Investigation of the Neuro-electrostimulation Mechanisms by Means

of the Functional MRI: Case Study

Vladimir Kublanov

, Lubomir Aftanas

, Timur Petrenko

, Konstantin Danilenko

, Rezakova Maria

Aleksandr Efimtcev

, Mikhail Babich

, Anton Dolganov

and Andrei Sokolov

Ural Federal University, Mira 19, Yekaterinburg, Russian Federation

State Scientific-Research Institute of Physiology & Basic Medicine, Novosibirsk, Russian Federation

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

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, Raynaud’s 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

, 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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