in accordance with the Declaration of Helsinki. All subjects provided written informed
consent after receiving a complete explanation of the.
2.3. Rs-fMRI
Imaging was obtained on a 3 T scanner (Siemens, Germany). Patients underwent
an MRI of the brain, which included the standard MRI protocol (using T1-, T2-, TIRM,
MPRAGE, DWI) and rs-fMRI (BOLD). The standard MRI protocol was used to exclude the
presence of organic brain pathology in patients following BC treatment and in the control
group. Patients were asked to remain awake, keep their eyes closed, and lie still.
2.4. Data Processing and Statistical Analyses
The postprocessing of the rs-fMRI data was carried out using the CONN v1.7 software
package. Statistical processing and evaluation of the neuroimaging study results of the
patients with post-treatment symptoms and the control group were carried out using seed-
based analysis and independent component analysis (ICA). The Statistica 10 program was
also used to analyze the dimensional data. A comprehensive statistical analysis of the study
data was carried out. For the statistical description of the measured data, their agreement
with the normal distribution and the estimation of the mean values and medians with 95%
confidence intervals was verified.
3. Results
All of the patients had certain complications after breast cancer treatment, such as
lymphedema of the upper limb on the side of surgical treatment (n= 23, 50%), sensitivity
disorders of the upper limb (n= 23, 50%), paresthesia (n= 21, 46%), muscle weakness
(n= 26, 56%)
, restriction of movement in the shoulder joint (n= 19, 41%), pain in the upper
limb (n= 24, 52%), headaches (n= 25, 54%), dizziness (n= 18, 39%), and sleep disorders
(n= 16, 34%). When performing functional tests, a positive Adson test was detected in
24 patients
(52%). In 26 out of 46 patients (56%), there was a decrease in hand strength on
the side of surgical treatment when performing hand dynamometry.
According to the anxiety scale, 20 patients (44%) showed high situational anxiety,
and 27 (60%) showed high personal anxiety. A total of 19 out of 46 patients (41%) were
diagnosed with mild depression using the Zung scale. According to the results of the SF-36
quality of life questionnaire, there was a decrease in the overall physical well-being index
in 40 patients (88%) and in the overall mental well-being index in 36 patients (80%).
The patients were divided into subgroups depending on the presence of certain clinical
syndromes after breast cancer treatment (Table 1).
J. Clin. Med. 2022,11, 617 4 of 13
Table 1. The number of patients in groups depending on syndrome.
Syndrome Number of Patients with the Syndrome Number of Patients without the Syndrome
Lymphedema 23 23
Postmastectomy pain syndrome 24 22
Vestibulocerebellar ataxia 18 28
Depression 19 27
During the postprocessing of the rs-fMRI data, changes in the functional connections
of the medial prefrontal cortex (MPFC) with other parts of the brain were analyzed. The
choice of the MPFC as a region of interest in the study is due to its importance as one of
the central connectivity hubs of the DMN. MPFC connects extensive areas, including the
orbitofrontal cortex and structures, such as the periaqueductal gray matter, the amygdala,
and the hypothalamus, and plays an important role in the transmission of somatosensory
information to the structures that are responsible for motor and visceral reactions, that
participate in the intrinsic reward system, and that are responsible for decision-making [
26
].
In the current study, an intergroup statistical analysis of the functional connectivity
of the DMN between several groups was carried out, where the following comparisons
were achieved:
(1)
Comparison of the connectivity differences between all patients after breast cancer
treatment who participated in the study and the control group;
(2)
Comparison between patients after breast cancer treatment with and without lym-
phedema;
(3)
Comparison between patients after breast cancer treatment with the presence of pain
in the upper limb and without;
(4)
Comparison between patients after breast cancer treatment with vestibulocerebellar
ataxia and without;
(5)
Comparison between patients after breast cancer treatment with depression and
without depression.
This analysis was carried out in order to assess how a particular syndrome affects the
functional connectivity of the DMN and how significant these changes are.
3.1. Resting State Functional MRI Results
3.1.1. All Patients after Breast Cancer Treatment in Comparison with Control Group
According to the results of the comparative analysis between the patients after breast
cancer treatment (n= 46) and the control group (n= 20), a decrease in functional connectivity
was revealed between the MPFC and the right fusiform gyrus (p= 0.046) and in the cortex
of the left precentral gyrus (p= 0.032) in patients after breast cancer treatment compared to
the healthy female volunteers. There was an increase in the functional connectivity between
the MPFC and the operculum cortex of the parietal lobes on both sides (p= 0.018, p= 0.036)
(Figure 1; Table 2).
3.1.2. Lymphedema
When comparing functional connectivity in patients after breast cancer treatment with
lymphedema and in patients without it, there was a decrease in the connectivity between
the MPFC and the occipital cortex on both sides (p= 0.012, p= 0.013), the cortex of the left
middle temporal gyrus (p= 0.014), the left fusiform gyrus (p= 0.045), and the cortex of
the left inferior (p= 0.020) and the middle frontal (p= 0.022) gyrus. There was an increase
in the number of positive connections between the MPFC and the thalami on both sides
(p= 0.017, p= 0.029) and the right cerebellar hemisphere (p= 0.036) (Figure 2; Table 3).
J. Clin. Med. 2022,11, 617 5 of 13
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 5 of 14
Figure 1. Three-dimensional reconstruction of the functional connections between the MPFC and
various areas of the brain in a group of patients after breast cancer treatment using seed-based
analysis. Positive functional connections between the MPFC and the zones of interest are indicated
in red, and negative ones are indicated in blue.
Table 2. Main regions of interest with MPFC connections in the group of patients after breast
cancer treatment.
Target Region Side T Beta p-unc
Parietal Operculum Lef
t
2.43 0.11 0.018390
Precentral Gyrus Left 2.20 0.11 0.032464
Parietal Operculum Right 2.15 2.15 0.036042
Fusiform Gyrus (Temp-Occ) Right 2.04 2.04 0.046336
3.1.2. Lymphedema
When comparing functional connectivity in patients after breast cancer treatment with
lymphedema and in patients without it, there was a decrease in the connectivity between
the MPFC and the occipital cortex on both sides (p = 0.012, p = 0.013), the cortex of the left
middle temporal gyrus (p = 0.014), the left fusiform gyrus (p = 0.045), and the cortex of the
left inferior (p = 0.020) and the middle frontal (p = 0.022) gyrus. There was an increase in the
number of positive connections between the MPFC and the thalami on both sides (p = 0.017,
p = 0.029) and the right cerebellar hemisphere (p = 0.036) (Figure 2; Table 3).
