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• Neuromodulation involves use of minimally invasive or noninvasive technologies to deliver a stimulus to specific neurologic sites, eg, CNS, cranial nerves, peripheral nerves, etc., for management of neurologic disorders.
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• Neuromodulation is used for symptomatic management of nonneurologic disorders and other systems through modulation of their innervation, mostly for relieving symptoms.
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• This article is a brief overview of neuromodulation technologies linking them to their applications in various neurologic disorders, some of which are described in detail in other Medlink Neurology articles.
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• A closed loop system can combine diagnostic biosensing with therapeutic neuromodulation in a closed system.
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• Use of wearable devices has enabled ambulatory care and linking with digital technologies for personalized management.
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• Neuromodulation has advantages over classical neurosurgical procedures for conditions such as pain and epilepsy as well as over neuropharmaceuticals with potential toxicity by allowing reduction of dosage or in some cases enabling their discontinuation.
Historical note and terminology
Neuromodulation is defined as the modulation of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or physical or chemical agents, to specific neurologic sites in the body. It is carried out to counteract abnormal function of the nervous system primarily but also of other systems through modulation of innervation for relieving symptoms and normalizing function where possible.
The modulation of brain function via the application of weak direct current was first observed directly in the early 19th century. In 1973, University of California, Los Angeles computer scientist Jacques Vidal observed modulations of signals in the electroencephalogram of a patient and wrote: “Can these observable electrical brain signals be put to work as carriers of information in man-computer communication or for the purpose of controlling such external apparatus as prosthetic devices or spaceships?” (34). The basic concepts of neuroprosthetics, devices that supplant or supplement the input and/or output of the nervous system, are now being used for neurorehabilitation. In the past 3 decades, transcranial magnetic stimulation, modulation of the cranial nerves, and deep brain stimulation have undergone clinical translation, offering alternatives to pharmacological treatment of neurologic and neuropsychiatric disorders. Further development of novel neuromodulation techniques employing ultrasound, microscale magnetic fields, and optogenetics is being propelled by a rapidly improving understanding of the clinical and experimental applications of artificially stimulating or depressing brain activity in human health and disease. With the current rapid growth in neuromodulation technologies and applications, it is timely to review the developments and state-of-the-art in this area. A classification of various technologies used for neuromodulation is shown in Table 1.
Table 1. Classification of Various Technologies Used for Neuromodulation
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Closed loop stimulation
• Completely implanted systems
• Wearable biosensors linked to implanted electrodes for stimulation
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Minimally invasive direct stimulation of the CNS by implanted electrodes
• Deep brain stimulation
• Spinal cord stimulation
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Minimally invasive direct stimulation of the spinal and peripheral nerves by implanted electrodes
• Occipital nerve
• Phrenic nerve stimulation (diaphragm pacing)
• Pudendal nerve
• Sacral nerve
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Neuroprosthetics: brain-computer interface
• Paralyzed limbs
• Robotic arms
• Speech prosthesis
• Visual prosthesis
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Noninvasive transcranial direct electric stimulation of the brain
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Noninvasive neuromodulation by using various forms of stimulation:
• Olfactory stimulation
• Optogenetics: light as a neuromodulator
• Transcranial magnetic stimulation
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Surgical techniques for direct neuromodulation of CNS: brain and spinal cord
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Techniques for direct stimulation of or cranial nerves usually by electrical stimulation
• Hypoglossal nerve
• Optic nerve and retinal stimulation
• Trigeminal nerve
• Vagus nerve
• Vestibular nerve
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Virtual reality and neuromodulation
Some of these techniques and their applications in management of neurologic disorders are described in other MedLink Neurology articles. Other techniques are described here briefly.
Occipital nerve stimulation. Occipital nerve stimulation is a neuromodulation technique originally designed for control of intractable occipital neuralgia. It is a minimally invasive, adjustable, and reversible approach using an implantable device composed of a subcutaneous regional electrode and a pulse generator. A retrospective review shows that occipital nerve stimulation is a safe and effective procedure for refractory occipital neuralgia (17). Indications have expanded to include the following: cluster headache, cervicogenic headache, hemicrania continua, and SUNCT syndrome.
Speech prosthesis. Various neuromodulation approaches are being investigated to communicate with mute patients with locked-in syndrome. In a speech prosthesis in development by Neural Signals Inc. special “neurotrophic” electrodes record from the speech cortex and neural signals are transmitted to the receiver, which sends the data to the processor (a laptop computer) where signals are decoded and the output is signals as speech through the computer speaker.
Auditory neuromodulation. Acoustic neural stimulation by a wearable device and headphones delivers a broadband acoustic signal embedded in music, which helps to stimulate change in the neural circuits in the brain that eventually desensitizes the person to the tinnitus. For persons who have tinnitus along with severe hearing loss, cochlear implants bypass the damaged portion of the inner ear and send electrical signals that directly stimulate the auditory nerve. The device brings in outside sounds that help mask tinnitus and stimulate change in the neural circuits.
