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Non-Invasive Multi-Channel Neuro-Stimulators In Treatment Of The
Nervous System Disorders
Y.P. Danilov1, V.S. Kublanov2, K.Ju. Retjunskij2, T.S. Petrenko2, M.V. Babich2
1 Tactile Communication and Neuromodulation Laboratory, Biomedical Engineering Department, University of Wisconsin-
Madison, 1550 Engineering Drive, Madison, WI, 52706, USA
2 Research Medical and Biological Engineering Center of High Technologies, Institute of Radio Engineering and
Information Technology, Ural Federal University, Mira Str., 32, Yekaterinburg, 620002, Russia
ydanilov@wisc.edu, kublanov@mail.ru
Keywords: Neurostimulation, Neurorehabilitation, Non-invasive, Medical Device.
Abstract: Approaches of non-invasive neuromodulation organization for rehabilitation brain injuries outcomes and
psycho-emotional disorders are discussed. One of technologies based on electrocutaneous stimulation of the
tongue (CN-NINM), and other technology based on transcutaneous stimulation of the neck
(SYMPATHOCORRECTION). Currently, two portable devices were developed and introduced in clinical
practice: PoNSTM and SYMPATHOCOR. Both technologies are complement each other and demonstrate
perspectives in various applications for purpose of neurorehabilitation and neurological symptoms
management in such difficult for rehabilitation areas, as traumatic brain injury, stroke, Parkinson’s disease,
multiple sclerosis and many other neurological disorders.
1 INTRODUCTION
The brain injuries and psycho-emotional disorders are
among the leading causes of severe human
neurological disabilities and high mortality rate. The
most common approach to treat such disorders is the
neuroprotective therapy. Indeed, such a therapy
facilitates, in some extent, the normalization and
strengthening the physiological activity of the brain
tissues. It is also can help to repair the system
damages inflicted by various kinds of pathogenic
impacts (traumatic, inflectional, inflammatory,
vascular, degenerative, etc.).
In general, the neuro-protective therapy is based
on the combinations of drug therapy with another
kind of therapies (physical, cognitive, speech, etc.)
that oriented on different symptoms, have an impact
on different mechanisms and affect various
physiological mechanisms and biochemical
pathways. Eventually, all these means affect various
components of a pathogenic process under treating
(Greenberg, 2009).
Recently, the low effectiveness of the traditional
methods has stimulated the development of new
approaches and methods of the neuroprotection,
which should be less dangerous, more effective and
non-invasive. During last decade, the whole family of
such methods have been discovered, based on various
forms of physical impact on the neural system. All
these methods were called the neurostimulation
methods. Multiple studies demonstrate the efficiency
of such neurostimulation methods and the perspective
in use of non-invasive technologies for rehabilitation
of the full spectrum of neural disorders. It has become
especially important for age-related disorders,
considering the growth of the human life span and the
wave of retirement of “baby-boomers” generation.
2 PATHOPHYSIOLOGICAL
PECULIARITIES OF THE
NERVOUS SYSTEM
DISORDERS
Any damage of the central nervous system leads to
many pathological processes and affects numerous
structural parts, pathways and physiological
mechanisms. In clinics, these phenomena appear in
multiple neurological, psychological, vegetative, and
regulatory damages. The “multidimensional” damage
needs the “multidimensional” treatment. Apparently,
instead of one "universal," fit-for-all" medical mean,
the complex therapy should be applied, as a
combination of different methods and technologies
that applied simultaneously can facilitate each other.
However, in case of drugs, such combination can
become very dangerous, because simultaneous use of
several medications can lead to summation of drug
side-effects, lead to the increasing adverse effects. In
this case, the positive treatment effects become
slower. The treatment becomes ineffective and even
harmful for the patient’s life.
This situation becomes even more dangerous
when the treatment interferes with the natural
regulatory and adaptive processes of the nervous
system, and, essentially, these interventions become
the stress factors. As a result, the corresponding
systems are reacting properly, initiating the stress
adaptation mechanisms. It is initiating a composite
regulatory complex that plays the main role in
activation and coordination of all changes in the
patient’s organism in a response to the stress.
Such system, so-called stress-system, is based on
mechanisms both self-regulation and outer-
regulation. The self-regulation of the stress-releasing
system is built on the feedback principle, where the
main role is played by the adrenal-corticotrophin
hormone, cortisol, and several other components of
the brain (Davis, 2008). The outer-regulation
mechanisms are released by the so-called stress-
limiting system that limits activity of the stress-
system and excessive stress-reaction on the central
and periphery levels. The central levels are consisted
of the GABA-ergic, opioid-ergic, and serotonin-ergic
systems. The peripheral level includes the adenosine,
prostaglandins, and antioxidant systems, and,
additionally, the nitrate-oxide generation system
(Stahl, 2008).