Figure 1.
Three-dimensional reconstruction of the functional connections between the MPFC and
various areas of the brain in a group of patients after breast cancer treatment using seed-based
analysis. Positive functional connections between the MPFC and the zones of interest are indicated in
red, and negative ones are indicated in blue.
Table 2.
Main regions of interest with MPFC connections in the group of patients after breast
cancer treatment.
Target Region Side T Beta p-unc
Parietal Operculum Left 2.43 0.11 0.018390
Precentral Gyrus Left 2.20 0.11 0.032464
Parietal Operculum Right 2.15 2.15 0.036042
Fusiform Gyrus (Temp-Occ)
Right 2.04 2.04 0.046336
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 6 of 14
Figure 2. Three-dimensional reconstruction of the functional connections between the MPFC and
various areas of the brain in a group of patients after breast cancer treatment with the presence of
lymphedema using seed-based analysis. Positive functional connections between the MPFC and
the zones of interest are indicated in red, and negative ones are indicated in blue.
Table 3. Main regions of interest where MPFC connections were present in patients after breast
cancer treatment with lymphedema.
Target Region Side T Beta p-unc
Lateral Occipital Cortex Lef
t
2.74 0.23 0.012076
Cerebellum Left 2.73 0.21 0.012222
Occipital Pole Right 2.69 0.18 0.013510
Middle Temporal Gyrus Left 2.66 0.28 0.014181
Thalamus Right 2.57 0.20 0.017496
Inferior Frontal Gyrus Left 2.49 0.24 0.020691
Middle Frontal Gyrus Left 2.46 0.23 0.022441
Thalamus Lef
t
2.33 0.16 0.029463
Cerebellum Right 2.22 0.18 0.036737
Fusiform Gyrus (Temp) Left 2.12 0.15 0.045543
3.1.3. Postmastectomy Pain Syndrome
A comparative statistical analysis of the functional connectivity of the patients with
postmastectomy pain syndrome compared to patients without postmastectomy pain
syndrome showed an increase in the number of negative connections of MPFC with the
cortex of the right inferior frontal gyrus (p = 0.003), right inferior temporal gyrus (p =
0.007), and right amygdala (p = 0.046). There was also an increase in the number of
negative functional connections between the MPFC and the salience network (p = 0.009)
as well as the dorsal attention network (p = 0.036). Positive connections were found
between the MPFC and the pole of the left occipital lobe (p = 0.029) and the left cerebellum
hemisphere (0.0034) (Figure 3; Table 4).
Figure 2.
Three-dimensional reconstruction of the functional connections between the MPFC and
various areas of the brain in a group of patients after breast cancer treatment with the presence of
lymphedema using seed-based analysis. Positive functional connections between the MPFC and the
zones of interest are indicated in red, and negative ones are indicated in blue.
J. Clin. Med. 2022,11, 617 6 of 13
Table 3.
Main regions of interest where MPFC connections were present in patients after breast cancer
treatment with lymphedema.
Target Region Side T Beta p-unc
Lateral Occipital Cortex Left 2.74 0.23 0.012076
Cerebellum Left 2.73 0.21 0.012222
Occipital Pole Right 2.69 0.18 0.013510
Middle Temporal Gyrus Left 2.66 0.28 0.014181
Thalamus Right 2.57 0.20 0.017496
Inferior Frontal Gyrus Left 2.49 0.24 0.020691
Middle Frontal Gyrus Left 2.46 0.23 0.022441
Thalamus Left 2.33 0.16 0.029463
Cerebellum Right 2.22 0.18 0.036737
Fusiform Gyrus (Temp) Left 2.12 0.15 0.045543
3.1.3. Postmastectomy Pain Syndrome
A comparative statistical analysis of the functional connectivity of the patients with
postmastectomy pain syndrome compared to patients without postmastectomy pain syn-
drome showed an increase in the number of negative connections of MPFC with the cortex
of the right inferior frontal gyrus (p= 0.003), right inferior temporal gyrus (p= 0.007), and
right amygdala (p= 0.046). There was also an increase in the number of negative functional
connections between the MPFC and the salience network (p= 0.009) as well as the dorsal
attention network (p= 0.036). Positive connections were found between the MPFC and
the pole of the left occipital lobe (p= 0.029) and the left cerebellum hemisphere (0.0034)
(Figure 3; Table 4).
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 7 of 14
Figure 3. Three-dimensional reconstruction of the functional connections between the MPFC and
various areas of the brain in a group of patients with postmastectomy pain syndrome using seed-
based analysis. Positive functional connections between the MPFC and the zones of interest are
indicated in red, and negative ones are indicated in blue.
Table 4. Main regions of interest where MPFC connections were present in patients with
postmastectomy pain syndrome.
Target Region Side T Beta p-unc
Cerebellum Left 3.34 0.24 0.003469
Inferior Frontal Gyrus Right 3.32 0.26 0.003615
Inferior Temporal Gyrus Right 3.02 0.21 0.007069
Salience network (SMG) Right 2.88 0.29 0.009688
Occipital Pole Lef
t
2.36 0.18 0.029258
Dorsal Attention. FEF 2.25 0.17 0.036340
Amygdala Right 2.13 0.14 0.046265
3.1.4. Vestibulocerebellar Ataxia
A comparative statistical analysis of the functional connectivity in patients after
breast cancer treatment with vestibulocerebellar ataxia compared to in patients without it
revealed a decrease in the connectivity between the MPFC and the temporo-occipital
fusiform cortex on both sides (p = 0.023, p = 0.032), the lateral occipital cortex on both sides
(p = 0.016, p = 0.049), the left cerebellum (p = 0.037), as well as in the right Heschl's gyrus
(p = 0.024). There was a significant increase in the number of positive connections of MPFC
with the right caudate nucleus (p = 0.003) (Figure 4; Table 5).
Figure 3.
Three-dimensional reconstruction of the functional connections between the MPFC and
various areas of the brain in a group of patients with postmastectomy pain syndrome using seed-
based analysis. Positive functional connections between the MPFC and the zones of interest are
indicated in red, and negative ones are indicated in blue.
J. Clin. Med. 2022,11, 617 7 of 13
Table 4.
