Investigation of the Neuro-electrostimulation Mechanisms by Means
of the Functional MRI: Case Study
Vladimir Kublanov
1
, Lubomir Aftanas
2
, Timur Petrenko
1
, Konstantin Danilenko
2
, Rezakova Maria
2
,
Aleksandr Efimtcev
3
, Mikhail Babich
1
, Anton Dolganov
1
and Andrei Sokolov
3
1
Ural Federal University, Mira 19, Yekaterinburg, Russian Federation
2
State Scientific-Research Institute of Physiology & Basic Medicine, Novosibirsk, Russian Federation
3
The Almazov National Medical Research Centre, St. Petersburg, Russian Federation
Keywords: Neuro-electrostimulation, Neuroimaging, Functional MRI, Head Injury.
Abstract: The article overviewed contemporary neuromodulation approaches and challenges. The importance of the
neurostimulation techniques was justified. The SYMPATHOCOR-01 neuro-electrostimulation device
characterization was presented. The case study of the neuro-electrostimulation mechanisms by means of the
neuroimaging was described. Case study consisted of 3 phases: imaging prior to the neuro-
electrostimulation procedure, imaging right after the neuro-electrostimulation procedure and imaging after a
5-day stimulation course. Results of the functional magnetic resonance imaging revealed improvement of
the functional connectivity strength in several brain regions as well as normalization of default mode
network activity.
1 INTRODUCTION
The relevance of new efficient methods
development for the central nervous system (CNS)
organic damages treatment is defined by the spread
of these diseases, aging of population, growth of
stress and technogenic factors (Zuliani et al. 2012).
To some extent, a barrier in the development is lack
of knowledge about the pathophysiological models
of the functional disorders in the human brain. It
justifies the necessity of contemporary methods
attraction for the investigation.
One of the most rapidly developing directions in
this sphere is the neuromodulation (Thin et al.
2013). However, the contemporary developments of
the neuro-electrostimulators, applied in the medical
practice, faces the high complexity of the nervous
system organization, including powerful
mechanisms of the adaptation to the external field’s
influence.
2 NEUROMODULATION
APPROACHES
At the moment, basic approach for the treatment of
central and peripheral nervous systems’ disorders is
the so-called neuroprotective therapy (Stocchi and
Olanow 2013). On the one hand, it improves
normalization and enhance physiological activity of
the neural tissue. On the other hand, it leads to
recovery of structural damage, caused by various
pathogenic effects, including traumatic, infectious-
inflammatory, vascular, and degenerative effects.
2.1 Physiological Mechanisms of the
Neural Adaptation
Generally, damage of the nervous systems, involves
whole complex of chains in the pathological process.
Clinically, it leads to numerous neurological, mental,
autonomic and regulatory disorders. Often it requires
application of not a single ‘universal’ drug, but a
complex therapy of the different medicines.
The situation becomes unfavorable, as
simultaneous usage of many drugs, accumulates not
Kublanov, V., Aftanas, L., Petrenko, T., Danilenko, K., Maria, R., Efimtcev, A., Babich, M., Dolganov, A. and Sokolov, A.
Investigation of the Neuro-electrostimulation Mechanisms by Means of the Functional MRI: Case Study.
DOI: 10.5220/0006712203190324
In Proceedings of the 11th International Joint Conference on Biomedical Engineering Systems and Technologies (BIOSTEC 2018) - Volume 4: BIOSIGNALS, pages 319-324
ISBN: 978-989-758-279-0
Copyright © 2018 by SCITEPRESS – Science and Technology Publications, Lda. All rights reserved
319
only treatment effects, but also the side effects,
which results from polypharmacy. In case of
polypharmacy, the side effects suppress therapeutic
effects, and the treatment becomes ineffective and
dangerous (Maher et al. 2014).
Described situation is especially unfavorable in
cases when treatment interferes with the natural
regulatory and adaptive process of the CNS,
essentially acting as the stress-factor. In this case,
stress adaptation systems take up work. These
systems represent sophisticated regulatory complex,
which is crucial for the activation and coordination
of all changes in the organisms as response to the
stress.
Through both, self-regulation process and
external regulation the stress system is implemented.
The self-regulation of the stress system is based on
feedback principles: adrenocorticotropic hormone
(ACTH), cortisol and brain structures are
fundamental (Jovanovic et al. 2010). Mechanisms of
the external regulation are implemented by the
stress-limiting system, which constrains stress
system activity and excessive stress-reaction on
central and periphery scale. Сentral scale includes
GABAergic, opioidergic and serotoninergic systems;
whereas the periphery scale includes adenosine,
prostaglandins and antioxidant system, as well as the
NO generation system (Stahl and Wise 2008).