Moreover, there are also other factors that play an
important role in the stress-reaction regulation. Those
are the endogenous neuropeptides (the substance P),
the brain growth factors, and some others (Dupont,
1981; Rothman, 2012). Therefore, the organization of
complicated multi-phase adaptation reaction (during
the stress) is provided by complex neurohumoral
mechanisms of interaction between the stress-
releasing and stress-limiting systems (Holaday, 1983;
Knapman, 2012).
Considering, that the stress is caused by both the
disease itself and the combination of direct and side
effects of several applied drugs, there is a high
probability of the immune system damages that can
lead to, so called, secondary immune-deficit state,
abnormal condition of the neurogenic origin
(Turnbull, 1999; Kronfol, 2000).
If adaptation performance of the neural regulation
is exceeded the natural limits, then the central
regulatory mechanisms should be initiated. It includes
the direct control of the endocrine, immune, cardio-
vascular, and digestive systems. This new level of
activation is implemented by complex
communication networks, including the
neurohumoral interactions, hormones,
neuromediators, and immunotoxic agents (McEwen,
2009; Dedovic, 2009).
Such natural basic and fundamental regulation
systems eventually become the primary target for
development of new neurostimulation methods.
3 SPECIFICITY OF
NEUROSTIMULATION
SYSTEMS
The non-medication methods of neuro-stimulation
can be classified by the following key features:
Depending on the part of nervous system involved in
activation, different clinical effects of the
neurostimulation can be obtained. Therefore, the non-
medication neurostimulation can modulate various
processes in the human body.
In contrast to the traditional pharmacotherapy, the
neurostimulation methods do not change directly the
balance of neurochemical and molecular compounds
in the regulatory, biochemical, and immune processes
in the organism. As a result, the non-invasive
neurostimulation (if applied properly) does not have
unwanted side effects and do not cause evident
additional stress-reaction of the organism. It is an
open wide spectrum of application of the
neurostimulation methods in the rehabilitation of
many kinds of pathologies.
To solve particular medical problems, it is
necessary to find the appropriate “targets” and
conditions for technical implementation of adequate
neurostimulation, based on the pathophysiology of
disorder and the knowledge of anatomy and
physiology of the CNS and pattern of innervation of
affected organs and systems.
In our investigations, the specific regions of the
neck and the dorsal surface of the tongue were chosen
as new targets for the transcutaneous electrical
neurostimulation.
There are several reasons why these areas were
selected as perspective targets:
Both the neck and tongue regions are located in
the close proximity of the major structures of the CNS
(brainstem, cerebellum and cranial nerve ganglia) and
its main sensory, motor and autonomic control
systems, i.e., close to structures of the vegetative
nervous system (VNS, both the sympathetic and
parasympathetic) on the level of its over-segmental
and segmental sections.
Regulating and controlling many functions of the
organism, these structures of the VNS essentially
control intimate mechanisms of compensation and
adaptation to various damaging factors of the outer
and internal environment. This determines
importance of the VNS in creating the prerequisites
and development of disorders. Therefore, the
malfunctioning in the work of the VNS can be
represented by its own nosologic forms, and at the
same time. The abnormal functions of VNS can go
together with many wide-spread disorders.
Considering, that even the treatment of pathological
processes in the VNS itself is rather problematic, it is
not surprising, that the vegetative disorders as
accompanied symptoms frequently are not the targets
of the major treatment at all.
Indeed, during stimulation of the neck and tongue
regions it is possible to impacts both the
parasympathetic and sympathetic structures of the
VNS and to affect the ascending afferent conductive
pathways, and correspond centers in the brainstem,
subcortical and cortical areas of the brain.
The neck section of the sympathetic stem consists
of three nodes and inter-node connection branches
that are located in the deep neck muscles behind the
pre-spinal plate of the neck fascia. Incoming afferent
fibers are coming from the vegetative cores of the
lateral intermediate (gray) substance of the eighth
neck and six-seven upper pectoral segments of the
spinal cord through the inter-node branches of the
pectoral section of the sympathetic stem.
The efferent branches (coming out of the neck
node) contain the post-ganglion sympathetic fibers
passing close to the upper nerves of spinal cord and
cranial nerves (glossopharyngeal, vagal, additional,
and hypoglossal) and next to the outer and internal
carotid arteries and other near located blood vessels.