Main regions of interest where MPFC connections were present in patients with postmastec-
tomy pain syndrome.
Target Region Side T Beta p-unc
Cerebellum Left 3.34 0.24 0.003469
Inferior Frontal Gyrus Right 3.32 0.26 0.003615
Inferior Temporal Gyrus Right 3.02 0.21 0.007069
Salience network (SMG) Right 2.88 0.29 0.009688
Occipital Pole Left 2.36 0.18 0.029258
Dorsal Attention. FEF 2.25 0.17 0.036340
Amygdala Right 2.13 0.14 0.046265
3.1.4. Vestibulocerebellar Ataxia
A comparative statistical analysis of the functional connectivity in patients after breast
cancer treatment with vestibulocerebellar ataxia compared to in patients without it revealed
a decrease in the connectivity between the MPFC and the temporo-occipital fusiform cortex
on both sides (p= 0.023, p= 0.032), the lateral occipital cortex on both sides (p= 0.016,
p= 0.049)
, the left cerebellum (p= 0.037), as well as in the right Heschl’s gyrus (p= 0.024).
There was a significant increase in the number of positive connections of MPFC with the
right caudate nucleus (p= 0.003) (Figure 4; Table 5).
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 8 of 14
Figure 4. Three-dimensional reconstruction of the set of functional connections between the MPFC
and various brain areas of patients after breast cancer treatment with the presence of
vestibulocerebellar ataxia using seed-based analysis. The positive functional connections between
the MPFC and the zones of interest are indicated in red, and the negative ones are indicated in blue.
Table 5. Main regions of interest where MPFC connections were present in patients after breast
cancer treatment with vestibulocerebellar ataxia.
Target Region Side T Beta p-unc
Caudate Righ
3.14 0.28 0.003531
Lateral Occipital Cortex Left 2.51 0.25 0.016856
Fusiform Gyrus (Temp) Right 2.38 0.19 0.023308
Heschl’s Gyrus Right 2.36 0.19 0.024008
Fusiform Gyrus (Temp-Occ) Left 2.23 0.17 0.032363
Cerebellum Left 2.16 0.16 0.037966
Lateral Occipital Cortex Right 2.04 0.19 0.049005
3.1.5. Depression
In a comparative statistical analysis of the functional connectivity in patients with the
presence of depression after breast cancer treatment compared to in patients without
depression, there was a decrease in the MPFC connectivity with the left cuneal cortex (p =
0.007), the right fusiform gyrus (p = 0.028), and the planum polare of the right temporal
lobe (p = 0.023). There was a bilateral change in the connectivity between the MPFC and
the parahippocampal gyrus: there was an increase in the number of positive connections
on the right and a decrease in the number of positive connections on the left (p = 0.047, p
= 0.011). There was an increase in the number negative connections in the dorsal attention
network (p = 0.002) (Figure 5; Table 6).
Figure 4.
Three-dimensional reconstruction of the set of functional connections between the MPFC
and various brain areas of patients after breast cancer treatment with the presence of vestibulocere-
bellar ataxia using seed-based analysis. The positive functional connections between the MPFC and
the zones of interest are indicated in red, and the negative ones are indicated in blue.
J. Clin. Med. 2022,11, 617 8 of 13
Table 5.
Main regions of interest where MPFC connections were present in patients after breast cancer
treatment with vestibulocerebellar ataxia.
Target Region Side T Beta p-unc
Caudate Right 3.14 0.28 0.003531
Lateral Occipital Cortex Left 2.51 0.25 0.016856
Fusiform Gyrus (Temp) Right 2.38 0.19 0.023308
Heschl’s Gyrus Right 2.36 0.19 0.024008
Fusiform Gyrus (Temp-Occ)
Left 2.23 0.17 0.032363
Cerebellum Left 2.16 0.16 0.037966
Lateral Occipital Cortex Right 2.04 0.19 0.049005
3.1.5. Depression
In a comparative statistical analysis of the functional connectivity in patients with
the presence of depression after breast cancer treatment compared to in patients without
depression, there was a decrease in the MPFC connectivity with the left cuneal cortex
(
p= 0.007
), the right fusiform gyrus (p= 0.028), and the planum polare of the right temporal
lobe (p= 0.023). There was a bilateral change in the connectivity between the MPFC and the
parahippocampal gyrus: there was an increase in the number of positive connections on the
right and a decrease in the number of positive connections on the left (p= 0.047,
p= 0.011
).
There was an increase in the number negative connections in the dorsal attention network
(p= 0.002) (Figure 5; Table 6).
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 9 of 14
Figure 5. Three-dimensional reconstruction of the set of functional connections between the MPFC
and various brain areas of patients with the presence of depression after breast cancer treatment
using seed-based analysis. Positive functional connections between the MPFC and the zones of
interest are indicated in red, and negative ones are indicated in blue.
Table 6. Main regions of interest where MPFC connections are present in patients with depression
after breast cancer treatment.
Target Region Side T Beta p-unc
Dorsal Attention. FEF 3.39 0.18 0.002925
Cuneal Cortex Left 2.99 0.21 0.007221
Parahippocampal gyrus Left 2.77 0.16 0.011720
Planum Polare Right 2.46 0.16 0.023100
Fusiform Gyrus (Temp) Right 2.37 0.13 0.028196
Parahippocampal Gyrus Right 2.11 0.14 0.047445
4. Discussion
When analyzing the rs-fMRI data in patients after breast cancer treatment compared
to the control group, there was a change in the functional connectivity between the MPFC
and a number of significant areas of the brain. In particular, a decrease in the connectivity
of the MPFC with the fusiform gyrus was revealed, which was observed both in the main
group of patients compared to the control group and in the groups of patients with
manifestations of lymphedema, vestibulocerebellar ataxia, and depression. The fusiform
gyrus is an important area at the junction of the ventral cortex of the temporal and
occipital lobes and is involved in the processes of visual perception, including in the
perception of faces, and plays a role in the cognitive processes of memory, attention, and
emotions. Changes in the functional connectivity of the fusiform gyrus have been
described in patients with amnesic mild cognitive impairment (aMCI) [27] as well as in
the pathogenesis of depressive disorders [28,29]. Changes in the functional connectivity
between the MPFC and fusiform gyrus in patients with neurological complications after
breast cancer treatment may indicate the presence of initial cognitive impairment caused
by the surgery, radiation, and/or by chemotherapy treatment. For clarification, the
Figure 5.