Optic nerve and retinal stimulation. This is basis of visual prostheses. The aim is to produce phosphenes, ie, the sensation of seeing spots of light arranged in patterns. Retinal prostheses, which directly stimulate retinal cells, have enabled blind persons with retinal diseases, such as retinitis pigmentosa and age-related macular degeneration, to see objects and letters.
An intraneural electrode array for optic nerve stimulation, OpticSELINE, has been tested in vivo on anesthetized rabbits and shown to induce selective activation patterns in the visual cortex (11). The intraneural electrode array is useful for investigations of the effects of electrical stimulation in the visual system and has the potential for further development as a visual prosthesis for blind patients.
Closed loop stimulation. In the concept of closed loop stimulation, diagnosis is linked to therapy. Implanted devices can incorporate diagnostics to trigger or adjust treatment. Use of mobile devices for diagnosis as well as therapy in 1 closed system is also being explored. Integration of closed loop stimulation with digital neurology technologies and personalized neurology is shown in figure 1.
An online closed system can be used for controlled drug delivery according to needs and demands. For example, touch-actuated microneedle array patch, a combination of a typical transdermal patch and a solid microneedle array, has been developed for transdermal delivery of liquid macromolecular drugs, especially heat-sensitive compounds, which can be easily filled and stored in the drug reservoir of touch-actuated microneedle array patches (35). Touch-actuated microneedle array patch can easily penetrate the skin and automatically retract from it to create microchannels through the stratum corneum layer using touch-actuated “press and release” actions for passive permeation of liquid drugs. A “closed loop” permeation control can be used for on-demand drug delivery for other conditions such as pain and tremor.
Optogenetics. Optogenetics is a technique in which genes for light-sensitive proteins are introduced into specific types of neurons to monitor and control their activity, eg, how they communicate, by using light signals. Light-gated Ca2+-permeant and K+-specific ion channels have been engineered by fusing a bacterial photoactivated adenylyl cyclase to cyclic nucleotide-gated channels with high permeability for Ca2+ or for K+, respectively (02). These synthetic ion channels, when illuminated, have been shown to activate or inhibit isolated rat neurons. Advances in viral vector technology for gene transfer substantially reduce vector-associated cytotoxicity and immune responses will enable transfer of this technology into the clinic as a possible alternative to deep brain stimulation (09).
Optogenetic techniques can activate or silence targeted neurons with high temporal and spatial accuracy and provide precise manipulation of genetically identified types of neurons. Photobiomodulation is light therapy that utilizes nonionizing light sources including lasers, light emitting diodes, or broadband light for a safe means of modulating brain activity without any irreversible damage and has established optimal treatment parameters in clinical practice (19).
Photobiostimulation. Photobiostimulation is a form of light therapy that utilizes nonionizing forms of light sources including lasers and broadband light in the visible and infrared spectrum. It is a process involving endogenous chromophores eliciting photophysical (ie, linear and nonlinear) and photochemical events at various biological scales at temperatures not exceeding 45oC. This process results in beneficial therapeutic outcomes including but not limited to the alleviation of pain or inflammation, immunomodulation, and promotion of wound healing and tissue regeneration. Key mechanisms of modulation of inflammation include nerve stimulation-inhibition. Photobiostimulation is beneficial for chronic back pain and can be combined with neuromodulation for pain control and neuromuscular rehabilitation. Photobiostimulation is an effective short-term therapy for pain due to myofascial temporomandibular disorder (23).
Transcranial direct current stimulation (tDCS). This is also referred to as cranial electrotherapy stimulation. Studies on normal subjects using functional resonance imaging and magnetic resonance spectroscopy targeted to left precentral gyrus have shown reduction of GABA concentrations and increase in SMN strength, both during anodal and cathodal, compared to sham transcranial direct current stimulation, confirming neuromodulatory effects of electric field (01).
Ultrasound. Focused ultrasound is noninvasive and has ablative as well as nonablative applications for neurologic and psychiatric diseases. The FDA has approved magnetic resonance-guided focused ultrasound ablation for essential tremor and its use is being explored for other neurologic disorders (18).
Low-intensity ultrasound has been used for study of various organs including the brain as well as for transient neuromodulation. Several studies have shown it to be a safe, noninvasive method of brain stimulation with improved spatial localization and depth targeting as compared with alternative methods (04).
Transcranial pulse stimulation is based on single ultrashort ultrasound pulses and markedly differs from existing focused ultrasound techniques. No certified clinical brain stimulation system for transcranial pulse stimulation is available yet and current techniques need further development.
Virtual reality and neuromodulation. Virtual reality provides a sense of realism as well as environmental interaction and virtual reality training improves neuroplasticity of the brain by coping with multisensory stimuli. It has been used as a therapy for neurologic disorders and neurorehabilitation. Virtual reality can be combined with neuromodulation. A pilot randomized, controlled, double-blind, clinical trial showed that transcranial direct current stimulation combined with virtual reality training could be a useful tool for improving gait in children with cerebral palsy (06). A clinical study has demonstrated the feasibility of applying transcranial direct current stimulation during virtual reality and preliminary data suggest a reduction in symptoms of posttraumatic stress disorders (33).