The parasympathetic nervous system in the neck
region is represented by components of the
pneumogastric or vagal nerve. Moreover, on the neck
level from this nerve came out pharyngeal, laryngeal,
and heart branches that participate in innervations and
regulations of muscles and mucous membrane of the
pharynx, larynx, trachea, esophagus, tongue root,
thyroid and near-thyroid glands, thymus,
myocardium, and lungs (by creating the lung plexus).
The oral cavity, including the tongue, is
intensively innerved by the motor, sensory, and
secretion control fibers. The motor, sensory, and taste
fibers are parts of the cranial nerve system. The
multiple glands of oral cavity are controlled by VNS
fibers divided into sympathetic and parasympathetic
ones. In total, five out of twelve cerebral nerves
participate in innervations of the tongue and oral
cavity. Those are the following nerves: trigeminal,
facial, hypoglossal, glossopharyngeal and pharyngeal
ones. The mentioned above five nerves (that innerve
the walls and organs in the oral cavity) have nuclei in
the brainstem just under the rhomboid fossa. These
cores are divided into motor, sensory, and vegetative
(autonomic) ones.
Both non-invasive multichannel neurostimulation
methods allow directly affect VNS for purpose of
neurorehabilitation. It is well known, that in control
of complex objects, the effectiveness of control is
increasing proportionally to degree of freedom of the
control system (McEwen, 2009). Considering the
neuro-stimulation problems, this rule can be applied
by extension of the control abilities by increasing the
number of specific ways of the neural structure's
activation. The stimulation effectiveness can be also
improved by using bio-tropic parameters of
stimulation signals similar to parameters of internal
processes.
In neurostimulation systems, the application of
low-frequency impulse series of one polarity current
seems to be perspective, especially in combination of
the multi-channel neuro-stimulation with
computerized process control.
In this article, we are presenting two original
multi-channel portable systems for noninvasive
stimulation of the tongue (PoNS device) and the neck
area (SYMPATHOCOR device) for purpose of
neurorehabilitation of sensory, motor and autonomic
functions.
Block diagram of the engineering feasibility of
multi-channel neurostimulation systems is shown in
Fig.1.
Figure 1: Block diagram of the engineering feasibility of
multi-channel neurostimulation systems.
3.1 CN-NINM Technology
The portable neuromodulation stimulator (PoNS™)
is an electrical pulse generator that delivers carefully-
controlled electrical stimulation to the tongue. The
pulses are generated and controlled by commercially
available counter, timer, and wave-shaping electronic
components. The components are mounted on a
single printed circuit board (Fig. 2). The circuit board
contains 143 gold-plated electrodes that contact the
tongue. A rechargeable lithium-polymer battery with
built-in charge safety circuitry provides the power.
Figure 2: PoNS device.
The PoNSTM device is placed in the mouth and has
been investigated in conjunction with physical
therapy for treatment of balance and gait disorders
caused by a variety of etiologies, including the
traumatic brain injury, multiple sclerosis, central and
peripheral vestibular disorder, migraine-related
balance disorder, chronic Meniere’s disease,
spinocerebellar ataxia, gentamicin ototoxicity,
idiopathic cerebellar ataxia, idiopathic vestibular
disorder, and cerebellar infarction (Danilov, 2007;
Wildenberg, 2010; Tyler, 2014).
The device is easily held at the place by the lips
and teeth around the neck of the tab that goes into the
mouth and rests on the anterior superior part of the
tongue. The paddle-shaped tab of the device has a
hexagonally patterned array of 143 gold-plated
circular electrodes (1.50 mm diameter, on 2.34 mm
centers). The array is created by a photolithograph
process used to make printed circuit boards. It uses
the low-level electrical current to stimulate the lingual
branch projections of at least two cranial nerves in the
tongue anterior through the gold-plated electrodes.
Device function is user-controlled by four buttons:
On, Off, Intensity 'Up', and Intensity 'Down'. The
system delivers triplets of 0.4 – 60 µs wide pulses at
5 ms intervals (i.e., of 200 Hz) every 20 ms (50 Hz)
that has been designed to achieve a balance of
stimulus dynamic range and sensation quality. The
sensation produced by the array is similar to the
feeling of drinking a carbonated beverage. The
system has operational limits of 19V (max) on the
tongue (a nominal 5–7 kOhm load). The biphasic
waveform is specifically designed to ensure zero net
DC current to minimize the potential for the tissue
irritation.