Three-dimensional reconstruction of the set of functional connections between the MPFC
and various brain areas of patients with the presence of depression after breast cancer treatment using
seed-based analysis. Positive functional connections between the MPFC and the zones of interest are
indicated in red, and negative ones are indicated in blue.
J. Clin. Med. 2022,11, 617 9 of 13
Table 6.
Main regions of interest where MPFC connections are present in patients with depression
after breast cancer treatment.
Target Region Side T Beta p-unc
Dorsal Attention. FEF 3.39 0.18 0.002925
Cuneal Cortex Left 2.99 0.21 0.007221
Parahippocampal gyrus Left 2.77 0.16 0.011720
Planum Polare Right 2.46 0.16 0.023100
Fusiform Gyrus (Temp) Right 2.37 0.13 0.028196
Parahippocampal Gyrus Right 2.11 0.14 0.047445
4. Discussion
When analyzing the rs-fMRI data in patients after breast cancer treatment compared to
the control group, there was a change in the functional connectivity between the MPFC and
a number of significant areas of the brain. In particular, a decrease in the connectivity of the
MPFC with the fusiform gyrus was revealed, which was observed both in the main group
of patients compared to the control group and in the groups of patients with manifestations
of lymphedema, vestibulocerebellar ataxia, and depression. The fusiform gyrus is an
important area at the junction of the ventral cortex of the temporal and occipital lobes
and is involved in the processes of visual perception, including in the perception of faces,
and plays a role in the cognitive processes of memory, attention, and emotions. Changes
in the functional connectivity of the fusiform gyrus have been described in patients with
amnesic mild cognitive impairment (aMCI) [
27
] as well as in the pathogenesis of depressive
disorders [
28
,
29
]. Changes in the functional connectivity between the MPFC and fusiform
gyrus in patients with neurological complications after breast cancer treatment may indicate
the presence of initial cognitive impairment caused by the surgery, radiation, and/or by
chemotherapy treatment. For clarification, the correlation of the obtained neuroimaging
data with the results of neuropsychological testing should be assessed.
Currently, it is believed that DMN is active when individuals are engaged in stimulus-
independent thought, such as autobiographical memory, and the activation of the DMN
decreases during external or attention-demanding tasks that involve mental control [
30
32
].
Therefore, the activation of the DMN is inversely correlated with activation in regions such
as the precentral gyrus, which is a part of the somatomotor cortex and is involved in the
brain networks that are activated for external tasks that demand attention and mental con-
trol [
33
]. Our study showed the significant decline in the functional connectivity between
the MPFC and left precentral gyrus in patients after breast cancer treatment compared to
the participants in the control group. These changes in the functional connectivity between
the DMN and somatomotor areas could be due to chronic pain syndrome, which can alter
DMN–somatomotor cortex connectivity [34].
In our study, there was a change in the functional connectivity between the MPFC
and the parahippocampal gyri in the patients with diagnosed mild depressive disorder.
The parahippocampal gyrus is one of the most important centers of the DMN and acts as a
connectivity hub between such structures as the MPFC and the posterior cingulate cortex on
the one hand and the hippocampus on the other [
35
]. According to recent data, a decrease in
the indirect effect of the MPFC on the hippocampus through functional connections with the
parahippocampal gyrus may be one of the pathogenetic mechanisms for the development
of cognitive deficits [
36
,
37
], and an increase in the connectivity between the posterior
cingulate cortex and the parahippocampal gyrus plays a role in the occurrence of depressive
symptoms [
38
,
39
]. Our study also showed a decline in the functional connectivity between
the MPFC and the cuneal cortex in patients with depression after breast cancer treatment,
which corresponds to previous studies on depressive disorders [40].
In patients with diagnosed postmastectomy pain syndrome in the upper limb and in
the postoperative area, a functional reorganization of the DMN was observed and included
the involvement of such structures as the cortex of the inferior frontal and middle temporal
gyrus and the amygdala. A number of recent studies have shown that the amygdala plays a
J. Clin. Med. 2022,11, 617 10 of 13
significant role in the spontaneous activation of “pain neural networks” [
41
,
42
] as well as in
the pathogenesis of chronic pain syndrome in general, including its emotional and cognitive
component [
43
]. The rs-fMRI data obtained in our study in patients with postmastectomy
pain syndrome not only indicate the excessive activation of the structures of the “pain
connectome”, but also a violation of the functional regulation between the structures of
the DMN and the salience network, the main centers of which are the anterior insular and
anterior cingulate cortex. The violation of connectivity between these two neural networks
is considered one of the key aspects of the centralization of chronic pain syndrome [
44
].
It is known that the transcranial magnetic stimulation (TMS) method is used for chronic
pain syndromes of various etiologies [
45
]. Knowledge about the structure of the functional
disorganization of the “pain connectome” makes it possible to influence specific areas of
the brain using TMS in patients to achieve a better effect of reducing the frequency and
the intensity of the pain. Taking into account the complexity of the organization of the
functional networks of the brain involved in the pathogenesis of pain syndrome, it may be
necessary to develop new approaches for the application of the TMS method.
A number of patients participating in the study had symptoms of cerebellar ataxia
in the form of dizziness, instability in the Romberg pose, and during gait changes. When
comparing the rs-fMRI data in this group of patients with data from the group of patients
who did not have vestibulocerebellar ataxia, there was an alteration in the connectivity
of the MPFC with the left hemisphere of the cerebellum, which indicates the presence of
cerebellar disorders in the pathogenesis of post-mastectomy syndrome in these patients.
These changes in DMN–cerebellar connectivity may be caused by a chronic vertebral-basilar
insufficiency in patients as a long-term effect of breast cancer surgery and/or radiation
therapy, such as local fibrous-atrophic changes in the postoperative area and hypertrophy of
the scalenus muscles, which leads to the spasming of the vertebral artery on the treatment
side [
46
,
47
]. This assumption requires further study and comparison with data from other
imaging techniques, such as ultrasounds of the arteries in the neck [48].
