Neurotherapy

Neurotherapy is medical treatment that implements systemic targeted delivery of an energy stimulus or chemical agents to a specific neurological zone in the body to alter neuronal activity and stimulate neuroplasticity in a way that develops (or balances) a nervous system in order to treat different diseases, restore and/or to improve patients' physical strength, cognitive functions, and overall health.^[3][4][5]

Synapsis during neurotherapy. Neurotherapy, through targeted delivery of energy stimuli, alters mitochondrial activity.^[1] Mitochondria are highly concentrated at synapses. Thus, the mitochondrial activity facilitates synaptic transmission by generating adenosine triphosphate (ATP) and regulating calcium (Ca2+) levels. Neurons rely on locally produced ATP to meet the high energy demands of synaptic activity.^[2]

Definition

A consensus in the academic community considers this notion within limitations of the contemporary meaning of neuromodulation,^[6] which is "the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body" (see Neuromodulation). While neurotherapy may have a broader meaning, its modern definition focuses exclusively on technological methods that exert an energy-based impact on the development of the balanced nervous system in order to address symptom control and cure several conditions.^[5] The definition of neurotherapy relies on evolving scientific concepts from different fields of knowledge, ranging from physics to neuroscience. Four central concepts that underlie the knowledge of neurotherapy are defined here:

Energy stimulus

Energy, as the ability to do work, cannot be created or destroyed; it can only be transformed from one form to another (the law of conservation of energy). There are different form of energy. Such forms of energy as radiant energy carried by electromagnetic radiation, electrical energy and magnetic energy,^[7] are of interest to neurotherapy. Medical devices for neuromodulation exert electrical, magnetic, and/or electromagnetic energy to treat mental and physical health disorders in patients.

Synaptic plasticity

LTP and LTD: Schematic of molecular mechanisms. Research in several nervous system regions has demonstrated a reliable capacity for synapses to undergo long-term changes in efficacy in response to systemic targeted delivery of an energy stimulus. Technological advances in non-invasive manipulation of brain activity and growing insights into mechanisms underlying long-term potentiation and depression now put us at the threshold of harnessing neurotherapeutic approaches in the management of a variety of neurological conditions, including neuropathic pain, epilepsy, depression, amblyopia, tinnitus, and stroke.^[8]

Synaptic plasticity, a particular type of neuroplasticity is the ability of the nervous system to modify the intensity of interneuronal relationships (synapses), to establish new ones and to eliminate some. This property allows the nervous system to modify its structure and functionality in a more or less lasting way and dependent on the events that influence them such as experience or neuromodulation.^[9]

Neuroplasticity

Brain plasticity refers to the ability of the brain to modify its structure and functionality depending on the activity of its neurons, related for example to stimuli received from the external environment, in reaction to traumatic lesions or pathological changes and in relation to the development process of the individual or neuromodulation.^[9]

A balanced nervous system

In the balanced nervous system with required cognitive functions, the sympathetic (SNS) and parasympathetic nervous systems (PNS) operate in synergy while opposing each other. Stimulation of the SNS boosts body activity and attention: it raises heart rate and blood pressure. In contrast, stimulation of the PNS is the rest and digest state: it reduces blood pressure and heart rate. The nervous system interplays with the immune system. Through these interactions, the nervous and immune systems ensure the nervous system maintains immune homeostasis.^[10]

Medical uses

According to the International Neuromodulation Society, neuromodulation-based therapy "addresses symptom control through nerve stimulation" in the following condition categories:^[5]

• Chronic pain
• Movement disorders
• Epilepsy
• Psychiatric disorders
• Brain injury / Stroke
• Cardiovascular disorders
• Gastrointestinal disorders
• Genitourinary and colorectal disorders
• Sensory deficits

Types

Neurotherapy, as many medical therapy, is based on knowledge from conventional medicine, relying on scientific approach and evidence-based practice. However, some neuromodulation techniques are still attributed to alternative medicine (healthcare procedures "not readily integrated into the dominant healthcare model")^[11] because of their novelty and lack of evidence to support them. The wide range of neurotherapy techniques can be divided into three groups based on the application of energy stimulus:

Electric energy

• Auditory brainstem implant
• Cranial electrotherapy stimulation
• Deep brain stimulation
• Electrical brain stimulation
• Electroanalgesia
• Electroconvulsive therapy (ECT)
• Functional electrical stimulation (FES)
• Hypoglossal nerve stimulation^[12]
• Neurofeedback
• Microcurrent electrical neuromuscular stimulator
• Occipital nerve stimulation (ONS)^[13]
• Percutaneous tibial nerve stimulation (PTNS)
• Peripheral nerve stimulation^[14]
• Sacral nerve stimulation (SNS) / sacral neuromodulation (SNM)
• Transcranial direct current stimulation (tDCS)
• Transcranial alternating current stimulation (tACS)
• Transcranial pulsed current stimulation (tPCS) )^[15]
• Transcranial random noise stimulation (tRNS)
• Transcutaneous electrical nerve stimulation (TENS)
• Vagus nerve stimulation

Magnetic energy

• Magnet therapy
• Magnetic resonance therapy
• Repetitive transcranial magnetic stimulation (rTMS)^[16]
• Transcranial magnetic stimulation

Electromagnetic radiation

• Acoustic photonic intellectual neurostimulation (APIN)^[1]
• Light therapy (phototherapy)
• Ultraviolet light therapy
• PUVA therapy
• Photodynamic therapy
• Photothermal therapy
• Pulsed electromagnetic field therapy
• Cytoluminescent therapy
• Blood irradiation therapy
• Laser therapy
• Low level laser therapy
• Transcranial pulsed electromagnetic fields (tPEMF)^[17]

Mechanisms

Origins behind the way that an external energy stimulus alters neuronal activity and stimulates neuroplasticity during various artificial neurostimulation techniques are still under discussion. It is important to note that electrical and magnetic energy are two forms of energy that are closely interconnected: a moving charge induces electrical and magnetic fields. Electrical current creates a magnetic field, and a magnetic field induces an electrical charge movement. Neurons are electrically active cells.^[18] Neuronal oscillations have a dual role in synapsis: they are affected by spiking inputs and, in turn, impact the timing of spike outputs.^[19] Because of the above facts, both electrical and magnetic fields may induce electrical currents in neuronal circuits.^[20] Therefore, similar mechanisms of altered neuronal activity may underlie different neuromodulation techniques that use electrical, magnetic, or electromagnetic energy in treatment.^[1]

A variety of hypotheses try to explain the mechanisms that contribute to synaptic activity during neurostimulation. According to empirical data, Ca2+ and Na+ channel activity can be altered by a static magnetic field^{[21][22][23][24]} and low frequency-pulsed electromagnetic fields.^[25] The voltage-gated Ca2+ channels are the primary conduits for the Ca2+ ions that cause a confluence of neurotransmitter-containing vesicles with the presynaptic membrane.^[24] The altered activity of Ca2+ and Na+ channel changes the timing and strength of synaptic output, contributing to neuronal excitability.^[24]

Another perspective hypothesis stands that electromagnetic fields increase in adenosine receptors release that facilitates neuronal communication.^[26] Because A(2A) adenosine receptors control the release of other neurotransmitters (e.g., glutamate and dopamine), this contributes to adjusting neuronal functions.^[26]

According to the natural neurostimulation hypothesis, energy stimuli induce mitochondrial stress and micro vascular vasodilation. These promote increasing Adenosine triphosphate (ATP) protein and oxygenation, inducing synaptic strength.^[1] This position explains neuromodulation from different scale levels: from interpersonal dynamics to nonlocal neuronal coupling.^[1] According to natural neurostimulation, the innate natural mechanism of physical interactions between the mother and embryo ensures the balanced development of the embryonic nervous system.^[1] The drivers of these interactions, the electromagnetic properties of the mother's heart, enable brain waves to interact between the mother's and fetal nervous systems.^[1] The electromagnetic and acoustic oscillations of the mother's heart converge the neuronal activity of both nervous systems in an ensemble, shaping harmony from a cacophony of separate oscillations.^[1] These interactions synchronize brain oscillations, influencing neuroplasticity in the fetus.^[1] During the mother's intentional actions with her environment, these interchanges provide hints to the fetus's nervous system, binding synaptic activity with relevant stimuli.^[1] This hypothesis posits that the physiological processes of mitochondrial stress induction (affecting neuronal plasticity) and vasodilation, which cooperatively increase microvascular blood flow and tissue oxygenation, are the basis of the natural neurostimulation. It is also thought to be a foundation of many non-invasive artificial neuromodulation techniques.^[1][27] Because if the mother-fetus interactions allow the child's nervous system to grow with adequate biological sentience, similar (while scaling) environmental interactions can heal the damaged nervous system in adults.