The current hypothesis for the underlying
mechanism by which the PoNS™ Cranial Nerve
Noninvasive Neuromodulation (CN-NINM)
stimulation leads to sustained neuromodulation (and
subsequent therapeutic effect) comes from previous
FMRI studies using optokinetic visual stimulation to
activate regions involved in processing balance
information (Wildenberg, 2010). Cortical procession
of the motion is performed primarily by the motion
sensitive visual cortex (hMT+).
Previous work from our group investigating
network behavior after the CN-NINM (Cranial Nerve
Noninvasive Neuromodulation) showed
hypersensitivity of the balance-processing network in
individuals with balance dysfunction compared to
healthy controls. The network behavior normalized
after the CN-NINM therapy. A high-resolution study
of activity within the brainstem suggested that the
trigeminal nucleus, the point at which afferents from
the tongue enter the central nervous system, had
altered neural responses to motion in the visual field
after stimulation.
We hypothesize that spatio-temporal trains of
spikes induced in the trigeminal and facial nerves by
electrical stimulation of the tongue produce changes
of activity in corresponding nuclei of the brainstem,
namely, at least in the sensory and spinal nuclei of
trigeminal nuclei complex (the largest nuclei in the
brainstem, extending from the midbrain to the nuclei
of the descending spinal tracts), and in the nucleus
tractus solitarius where both stimulated nerves have
direct projections. We postulate that intensive
activation of these structures initiates a sequential
cascade of changes in neighboring and/or connected
nuclei by direct collaterals, interneuron circuitry, or
passive transmission of biochemical compounds in
the intercellular space. Accordingly, electrotactile
stimulation of cranial nerve endings, particularly in
the lingual tract of the trigeminal and the facial nerve,
initiate activity in the corresponding nuclei similar to
long-term potentiation/inhibition, which, in the turn,
increases the receptivity of multiple neural circuitries
and/or affect internal mechanisms of homeostatic
regulation.
This, in the turn, causes radiating therapeutic
neurochemical and neurophysiological changes
affecting both neural and glial networks affecting
information processing of afferent and efferent neural
signals involved in the motion control, including the
cerebellum and nuclei of spinal motor pathways. PET
scans study on the blind subjects before and after
training with the visual sensory substitution system
via the tongue stimulation (electrotactile feedback)
system demonstrates massive activation in cortical
and subcortical levels of the brain (Kronfol, 2000). It
may also increase the receptivity of multiple neural
circuitries and/or affect internal mechanisms of
homeostatic regulation according to the
contemporary concept of synaptic plasticity. We as
well cannot exclude also that this induces
simultaneous activation of serotoninergic and
noradrenalinergic regulation systems components
located in the brainstem.
In the course of testing and training numerous
persons having a primary indication of balance and
gait disorder using the balance recovery therapeutic
method we developed, we observed therapeutic
benefits well beyond balance (attention, memory,
multitasking, vision, fine motor control, sleep,
tremor, tinnitus) regardless of their etiology
(peripheral vestibular, central or idiopathic vestibular
loss, cerebellar stroke, Meniere's, Parkinson's, MS).
3.2 SYMPATHOCORRECTION
Technology
The portable corrector of activity of the sympathetic
nervous system (SYMPATHOCOR) is an electrical
pulse generator that delivers the spatially-distributed
field of the carefully-controlled current pulses in the
neck (Kublanov, 2008). The general view of the
SYMPATHOCOR device is presented in Fig. 3.
Figure 3: The general view of the SYMPATHOCOR
device.
The spatially-distributed field of the current
impulses in the SYMPATHOCOR device is formed
between two multi-element electrodes. Each
electrode comprises a cluster of thirteen partial
current-conducting elements with galvanic isolation
of each other. The multi-element electrodes are
arranged on the neck into left and right arrays. In the
working state, the central element of one array plays
the role of the anode. Electrodes on the other side
become the cathodes. If it is necessary, the
arrangement can be reversed in opposite direction.
Placing the multi-element electrodes on the
subject neck, the anodes have to be located in
projections of the neck ganglia of the sympathetic
nervous system (Fig.4).
Figure 4: Scheme of location (on the patient ‘neck) for the
partial current-conducting elements of the multi-element
electrodes.
The electric current impulses are delivered to the
partial elements of the multi-element array from the
processor through the multi-channel switch. At each
instant moment, the impulse of current is formed only
between only one partial cathode element and the
anode partial element on the opposite side of the neck.