The most vivid neuroimaging picture obtained during rs-fMRI was observed in pa-
tients with the presence of upper limb lymphedema after breast cancer treatment. In this
group of patients, there were significant changes in the connectivity of the DMN in com-
parison to the patients without the presence of lymphedema, with the overall decline in the
functional connectivity of the DMN and a more pronounced decline in the connectivity
between the MPFC and inferior and middle frontal gyri cortex, middle temporal gyrus,
and lateral occipital cortex on the left. These results may indicate a significant role of
lymphedema in the pathogenesis of neurological disorders in patients after surgical treat-
ment for breast cancer and may be due to a complex of vascular and neurodegenerative
changes [
49
]. However, it should be noted that the development of lymphedema occurs
more often in women with a more severe stage of the disease, and the effects of chemo- and
radiation therapy should not be excluded from the pathogenesis of neuronal damage [
50
,
51
].
Nevertheless, fMRI can be used as a helpful tool for diagnosing neurological disorders in
women after breast cancer treatment and even for the prediction of the long-term cognitive
deficits [52].
5. Conclusions
In conclusion, the application of rs-fMRI provides a possibility to assess functional
changes in the brains of patients following breast cancer treatment that occur against the
background of lymphedema, postmastectomy pain syndrome, vertebrobasilar insufficiency,
anxiety, and depressive disorders. The variety of clinical symptoms, diagnostic difficulties,
multi-system complications of breast cancer treatment, and significant decreases in the
quality of life determine the need for a comprehensive diagnostic (including method
for assessing functional changes in the brain—rs-fMRI), treatment, and rehabilitation
approaches for this group of patients.
Author Contributions:
Conceptualization, T.B., M.P., A.E., S.C. and M.S.; methodology, T.B., M.P.
and A.E.; validation, T.B., M.P., A.E., O.F., T.A., K.S., G.T. and M.S.; formal analysis, T.B., M.P., A.E.,
J. Clin. Med. 2022,11, 617 11 of 13
O.F., T.A., K.S., V.K., E.G., A.L., A.M., G.T. and M.S.; investigation, T.B., M.P., A.E., E.G., A.M. and
A.L.; resources, M.P., A.E., O.F., T.A., K.S., E.G. and M.S.; data curation, M.P., A.E. and G.T.; writing—
original draft preparation, T.B., S.C., and M.S.; writing—review and editing, M.P., A.E., S.C. and M.S.;
visualization, T.B., E.G. and A.L.; supervision, M.P., A.E., K.S. and G.T.; project administration, M.P.,
A.E. and M.S.; funding acquisition, M.P., K.S., G.T., S.C. and M.S. All authors have read and agreed to
the published version of the manuscript.
Funding:
This research was funded by the Ministry of Science and Higher Education of the Russian
Federation (Agreement No. 075-15-2020-901), Technische Universität München (TUM) within the
DFG funding programme Open Access Publishing.
Institutional Review Board Statement:
The study was carried out in compliance with the principles
of the Declaration of Helsinki of the World Medical Association and received consent from the
Ethics Committee of the Federal State Budgetary Institution “Almazov National Medical Research
Center” of the Ministry of Health of the Russian Federation (Protocol number 05112019 from 11
November 2019).
Informed Consent Statement:
Informed consent was obtained from all subjects involved in
the study.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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... The main clinical manifestations for breast cancer survivors (BCSs) include postoperative defect on the side of the operation, cicatricial changes [16], plexopathy of the brachial plexus [17,18], impaired biomechanics in the shoulder joint [19], anxiety and depressive disorders [20,21], lymphedema of the upper limb [9,[22][23][24], and vestibulo-atactic syndrome (VAS) [25]. Disorders of the central nervous system (CNS) that occur against the background of the complex treatment of breast cancer can lead to functional and structural changes in the brain of patients in the postoperative period, such as changes in functional connectivity in the Default Mode Network and quantitative fractional anisotropy in the white matter tracts [26]. Resting-state fMRI has previously shown alterations in the connectivity of the medial prefrontal cortex in the left hemisphere of the cerebellum in BCS with symptoms of cerebellar ataxia [26,27]. ...
... Disorders of the central nervous system (CNS) that occur against the background of the complex treatment of breast cancer can lead to functional and structural changes in the brain of patients in the postoperative period, such as changes in functional connectivity in the Default Mode Network and quantitative fractional anisotropy in the white matter tracts [26]. Resting-state fMRI has previously shown alterations in the connectivity of the medial prefrontal cortex in the left hemisphere of the cerebellum in BCS with symptoms of cerebellar ataxia [26,27]. Breast cancer patients treated with cytotoxic agents regularly report cognitive problems. ...
Article
Full-text available
Vestibulo-atactic syndrome (VAS), which represents a combination of motor and vestibular disorders, can be manifested as a clinical complication of breast cancer treatment and has a significant impact on patients’ quality of life. The identification of novel potential biomarkers that might help to predict the onset of VAS and its progression could improve the management of this group of patients. In the current study, the levels of intercellular cell adhesion molecule 1 (ICAM-1), platelet/endothelial cell adhesion molecule 1 (PECAM-1), NSE (neuron-specific enolase), and the antibodies recognizing NR-2 subunit of NMDA receptor (NR-2-ab) were measured in the blood serum of BC survivor patients with vestibulo-atactic syndrome (VAS) and associated with the brain connectome data obtained via functional magnetic resonance imaging (fMRI) studies. A total of 21 patients were registered in this open, single-center trial and compared to age-matched healthy female volunteers (control group) (n = 17). BC patients with VAS demonstrated higher serum levels of ICAM-1, PECAM-1, and NSE and a lower value of NR-2-ab, with values of 654.7 ± 184.8, 115.3 ± 37.03, 49.9 ± 103.9, and 0.5 ± 0.3 pg/mL, respectively, as compared to the healthy volunteers, with 230.2 ± 44.8, 62.8 ± 15.6, 15.5 ± 6.4, and 1.4 ± 0.7 pg/mL. According to the fMRI data (employing seed-to-voxel and ROI-to-ROI methods), in BC patients with VAS, significant changes were detected in the functional connectivity in the areas involved in the regulation of postural-tonic reflexes, the coordination of movements, and the regulation of balance. In conclusion, the detected elevated levels of serum biomarkers may reveal damage to the CNS neurons and endothelial cells that is, in turn, associated with the change in the brain connectivity in this group of patients.
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... One of the key confounding factors is past medical history. For instance, a patient may have had prior illness and/or treatment other than TBI that could potentially contribute to the patient's symptoms or affect brain connectivity (Bukkieva et al., 2022;Douaud et al., 2022). In this study, the participants were asked to report prior medical history on a voluntary basis and based on their recollection, so it is feasible that Table 3 Differences of SC in percentage between TBIcs and CG and connections between DK parcels shown in Fig. 4(a). ...