Moreover, the endogenic neuropeptids, like
substance P, Brain-derived neurotrophic factor
(BDNF) and others, are also important for the stress
reaction regulation. (Dupont et al. 1981, Rothman et
al. 2012). At the same time, complex neurohumoral
mechanisms of the stress-realizing and stress-
limiting interaction, organize multiphasic adaptation
reaction of the organism (Holaday 1983, Knapman
et al. 2012).
Furthermore, in case of a stress, caused by the
disease, by the direct and side-effects of the drugs,
complicated mechanisms of immune system
disorders are implemented. Immune system disorder
may result in the secondary immunodeficiency state
of the neurogenic origin (Turnbull and Rivier 1999,
Kronfol and Remick 2000, Davis et al. 2008).
If one improves the adaptive possibilities of
autonomic regulation, then central regulation
mechanisms come to help. Central regulation
mechanisms include direct control of endocrine,
immune, cardiovascular and digestive systems, by
means of the comprehensive communication
networks of neurohumoral interaction, hormones,
neuromediators and immunotoxic agents (Dedovic et
al. 2009).
2.2 Therapeutic Techniques
There is a tendency to assume, that the basis of the
neuro-protective therapy are numerous medicines,
which have wide range of action mechanisms and
pharmacokinetic properties. Different medicines
affect on range of the pathogenetic components of
the particular pathologic process (Greenberg et al.
2009).
However, the pharmacological approach is
effective only among the one third of the patients. In
most cases, the life-long drug regimen is implied,
which is accompanied by the quantity side effects.
Essentially, the pharmacological approach is just a
substitution therapy and does not treat the disorder
itself (Stahl and Moore 2013).
2.3 Neuro-electrostimulation
Techniques
During recent years, a number of investigations have
intensified for the universal and less harmful
neuroprotection techniques. Such techniques were
labeled as neurostimulation (Charleston et al. 2010).
To the date numerous data on specific
neurostimulation techniques application have been
accumulated. A number of such key features can
classify such techniques:
exposure area brain, spinal cord, periphery
nerves;
invasive and non-invasive techniques;
physiological properties of stimulated neural
structures - afferent and efferent stimulation;
mechanism of the stimulation internal and
external stimulation;
the size of stimulated neural tissues local
and general stimulation;
physical nature of the stimulating factor
magnetic, electric, ultrasound, optic
stimulation.
One can obtain different clinical effects of the
neurostimulation depending on the stimulated
department of the nervous system. In either case, the
nervous system performs the integral function and
provide interconnected regulation of whole organism
systems activities. It means that neurostimulation
effects are not limited by the nervous system itself,
but also can influence the variety of processes in the
organism as a whole.
Contrary to the complex medicines therapy,
proper application of the physical neurostimulation
does not cause additional stress reactions of the
organism, as it does not actively interfere in
NENT 2018 - Special Session on Neuro-electrostimulation in Neurorehabilitation Tasks
320
regulatory, biochemical and immune process of the
organism. This fact allows widely applying
neurostimulation techniques for the medical
rehabilitation in many pathological cases.
It is of great interest to find new targets and
technical means of neurostimulation, based on the
anatomical knowledge and knowledge of the
nervous system physiology, for the particular
medical tasks.
2.4 SYMPATHOCOR-01 Device
The SYMPATHOCOR-01 device implements the
technology of multi-channel neuro-
electrostimulation. Spatially distributed physical
field is formed: its features are in accordance with
endogenic process in the neural structures. This
technology allows managing activity of the
conducting formations and performs the
neuromodulation process. The medical application
of the SYMPATHOCOR-01 device is implemented
as the DCASNS technique - Dynamic Correction of
the Sympathetic Nervous System Activity. The
DCASNS technique provides correction of
autonomic balance, defined by the relation between
the activities of the parasympathetic and sympathetic
departments of the autonomic nervous system
(ANS) (Kublanov, Shmirev, et al. 2010).
