Introduction

Overview

Rapid advances in technology in the last few decades have empowered clinicians with a variety of tools designed to increase or decrease the activity of a specific region of the nervous system to achieve an intended clinical effect. This branch of treatment, neuromodulation, has revealed multiple options for improving neurologic symptoms or restoring sensory or motor impairments after neurologic injury. Neuromodulation may exert its effect through various sources, including direct electric stimulation, site-directed pharmacology, light, or ultrasound. Several invasive and noninvasive neuromodulation treatments and diagnostic tools have entered routine practice. Deep brain stimulation is used for tremors, and intrathecal baclofen reduces spasticity in cerebral palsy, multiple sclerosis, hereditary paraplegia, or spinal cord injury. Electric stimulation of pharyngeal muscles treats dysphagia, and invasive vagus nerve stimulation can improve upper extremity weakness after stroke. Some techniques initially limited to preclinical use, such as optogenetics, are undergoing translation to clinical application. Here we present an introductory, rather than comprehensive, overview for the neurology clinician of this exciting but daunting topic. We review general neuromodulation principles and contrast two illustrative clinical conditions.

Key points

Historical note and terminology

The Bolognese physician Giuseppe Veratti may have provided one of the earliest accounts of clinical neuromodulation with his 1748 treatise, Physical and Medical Observations about Electricity. In one chapter, he described a 70-year-old woman with tinnitus that improved with 3 days of 5 to 10 minutes of electricity transmitted electrostatically through glass (30).

Routine applications of neuromodulation, however, began with innovations in the middle of the 20^th century. Many continue to be part of modern practice. Inspired by the work of French physicians Charles Eyriès and André Djourno, who restored hearing with an electrode in the internal auditory canal in 1957, the American surgeon William House placed the first cochlear implant in 1961 (34). Functional electrical stimulation was also achieved in 1961 when the team of physiatrist Wladimir Liberson developed the first neuroprosthesis applying peroneal nerve stimulation paired with the swing phase in hemiplegia (25).

Meanwhile, the roots of deep brain stimulation (as well as stereotactic surgery) date to the 1930s, when neurosurgeon Wilder Penfield used an electric probe to identify and ablate the foci of seizures. In 1967, Neurosurgeon Norman Shealy used modified cardiac pacemakers manufactured by Medtronic to stimulate the brains of patients with intractable pain. Medtronic developed the first neurostimulator in 1968 for chronic pain. Deep brain stimulation was approved for Parkinson disease in the United States in 1997, and by 2008 deep brain stimulation was standard and accepted treatment for Parkinsons disease (17).

The past 3 or 4 decades have seen the blossoming of additional neuromodulation techniques. In 1981, Alan B Scott pioneered the chemodenervation of botulinum toxin for blepharospasm (21). Noninvasive brain stimulation with transcranial magnetic stimulation and minimally invasive vagal nerve stimulation have undergone clinical translation, offering alternatives to pharmacological treatment of neurologic and psychiatric disorders. Further development of low-intensity focused ultrasound and optogenetics is being propelled by a rapidly improving understanding of the clinical and experimental applications of neuromodulation. In 2023, a Swiss group restored ambulation in a patient with traumatic spinal cord injury using a closed-loop brain-spine interface (27).

It is not possible to cover all clinical neuromodulation techniques here. Various techniques are outlined in Table 1,and described thereafter in detail:

Table 1. Classification of Various Technologies Used for Neuromodulation

Electric stimulation

Minimally invasive electric stimulation. The nervous system is basically an electrochemical signaling system, and it makes sense that modulation of a nerve or population of neurons can be readily achieved by stimulating it directly with an electrode. This direct stimulation is the most widely used neuromodulation and forms the mechanism for several semi-permanent implantable stimulators in common use. Minimally invasive neuromodulation can target both the central and peripheral nervous systems.

In the central nervous system, deep brain stimulation using stereotactically placed electrodes allows direct electrical stimulation to specific targets. Deep brain stimulation of the globus pallidus pars interna or subthalamic nucleus may reduce symptoms of Parkinson disease (26). Other targets in the basal ganglia, such as the ventral intermediate nucleus of the thalamus, may improve essential tremor. Deep brain stimulation is also used for epilepsy (16). Cortical stimulation mapping uses direct electrical stimulation for intraoperative identification of eloquent cortex as well as seizure foci (20). Intrathecal stimulation of the spinal cord using spinal cord stimulators can target treatment-resistant pain and is being explored for applications in neurorehabilitation (32).

Several peripheral nerve targets are electrically stimulated as part of routine clinical care. The cochlear implant is a sensory neural prosthesis that helps provide or restore hearing by stimulating the auditory nerve. A cochlear implant converts sound from a digital signal into a radiofrequency signal. This radiofrequency signal is converted to electric currents that directly stimulate wires threaded through the cochlea and stimulate the auditory nerve (48). Stimulation of the vagus nerve provides a wide array of clinical indications; for example, implantable stimulators are in use for depression, epilepsy, and upper extremity rehabilitation after stroke (18).

Lorach and colleagues implemented a brain-spine interface using epidural lumbosacral electric stimulation to restore ambulation in an individual with cervical spinal cord injury. Lesion bypass was achieved with electrocorticographic sensors above the motor cortices as part of a digital bridge between the brain and lumbosacral nerve roots (27). Epidural sacral nerve stimulation can also be used to treat bladder or bowel incontinence, although the mechanisms are incompletely understood (12). Tibial nerve stimulation can treat bladder incontinence via retrograde stimulation of the sacral plexus (05).