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Diffusion properties from diffusion tensor imaging (DTI) are exquisitely sensitive to white matter abnormalities incurred during traumatic brain injury (TBI), especially for those patients with chronic post-TBI symptoms such as headaches, dizziness, fatigue, etc. The evaluation of structural and functional connectivity using DTI has become a promising method for identifying subtle alterations in brain connectivity associated with TBI that are otherwise not visible with conventional imaging. This study assessed whether TBI patients with (n = 17) or without (n = 16) chronic symptoms (TBIcs/TBIncs) exhibit any changes in structural connectivity (SC) and mean fractional anisotropy (mFA) of intra- and inter-hemispheric connections when compared to a control group (CG) (n = 13). Reductions in SC and mFA were observed for TBIcs compared to CG, but not for TBIncs. More connections were found to have mFA reductions than SC reductions. On the whole, SC is dominated by ipsilateral connections for all the groups after the comparison of contralateral and ipsilateral connections. More contra-ipsi reductions of mFA were found for TBIcs than TBIncs compared to CG. These findings suggest that TBI patients with chronic symptoms not only demonstrate decreased global and regional mFA but also reduced structural network connectivity.
... Анализ проводился между функциональными связями медиальной префронтальной коры и задней поясной извилиной, которые относятся к сети режима по умолчанию, с другими областями мозга [19,20]. Сеть режима по умолчанию тесно связана с развитием бессонницы, по данным D. R. Marques и соавт. ...
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INTRODUCTION: Insomnia is one of the most common sleep disorders, the interest of scientists in the occurrence and pathophysiology of insomnia is growing every year. In particular, the brain connectome and its changes in sleep disorders are being actively studied based on the data of resting state functional magnetic resonance imaging. OBJECTIVE: The study is to assess changes in brain connectomes in patients with chronic insomnia using functional magnetic resonance imaging. MATERIALS AND METHODS: 53 people took part in the study, of which 34 patients who applied for a somnologist’s appointment at the Almazov National Research Medical Center of the Ministry of Health of the Russian Federation were diagnosed with chronic insomnia, confirmed by polysomnography. All participants of the study had an MRI of the brain on tomographs with a magnetic field induction force of 3.0 Tl at two time points. Statistics: Statistical analysis of MRI data was performed using MathLab 2018a, CONN v1.7. Descriptive statistics, the Kolmogorov-Smirnov criterion were used to process the materials, depending on the characteristics of the data, the MannWhitney U-criterion and Pearson Chi-squared were used to analyze demographic data. RESULTS: The study, neuroimaging markers of insomnia were identified and changes in the functional networks of the brain were described in patients with insomnia and a group of healthy volunteers at different time points. DISCUSSION: The obtained functional data demonstrate ambiguous results. Both an increase and a decrease in the functional connectivity of the medial prefrontal cortex with the structures of the visual analyzer, an increase in functional connections with the temporal pole, in particular with the hippocampus, is determined, which indicates changes in the consolidation of visually encoded information. The relative limitation in this study can be considered the heterogeneity of the age composition of the group. CONCLUSSION: Resting state functional MRI of the brain is a key neuroimaging method in determining the functional connections of the brain in patients with sleep disorders, which allows us to establish a impairment of functional interaction between brain structures involved in the processes of falling asleep and maintaining sleep.
... В последние годы рак молочной железы (РМЖ) стал одним из наиболее распространенных онкологических заболеваний у женщин [1]. По данным GLOBOCAN, в 2020 г. во всем мире зарегистрировано 2,26 млн случаев РМЖ, и с каждым годом это количество увеличивается [2,3]. В настоящее время определение сторожевого лимфатического узла составляет неотъемлемую часть всех мировых клинических рекомендаций по хирургическому лечению РМЖ [4][5][6][7].Российские технологии демонстрируют высокую эффективность в разработке и внедрении медицинского оборудования для онкологической служды. ...
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Objective: To analyze the effectiveness of identifying the sentinel lymph node in breast cancer using the «MARS» system for fluorescent diagnostics in near infrared light. Material and methods: There were 51 patients with breast cancer cT0-2N0M0 between July 2023 and October 2023. Mean age of patients was 52.3 years. Invasive ductal carcinoma was diagnosed in 39 (76.5%) patients, invasive lobular carcinoma - in 8 (15.7%) patients, other forms of breast cancer - in 4 (7.8%) patients. Results: Sentinel lymph node was successfully identified in all cases (n=51). A total of 122 sentinel lymph nodes were detected and mapped (2.4 nodes per a patient). Conclusion: The MARS system for intraoperative fluorescence diagnostics in near-infrared light is effective for identifying the sentinel lymph node in breast cancer.
... The article dated 2007 discussed the "gradual abandonment of the Halsted operation" [45]. In papers dated 2015-2022, the Patey operation was still mentioned as a routine procedure; but the preservation of both pectoral muscles was finally becoming a standard [46][47][48]. Today, the recommendations are adjusted to international patterns. ...
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... According to our results, we can assume that the damage of the white matter tracts of the brain is a result of endothelial dysfunction in patients following the treatment protocol ( Figure 2). In favor of this hypothesis is the recently published study by Bukkieva et al., where the authors employing resting state functional magnetic resonance imaging (rs-fMRI) demonstrated the changes in functional connectivity in patients following breast cancer treatment [55]. The levels of soluble ICAM-1 and PECAM-1 could provide biomarkers for predicting the degree of damage in the CNS, and longitudinal studies might enable the monitoring of the effectiveness of therapeutic and rehabilitation measures. ...
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Breast cancer (BC) is the most common tumor in women worldwide with high mortality rates. Surgical methods followed by radio–chemotherapy are used to treat these tumors. Such treatment can lead to various side effects, including neurological complications. The development of a reliable biomarker to predict the onset of CNS complications could improve clinical outcomes. In the current study, ICAM-1 and PECAM-1 serum levels were measured as potential biomarkers in 45 female patients in a long-term follow-up period after breast cancer treatment, and compared to 25 age-matched female healthy volunteers. Serum levels of both biomarkers, ICAM-1 and PECAM-1 were significantly higher in patients after breast cancer treatment and could be associated with cognitive dysfunction, depression, and vestibulocerebellar ataxia. In conclusion, our results provide a first hint that elevated serum levels of ICAM-1 and PECAM-1 could serve as early predictive biomarkers in breast cancer survivors that might help to improve the management of these patients.