At present, the SYMPATHOCOR-01 device is
applied in the clinical practice to correct and control
the following pathologies: migraine,
neurocirculatory dystonia, traumatic brain injury and
brain concussion, alcohol and narcotic abstinences,
hypertonic diseases, obliterate atherosclerosis of the
lower limbs, Raynauds disease, trigeminal nerve
inflammation, sensorineural deafness, degenerative
diseases of vision and atrophy of the optical nerve,
osteochondrosis of the back bone, neuropathies of
various genesis, cephalalgia syndrome,
hyperhidrosis syndrome, syndrome of the orthostatic
hyposthenia and postural tachycardia, vestibular
disease, vegetative deregulation syndrome, epilepsy
(Kublanov et al. 2017).
The design process of the SYMPATHOCOR-01
device medical application was accomponied by the
experimental studies on laboratory animals by
modelling the chronical pathological (muscle
ischemia) and the actute (immobilising stress) states
(Kublanov, Danilova, et al. 2010, Kublanov et al.
2012).
For pathological state, in the previous works was
noted that on organs and tissue level the blood
supply recovery is associated with increase in the
number of the capillaries. On the cross-section of the
muscle, after the neuro-electrostimulation
application, the swelling, which is characteristic for
the ischemia case, was also decreased. Moreover,
the visually noted recovery of the transverse
striation, define the regeneration of the muscle
tissues. On the cellular level, the decrease of the
permeability of the damaged membranes is noted.
On the molecular level, the endogenic toxins number
was reduced.
For the acute state, after a single procedure of
the neuro-electrostimulation, the motion activity had
a tendency towards the normalization. On the cell
level, the increased membranes permeability of the
cells and muscle fibers did not worsen. On the
organism level, the behavior reaction changed: the
adaptation to the immobilized stress was improved
and the animal became less aggressive.
The single-photon emission computed
tomography images have shown that the neuro-
electrostimulation by the ‘SYMPATHOCOR-01’
device allows to change neurogenic regulation of the
vascular tone, to improve neurometabolism in the
brain, to suppress epileptic activity, stimulating
neurotransmission, to recover intracerebral
connections (Kublanov et al. 2004).
Emergence of the modern neurovisualization
methods opens the possibilities in the neuroplasticity
investigation. In particular, functional magnetic
resonance imaging (fMRI), which is an intravital
non-invasive dynamic investigation of active brain
structures during their functioning. The fMRI
method is based on different properties of
oxyhemoglobin, carrier of O
2
, and
deoxyhemoglobin, a product formed in the brain
parenchyma in magnetic field. This proportion is
reflected by the BOLD-phenomenon (blood
oxygenation level independent), a marker of
neuronal activity. Stereotyped or, on the contrary,
heuristic actions as well as sensorimotor, visual-
auditory, and speech operations are associated with
the formation and/or reorganization of preexisting
neuronal ensembles (NE) in the brain. Their activity,
being spontaneous or produced by the environment,
appears as an increase of local blood filling of the
brain tissue and in modulation of the mechanisms of
blood flow rate and volume regulation in the brain
(Savostyanov et al. 2016).
The goal of the current pilot study is to
investigate the influence of the SYMPATHOCOR-
01 stimulation by means of the functional
neurovisualisation.
Investigation of the Neuro-electrostimulation Mechanisms by Means of the Functional MRI: Case Study
321
3 CLINICAL CASE STUDY
In the December of 2016, at the State Scientific-
Research Institute of Physiology & Basic Medicine,
the pilot study of the hemodynamic reactions,
caused by the neuronal activity of the brain, by
means of the fMRI, was conducted.
Single male patient K., age 25, diagnosed with
ICD T90.5 (Sequelae of intracranial injury), has
participated in the pilot study. The patient K. has
signed the informative participation consent. The
study was carried out on the MR system GE
Discovery MR750W, 3.0 Tesla, in accordance with
the following protocols:
1) T1 SPGR 3D reconstruction, up to 256 cross-
sections, voxel size 1 mm3; mandatory
capturing the whole head surface, including
nose and ears;
2) fMRI in the resting state mode, and in visual
stimuli presentation mode (33 cross-sections,
thickness up to 4,5 mm)
3) tractography (diffusion tensor imaging - DTI,
72 cross-sections, 2 mm each; 64 directions)
4) T2-WI, FLAIR (weighted images for
exclusion of the chronic gliosis sources). The
stimuli were send by means of the Nordic
NeuroLab BrainEx.