History

Electric catfish in Mastaba of Ti bas-relief colour

While neurotherapy is a relatively young medical treatment in conventional Western biomedicine (that relies on a scientific approach and evidence-based practice),^[28] different age-old cultural practices of traditional Indian, Egyptian, and Chinese medicine have been using neuromodulation elements thousands of years ago. Before the basic processes of neurotherapy were scientifically studied, humans used the electrical properties of animals for therapeutic purposes. The Egyptians used the Nile catfish (Synodontis batensoda and Malapterurus electricus) to stimulate tissue electrically, according to an interpretation of frescoes in the tomb of the architect Ti at Saqqara, Egypt. The first documented use of electrical stimulation for pain relief dates back to 46 AD when Scribonius Largus of the ancient Roman Empire used the electric properties of torpedo fish to relieve headaches.^[29]

Scientific studies of neuromodulation began in 1745, when German physician De Haen published “a number of cases of spasmodic, paralytic and other nervous affections cured by electricity”.^[30]

The first implementation of electrocutical apparatus in hospital medical treatment recorded in Middlesex Hospital of London in 1767.^[30]

In 1780, Italian physicist and biologist Luigi Galvani investigated how electrical signals in nerves could control muscle movement, further evidence of the electrical nature of the neuronal activity.^[31]

Electrical apparatus used to detect nerve signals. From Emil du Bois-Reymond, "Investigations in Animal Electricity" (1848).

Galvani's hypothesis was proven in 1843 by Carlo Matteucci and Emil du Bois-Reymond with their discovery of the action potential. Du Bois-Reymond went on to devise a variety of electrical devices to stimulate and measure electrical activity in nerves and muscles, which he demonstrated to large audiences in Berlin, Paris, and London.^[32]

In 1856, Guillaume Duchenne photographed electrotherapeutic stimulation of muscle contractions, stating that alternating current was superior to direct current in this stimulation.^[33]

Portrait of G. Fritsch and E. Hitzig, about 1866

In 1870, German physicians Gustav Fritsch and Eduard Hitzig reported the modulation of brain activity in dogs by electrical stimulation of the motor cortex.^[34]

In 1887, Spanish neuroanatomist professor Santiago Ramón y Cajal improved the Golgi's method of visualizing nervous tissue under light microscopy by using a technique he termed "double impregnation". He discovered a number of facts about the organization of the nervous system: the nerve cell as an independent cell, insights into degeneration and regeneration, and ideas on brain plasticity.^[35]

In 1894, neurologist and psychiatrist Edward Flatau published a human brain atlas “Atlas of the Human Brain and the Course of the Nerve-Fibres” which consisted of long-exposure photographs of fresh brain sections. It contained an overview of the knowledge of the time on the fibre pathways in the central nervous system.^[36]

In 1924, the German psychiatrist Hans Berger attached electrodes to the scalp and detected small currents in the brain.^[6]

In the 1940s, the US War Department investigated the use of electrical stimulation and used so-called "galvanic exercises" on the atrophied hands of patients with ulnar nerve damage from wound surgery, not only to slow and prevent atrophy, but also to restore muscle mass and strength.^[37]

In the mid-20th century, the scientific study of neuromodulation in humans expanded significantly. Neurologist Professor Spiegel and neurosurgeon Professor Weissys of Temple University presented a stereotactic device to perform "ablation procedures" in humans; "intraoperative electrical stimulation" was introduced to test the brain's target zone before surgery in 1947.