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BACKGROUND: The Disorders of cerebral circulation and sleep are inextricably related, since sleep disorders, including hypersomnia, are closely intertwined with cardiovascular diseases and increase the risk of stroke. Research works on visualization of functional brain changes in patients with sleep disorders and acute ischemic stroke are very few and need more study. AIM: to determine the functional connections of the brain in hypersomnia in patients with acute ischemic stroke by performing functional magnetic resonance imaging at rest. A study of 40 patients with acute ischemic stroke and sleep disorders was performed on the basis of the Federal State Budgetary Institution Almazov Research Center of the Ministry of Health of the Russian Federation. All patients underwent neurological examination, assessment of sleepiness, worry and depression, magnetic resonance imaging was performed on tomographs with a magnetic field induction force of 1.5T, using a standard protocol and special pulse sequences of T-gradient echo 3D MPRAGE and BOLD. Functional magnetic resonance imaging of the brain at rest was used to assess functional connections. Postprocessing was performed using specialized CONN-TOOLBOX software with an appropriate graphical representation of quantitative results based on the selection of areas of interest. RESULTS: Among the examined patients, 23 had hypersomnolence; of these, 8 patients were diagnosed with secondary hypersomnia associated with sleep apnea syndrome. Thus, in the examined sample, post-stroke hypersomnolence was detected in 15 patients (34%). Patients with an unspecified subtype of stroke and right-sided lesions showed a high degree of drowsiness (p 0.05). With the help of functional magnetic resonance imaging of the brain at rest, changes in functional connections between the main nodes of the default mode network with the left temporal pole, cerebellum, central cerebral cortex on the left, angular gyrus on the left, with the dorsal attention network on the right are determined (p 0.05). CONCLUSION: The use of complex magnetic resonance imaging, which includes structural and functional magnetic resonance imaging in patients with acute ischemic stroke and sleep disorders, allows us to identify structural changes and changes in functional connectivity and identify neuroimaging markers of this pathology. Hypersomnolence is typical for patients with an unspecified subtype of ischemic stroke and damage to the right hemisphere of the brain.
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The purpose of this study was to perform a systematic review of the available literature on morphological and functional brain changes measured by modern neuroimaging techniques in patients suffering from chronic cancer-related pain. A systematic search was conducted in PubMed, Embase, and Web of Science using different keyword combinations. In addition, a hand search was performed on the reference lists and several databases to retrieve supplementary primary studies. Eligible articles were assessed for methodological quality and risk of bias and reviewed by two independent researchers. The search yielded only four studies, three of which used MRI and one PET-CT. None of the studies measured longitudinal morphological (i.e., gray or white matter) changes. All studies investigated functional brain changes and found differences in specific brain regions and networks between patients with chronic cancer-related pain and pain-free cancer patients or healthy volunteers. Some of these alterations were found in brain networks that also show changes in non-cancer populations with chronic pain (e.g., the default mode network and salience network). However, specific findings were inconsistent, and there was substantial variation in imaging methodology, analysis, sample size, and study quality. There is a striking lack of research on morphological brain changes in patients with chronic cancer-related pain. Moreover, only a few studies investigated functional brain changes. In the retrieved studies, there is some evidence that alterations occur in brain networks also involved in other chronic non-cancer pain syndromes. However, the low sample sizes of the studies, finding inconsistencies, and methodological heterogeneity do not allow for robust conclusions.
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Major depressive disorder (MDD) is associated with abnormal neural circuitry. It can be measured by assessing functional connectivity (FC) at resting-state functional MRI, that may help identifying neural markers of MDD and provide further efficient diagnosis and monitor treatment outcomes. The main aim of the present study is to investigate, in an unbiased way, functional alterations in patients with MDD using a large multi-center dataset from the PsyMRI consortium including 1546 participants from 19 centers (www.psymri.com). After applying strict exclusion criteria, the final sample consisted of 606 MDD patients (age: 35.8 ± 11.9 y.o.; females: 60.7%) and 476 healthy participants (age: 33.3 ± 11.0 y.o.; females: 56.7%). We found significant relative hypoconnectivity within somatosensory motor (SMN), salience (SN) networks and between SMN, SN, dorsal attention (DAN), and visual (VN) networks in MDD patients. No significant differences were detected within the default mode (DMN) and frontoparietal networks (FPN). In addition, alterations in network organization were observed in terms of significantly lower network segregation of SMN in MDD patients. Although medicated patients showed significantly lower FC within DMN, FPN, and SN than unmedicated patients, there were no differences between medicated and unmedicated groups in terms of network organization in SMN. We conclude that the network organization of cortical networks, involved in processing of sensory information, might be a more stable neuroimaging marker for MDD than previously assumed alterations in higher-order neural networks like DMN and FPN.
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This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2‐fold to 3‐fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2‐fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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Pain during adolescence is common and is associated with future pain chronicity and mental health in adulthood. However, understanding of the neural underpinnings of chronic pain has largely come from studies in adults, with recent studies in adolescents suggesting potentially unique neural features to this vulnerable developmental period. In addition to alterations in the pain network, resting state functional magnetic resonance imaging studies in adults suggest alterations in the default mode network (DMN), involved in internally-driven, self-referential thought, may underlie chronic pain; however, these findings have yet to be examined in adolescents. The current study sought to investigate associations between pain frequency and intensity, and disruptions in DMN connectivity, in adolescents. Adolescents (ages 12-20) with varying levels of pain frequency and intensity, recruited from a pediatric pain clinic and the local community (n = 86; 60% female), underwent resting state functional magnetic resonance imaging. Using independent components analysis, the DMN was identified and correlated voxel-wise to assess associations between pain frequency and intensity and DMN connectivity. Findings revealed that adolescents with greater pain frequency demonstrated greater DMN to superior frontal gyrus connectivity, while adolescents with greater pain intensity demonstrated greater DMN to cerebellum (lobule VIII) connectivity, during rest. These findings suggest that increasing levels of pain are associated with potential desegregation of the DMN and the prefrontal cortex, important for cognitive control, and with novel patterns of DMN to cerebellum connectivity. These findings may prove beneficial as neurobiological targets for future treatment efforts in adolescents.