For registration to standard space a T1 high-
resolution 3D MPRAGE (magnetization prepared
rapid gradient echo) was performed. with the
following scan parameters: repetition time (TR) = 2.5
s, echo time (TE) = 3.52 ms, 190 sagittal slices with
no gap, field-of-view (FoV) = 230 mm, flip angle
(FA) = 8°, in-plane resolution = 1.2×1.2 mm2, slice
thickness = 1.2 mm. During RS-fMRI acquisition,
using gradient echo T2* weighted EPI, participant
was instructed to keep the eyes closed and not to
think about anything. The imaging parameters were:
100 volumes, TR = 3 s, TE = 52 ms, FA = 90°, 28
interleaved slices, slice thickness = 5 mm, imaging
matrix 64×64 and FoV = 220 mm.
The study timeline is presented in the table 1.
Table 1: Study timeline.
I phase
II phase
III phase
-T1-sag
-RS
-Visual Nordic
-DTI
-MRA
-T1-sag
-Visual Nordic
-DTI
-MRA
-T1-sag
-RS
-Visual Nordic
-DTI
-MRA
Here:
T1-sag weighted image in the sagittal projection;
RS - resting state functional MRI (BOLD signal);
Visual Nordic functional MRI in the visual stimuli
paradigm (activation of the visual cortical areas);
MRA - MR-angiography, a medical test that helps
physicians diagnose and treat medical conditions
and diseases of the blood vessels.
The first phase was conducted for the baseline
state evaluation. The second phase was conducted
immediately after the neuro-electostimulation
procedure in order to evaluate short-term reaction of
the CNS. The third phase was conducted 3 days after
5 procedures of the DCASNS in order to evaluate
long term reaction of the CNS. The biotropic field
features of the SYMPATHOCOR-01 were set in
accordance with the DCASNS technique. There
were two 30-minutes procedure every day.
Data were analysed using Matlab (SPM12,
CONN14). For a ROI-based analysis, Medial
Prefrontal Cortex was chosen as a seed ROI, as it is
considered a part of default mode network (DMN).
4 RESULTS
The one-sample t-test showed spatial pattern of
activation (connectivity) and deactivation in DMN.
In I and II phases along decreased functional
connectivity in DMN, following changes were
identified:
increased negative functional connectivity
strength (FCs) with Anterior and Dorsolateral
Prefrontal Cortex (BA9, BA46),
decreased positive FCs with Ventral
Posterior Cingulate Cortex (BA31), Premotor
(BA6) and Somatosensory Cortex (BA7).
In phase III positive FCs with Angular Gyrus
(BA39), Dorsal Posterior Cingulate Cortex (BA 31),
Dorsal Frontal Cortex (BA8), Associative Visual
Cortex (BA19), Orbitofrontal Cortex (BA11),
Inferior Prefrontal Gyrus (BA47) appeared stronger.
Although less areas of deactivation were present.
Besides, the whole DMN activity showed symmetry.
In phase II a slight increase in overall activation
strength was noted.
The participant suffered periodic headaches of a
pressing nature without a clear localization,
provoked by increased physical and emotional
stress, as well as excessive sleep, and episodic
tension headaches. With that in mind, we can
outline, that, regarding DMN activity, stress induced
functional connectivity alterations took place
initially in the medial prefrontal cortex, medial
orbitofrontal cortex, posterior cingulate cortex and
some other regions. The follow-up examination
showed definite normalization of DMN activity.
NENT 2018 - Special Session on Neuro-electrostimulation in Neurorehabilitation Tasks
322
Figure 1: I phase prior to the treatment.
Figure 2: II phase after a single DCASNS procedure.
Figure 3: III phase after 5 DCASNS procedures.
5 CONCLUSIONS
Results of the SYMPATHOCOR-01 neuro-
electrostimulation effects by means of the functional
neuroimaging allowed revealing areas of the most
active changes in the brain tissues. One can claim
that effect of the SYMPATHOCOR-01 device is
spreading from the neck area through the afferent
conducting paths up to the cortical formations of the
brain.
Obtained in the pilot study data allows to
consider the fMRI technology as the promising tool
for the neuro-electrostimulation mechanisms
investigation. The data could also form new
treatment techniques of the non-invasive multi-
electrode neck neural structures electrosimulation
application for treatment of the psychiatric and
neurological disorders. Namely, disorders
accompanied by the neurodeheneration (Alzheimer
disease, Parkinson disease, dementias);
consequences of the brain traumas, neurotoxications,
depressive and anxiety disorders, strokes.
ACKNOWLEDGEMENTS
The work was supported by Act 211 Government of
the Russian Federation, contract 02.A03.21.0006.
The authors thank Ivan Brak, Elena Filimonova and
Eugenia Kobeleva for participation in the data
processing.
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