Therefore, the current flows between the opposite
multi-element electrodes across the neck. The spatio-
temporal pattern of stimulation is controlled by
processor, using specially developed software. Such
control provides the necessary input information on
variation of structure of the spatially-distributed field
of the current and implements pre-calculated pattern
for activation the partial cathodes. Pre-calculated
pattern was designed to manipulate continuously
changing vectors of the current and provide the
maximum current density (onto the volume unit) in
the active anode zone.
Note the following basic bio-tropic characteristics
of the field: the current partial impulse length is from
20 to 60 -sec. The number of partial impulses in the
period (impulse group) is 12. The frequency of
impulse group is from 10 to 150 Hz. The partial
electrodes are switched accordingly to each given rule
(for example, a pseudo-random with the clockwise or
counterclockwise direction of switching, and so on).
The current impulse amplitude can be up to 20 mA.
SYMPATHOCORRECTION Technology is a
method of the dynamic correction of the activity
sympathetic nervous system is used for the neck
neuro-stimulation in limits of the “homeostatic
corridor," under which the vegetative regulation is not
violated (Kublanov, 2010).
Depending on pathogenesis of the peripheral or
central dysfunctions of the vegetative nervous
system, the dynamic correction of the activity
sympathetic nervous system algorithm has two
different branches. Decision of which branch should
be executed is based on nature of the VNS
dysfunction. The bio-tropic parameters of the
implemented current impulse field (the field
structure, impulse amplitude, frequency, and length)
are calculated from the analysis of the heart rhythm
variability. In particular, in the case of the abnormal
hyperactivity of sympathic innervation, it is necessary
to block or suppress the activity of the sympathetic
nervous system. In contrast, sympathic innervation
should be increased, if the hyperactivity of the
parasympathic innervation is observed.
In case of central dysfunctions, the bio-tropic
parameters of the stimulation field are calculated,
based on analysis of the main activity rhythms of the
cerebral cortex and its deviation from the norm.
The first model of the SYMPATHOCOR unit is
certified for fabrication, marketing, and application
on the Russian Federation territory. In clinic
practice, the SYMPATHOCOR device and the
dynamic correction of the activity sympathetic
nervous system technology are efficiently applied to
treatment (Kublanov, 2010):
Diseases involving organic and / or functional
disorders of the CNS and / or the VNS:
consequences of trauma or stroke, epilepsy,
chronic headache, somatoform disorders,
anxiety and depressive spectrum disorders,
attention-deficit hyperactivity and tic disorder,
consequences of alcoholism, disorders of
autonomic nervous system, hypertension and
its consequences;
Diseases associated with impaired visual,
auditory and vestibular function.
4 CONCLUSIONS
Analysis of topological structures of the neural
network of the neck and tongue shows that the
structures affected by neurostimulation are organized
in the similar way. The primary activation targets
have several common components (e.g. solitary
nucleus) and spectrums of observed effects for both
neurostimulation systems are significantly
overlapped. Therefore, both presented technologies
are complimentary to each other. The CN-NINM
technology primarily affects sensory-motor
integration in CNS and partially autonomic system.
The DCASNS technology is affecting primarily VNS
and partially sensory-motor integration. Both
technologies can affect cognitive (memory, attention)
and psychosocial (depression and anxiety) functions
as well.
Considering the complimentary nature of both
systems, the results of pilot research and experience
in the clinical applications of the PoNS and
SYMPATHOCOR units, we can recommend the
parallel use of the neck and tongue neurostimulation
in the rehabilitation process. It has become especially
important in cases of the brain polytrauma or multiple
functional damage after stroke, moderate traumatic
brain injury or in advanced stage of multiple sclerosis.
Moreover, it can be the only way, non-invasively, to
recover various autonomic functions – bladder and
bowl control, GI motility, hypertension, etc.
The result of this transcutaneous non-invasive
neurostimulation is essentially brain plasticity on
demand, i.e., a priming or up-regulating of targeted
neural structures to develop new working pathway
that is the goal of neurorehabilitation and a primary
means of functional recovery from permanent
physical damage caused by a stroke or trauma, by
neurodevelopmental or by neurodegenerative
disorders.
We believe on the theoretical grounds that both
neurostimulation systems activate and synchronizes
several large brainstem nuclei and the cerebellum,
neck ganglia and VNS centers enabling the beneficial
neuroplastic changes in multiple CNS and VNS
control circuitries. We envision the application of
these technologies to functional recovery to the broad
range of sensory, motor, cognitive, autonomic and
mood disorders.
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