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The parahippocampal gyrus–orbitofrontal cortex (PHG–OFC) circuit in humans is homologous to the postrhinal cortex (POR)–ventral lateral orbitofrontal cortex (vlOFC) circuit in rodents. Both are associated with visuospatial malfunctions in Alzheimer’s disease (AD). However, the underlying mechanisms remain to be elucidated. In this study, we explored the relationship between an impaired POR–vlOFC circuit and visuospatial memory deficits through retrograde tracing and in vivo local field potential recordings in 5XFAD mice, and investigated alterations of the PHG–OFC circuit by multi-domain magnetic resonance imaging (MRI) in patients on the AD spectrum. We demonstrated that an impaired glutamatergic POR–vlOFC circuit resulted in deficient visuospatial memory in 5XFAD mice. Moreover, MRI measurements of the PHG–OFC circuit had an accuracy of 77.33% for the classification of amnestic mild cognitive impairment converters versus non-converters. Thus, the PHG–OFC circuit explains the neuroanatomical basis of visuospatial memory deficits in AD, thereby providing a potential predictor for AD progression and a promising interventional approach for AD.
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Chronic pain is a major health problem, affecting 10–30% of the population in developed countries. While chronic pain is defined as “a persistent complaint of pain lasting for more than the usual period for recovery,” recently accumulated lines of evidence based on human brain imaging have revealed that chronic pain is not simply a sustained state of nociception, but rather an allostatic state established through gradually progressing plastic changes in the central nervous system. To visualize the brain activity associated with spontaneously occurring pain during the shift from acute to chronic pain under anesthetic-free conditions, we used manganese-enhanced magnetic resonance imaging (MEMRI) with a 9.4-T scanner to visualize neural activity-dependent accumulation of manganese in the brains of mice with hind paw inflammation. Time-differential analysis between 2- and 6-h after formalin injection to the left hind paw revealed a significantly increased MEMRI signal in various brain areas, including the right insular cortex, right nucleus accumbens, right globus pallidus, bilateral caudate putamen, right primary/secondary somatosensory cortex, bilateral thalamus, right amygdala, bilateral substantial nigra, and left ventral tegmental area. To analyze the role of the right amygdala in these post-formalin MEMRI signals, we repeatedly inhibited right amygdala neurons during this 2–6-h period using the “designer receptors exclusively activated by designer drugs” (DREADD) technique. Pharmacological activation of inhibitory DREADDs expressed in the right amygdala significantly attenuated MEMRI signals in the bilateral infralimbic cortex, bilateral nucleus accumbens, bilateral caudate putamen, right globus pallidus, bilateral ventral tegmental area, and bilateral substantia nigra, suggesting that the inflammatory pain-associated activation of these structures depends on the activity of the right amygdala and DREADD-expressing adjacent structures. In summary, the combined use of DREADD and MEMRI is a promising approach for revealing regions associated with spontaneous pain-associated brain activities and their causal relationships.
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During nociceptive processing of pain, activated regions, specified as the 'pain matrix', have been proven not selectively or preferentially tied to pain. Counterintuitively, the deactivated regions, especially the default mode network (DMN), are recently revealed to be simultaneously and functionally involved. In this study, we searched for pain-specific structural correlates among pain-free young adults using the voxel-based morphometry (VBM) approach within regions of interest comprising the pain matrix and DMN. Variances in confounding factors, namely the thermal detection threshold, thermal pain tolerance threshold and pain-related psychological traits, were statistically controlled to obtain pain-specific structural correlates. As a result, we found that less grey matter volume (GMV) of a critical DMN region, the precuneus, predicts enhanced thermal pain sensitivity (i.e., lower threshold). In contrast, this relationship is absent in all regions within the pain matrix. Such a dissociation between pain matrix and precuneus highlights the significance of precuneus in processing of pain, and is discussed with a conception taking pain as a salience detection system for the body, rather than as a nociceptive-specific system restricted within the so-called pain matrix.
Conference Paper
Background Thoracic Outlet Syndrome (TOS) is a syndrome involving compression at the thoracic inlet, which is known clinically as the superior thoracic outlet resulting from excess pressure placed on a neurovascular bundle passing between the Anterior Scalene and Middle Scalene muscles. It can affect one or more of the nerves that innervate the upper limb, specifically in the Brachial Plexus.Lymphedema is the most common complication and it is also the most disabling for women after breast cancer surgery. It is not a frequent cause of TOS, but the scar of breast surgery, the scar of lymphatic surgery and also the oedema can compress nerve structures of upper limb. Methods Two women have been studied because they suffered from cervical and dorsal pain associated with paresthesias in left upper limb for months. Paresthesias get worse in summer and with tight clothing, but mainly with deep breathing and Valsalva manoeuvre. Both had a precedent of breast cancer surgery with big scars in breast and underarm.The study started with a physical exam. We did not found Trigger Points in cervical or dorsal spine. The articular balance of spine was normal, but the right flex and rotation was difficult. Adson’s sign and the Costoclavicular manoeuvre were nonspecific, and Wright’s Test was positive. Tinnel and Fabere signs were also positive. We used an ultrasound study of Serratus Anterior muscle and Diaphragm muscle with Rusi technique. We also study with ultrasound the function of the shoulder and cervical muscles (Trapezius, Longus Colli and deep posterior spinal muscles). We applied for complementary test (like X-ray and Electromyogram) and we started Manual Lymphatic Drainage. Results Ultrasound study reveals an increase of skin and subcutaneous tissue thickness around the shoulder and arm, especially with isokinetic movements. The rest of the study was absolutely normal.After 15 drainage sessions the symptoms entirely disappeared (oedema, pain, restricted mobility and paresthesias). Complementary test was normal and a new ultrasound study was now completely normal. Conclusions Lymphedema after breast cancer surgery can cause a TOS with a compression of the brachial plexus. In these patients ultrasound can help with the differential diagnosis and it can be the unique test method.
Article
Radiation arteritis is a rare but serious complication following radiation therapy for the treatment of breast cancer. We present the case of a 53-year-old female presenting with right upper extremity claudication 4 months following radiation therapy for the treatment of right breast cancer, stage 3b invasive ductal carcinoma. She was referred to vascular surgery and initial imaging with computed tomography angiography (CTA) revealed occlusion from the origin of the subclavian to axillary artery. We discuss the implications that these vascular findings have on potential breast reconstruction options.