In the 1950s, Professor Heath reported about subcortical stimulation with precise descriptions of behavioral changes.^[38] A first clinical positron imaging device, a prototype of a modern Positron Emission Tomography (PET), was invented in 1953 by Dr. Brownell and Dr. Aronow. ^[39] American scientists specializing in nuclear medicine David Edmund Kuhl, Luke Chapman and Roy Edwards developed this new method of tomographic imaging and constructed several tomographic instruments in the late 1950s. The development of implantable devices like pacemakers and spinal cord stimulators also began in the mid-20th century.^[40]

In 1965, the Gate Theory of Pain was established by Roland Melzack and Patrick D. Wall,^[41] allowing the beginning a gradual move away from destructive surgical treatments such as cutting nerves and towards reversible, modulatory treatments: neuromodulation.^[42]

Devices to manage pain received FDA (USA) approval in the late 1960s.^[43]

In 1967, Dr. Norm Shealy from Western Reserve Medical School presented “the first dorsal column stimulator for pain control”. It was developed based on the Gate Theory of Wall and Melzack,^[44] which stated that pain transmissions from tiny nerve fibers would be blocked if competing transmissions were made along larger sensory nerve fibers.^[45]

In 1987, the team of neurosurgeons/neurologists Professor Benabid and Professor Pollak and their colleagues (Grenoble, France) published results on this topic about thalamic Deep Brain Stimulation.^[46] Deep brain stimulation began to be used to treat motor symptoms of movement disorders such as Parkinson’s disease.^[42]

In 1989, the International Neuromodulation Society (INS) was founded in Paris after the first International Congress on Epidural Spinal Cord Stimulation in Groningen, the Netherlands, by a select group of physicians: Dr. Augustinsson, a Swedish neurosurgeon; Dr. Galley, a French cardiologist; Dr. Illis, a British neurologist; Dr. Kranick, a German neurosurgeon: Dr. Meglio, an Italian Neurosurgeon; Dr. Sier, a Dutch vascular surgeon and Dr. Staal, a Dutch neurosurgeon.^[42]

In the mid-2010s, new settings of Deep Brain Stimulation and Spinal cord stimulation, such as high frequency or burst modes of stimulation, were invented.^[42]

In 2021, it was registered that shaping the electrical field could trigger a natural neurological mechanism of lateral or surround inhibition, leading to fast-onset sub-perception Spinal cord stimulation. Lateral inhibition promotes refining somatosensory information. Ascending dorsal root ganglia (DRG) fibers transmit excitatory impulses to higher-order neurons and inhibitory interneurons, which communicate with neighboring relay neurons. Thus, neurons encircling the primary target of an ascending stimulated DRG axon are inhibited, which decreases the “noise” in the system and induces higher-order neurons to trigger only when they obtain a strong and consistent signal. Further progress was made in 2022, with study results on adjusting stimulation fields to preferentially target dorsal horn dendrites, a key site for initial pain processing, rather than axons.^[42]

In 2024, the theory of Natural Neurostimulation was introduced, opening the way to neurostimulation techniques which emulate, in neurological treatment, natural processes that appear during pregnancy. This notion was established by Prof Igor Val Danilov and his colleagues from Latvian universities.^[1][42] Latvian scientists claim that natural neurostimulation provides positive neuroplasticity, balancing the patient's nervous system in a case of systematic use of this sort of neurostimulation, emulating the natural process that causes mitochondrial and cognitive stress under similar environment. They provided evidence of the therapeutic effect of the complex impact of electromagnetic fields and acoustic waves, along with cognitive load, scaled based on the parameters of the physical interaction between mother and fetus.^{[47][48][49][50]}

Teleneurotherapy

Teleneurotherapy utilizes computers and communication technology to execute neurotherapy remotely.^[47] Organisms receive physical stimuli, such as sounds (through mechanoreceptors and mitochondria across different organ systems) and light (through photoreceptors located in the retina and mitochondria) that alter neuronal activity in specific brain zones.^[1] Research indicates that systematic physical stimuli produced by standard electronic devices, such as tablets and headphones, may treat online injured nervous systems by modulating neuronal plasticity.^[47] Teleneurotherapy "emulates the central parameters of natural brain stimulation during gestation."^[47] "Because natural neurostimulation contributes to the balanced development of the nervous system in fetuses with adequate biological sentience, the scaled parameters of these natural forces can potentially treat an injured nervous system in adults."^[47] Evidence suggests that teleneurotherapy can enable neurological treatment ^[47] if it considers key parameters of the mother-fetus interaction that provide the therapeutic effect in case of a systematic impact.^[48][49][50] Recent research implemented the APIN method (see above) in the online treatment of patients with different neurological conditions, which showed significant therapeutic effects.^{[47][48][49][50]}

See also

• International Neuromodulation Society
• Neuromodulation
• Neurostimulation
• Neurotechnology
• Non-invasive cerebellar stimulation