Although cardiac myocytes share some similar electrochemical properties with neurons, cardiac pacemakers for rhythm disorders function by directly stimulating cardiac muscle and do not fall under the definition of neuromodulation; however, cardiac neuromodulation therapy is being investigated for hypertension by modulating sympathetic nervous system afferents (23). Other clinical applications are available. The curious reader is encouraged to explore them on the International Neuromodulation Society web site.

Noninvasive (transcutaneous) electric stimulation. Greater efficacy is seen with minimally invasive versus noninvasive stimulation. However, noninvasive stimulation has a high level of convenience and portability. Many noninvasive devices are available via specialty pharmacies by prescription or even at the retail level online or in major department stores. Noninvasive electric stimulation of the trigeminal, occipital, or vagus nerves can alleviate various headache syndromes, eg, migraine. Transcutaneous electrical nerve stimulation is readily accessible at the consumer level and is frequently used for chronic pain. Transcutaneous afferent patterned stimulation of the median nerve may alleviate tremor in essential tremor or Parkinson disease (08; 28).

Electromagnetic noninvasive brain stimulation. Several techniques are available for noninvasive direct electric or magnetic stimulation. Repetitive transcranial magnetic stimulation (rTMS) can deliver a high-precision stimulus by inducing a magnetic field with accuracy on the order of millimeters (35). Repetitive transcranial magnetic stimulation can depolarize neurons, which can create a reversible virtual lesion; this property allows repetitive transcranial magnetic stimulation to aid in cortical mapping (04).

In contrast, transcranial electrical stimulation (tES) can bring neurons closer to depolarization without actually creating an action potential. Transcranial electrical stimulation itself is divided into transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS). Of these techniques, transcranial direct current stimulation is the best studied. In transcranial direct current stimulation, current flows from one electrode to the other, allowing for regional stimulation, although its spatial resolution is low (29).

Noninvasive brain stimulation is approved in the United States for select psychiatric conditions. Its role in neurology is under investigation. The heterogeneity in outcomes illustrates the complexity of stimulation protocols and our understanding of the interaction of the hemispheres after injury (07).

Remote electrical neuromodulation. Symptoms localizing to a certain region of the nervous system can be alleviated by stimulating an essentially unrelated nerve territory. Remote electrical neuromodulation of the upper arm is approved in the United States to alleviate or prevent migraine. The proposed mechanism for remote electrical neuromodulation entails stimulation of nociceptive nerves in the upper arm, which activate an endogenous mechanism of pain inhibition primarily located in the brainstem (01).

Light-based neuromodulation

Phototherapy and photobiomodulation. Light at various wavelengths can be used to modulate nervous system activity. Photobiomodulation is limited to red or near-infrared light and is also referred to as low-level laser therapy (LLLT). Transcranial photobiomodulation can penetrate the skull. Several mechanisms of action have been proposed, one being the absorption of light by cytochrome c oxidase, resulting in a net increase of ATP (adenosine triphosphate) (33). Photobiomodulation has had mixed evidence for clinical use, but refined approaches are being investigated for neurorehabilitation, neurodegenerative conditions, and back pain. Green light phototherapy acting on the retina may be a promising treatment for headache; a variety of neuromodulatory mechanisms have been proposed (19).

Optogenetics. Optogenetics combines genetic engineering with light-based neuromodulation to selectively activate neurons. Selected neurons are engineered to express opsins, ie, proteins that respond to specific wavelengths. When such neurons are exposed to light, conformational changes to the opsins can alter the neurons behavio, such as by opening or closing an ion channel and influencing its membrane potential. Optogenetics can provide a high degree of precision. The application of optogenetics has been largely preclinical, but clinical uses are emerging; one group has utilized optogenetics to partially restore visual impairment in a patient with retinitis pigmentosa (41).

Sound-based neuromodulation. Although acoustic stimulation using high-intensity focused ultrasound can permanently ablate neural structures, low-intensity focused ultrasound can reverse modulate neuronal activity. Mechanisms of low-intensity focused ultrasound may include modification of structural and thermal properties of membranes (10). MRI-guided focused ultrasound is in use for tremors, and applications of low-intensity focused ultrasound for peripheral stimulation are also in investigation (10).

Auditory or acoustic neuromodulation using auditory pathways has been explored. Auditory neuromodulation may have a role in alleviating tinnitus. Binaural acoustic stimulation, particularly with binaural beat stimulation or entrainment, may have a role in modulating mood and cognition in various psychiatric and neurologic conditions (36; 22). Binaural beat stimulation takes advantage of a phenomenon in which stimulation of each ear using sound of two different frequencies produces the illusion or perception of a third tone, or binaural beat, with a frequency that is the difference between the two inputs. Possible mechanisms may involve cortical entrainment (36; 22).

Pharmacologic neuromodulation

Targeted pharmacology. Pharmacology can be considered a form of chemical neuromodulation when an agent is delivered to a specific component of the nervous system (29). Lower extremity spasticity can be controlled via intrathecal baclofen pumps, which deliver baclofen at a programmed rate; the location of drug delivery in the spine limits sedating effects. Spasticity can also be controlled by injecting botulinum toxin or phenol into specific muscles, and phenol can be used intrathecally. Botulinum toxin is also used for sialorrhea, migraine, and dystonia. Localized nerve blocks using an anesthetic with or without steroids serve as a component of pain management.

Designer receptors activated only by designer drugs (DREADDs). Currently used in the preclinical setting, DREADDs allow the study of highly selective neuromodulation using bespoke pharmacology. With this chemogenetic technique, an animal is designed to selectively express drug receptors in a desired part of the body. These receptors are designed to respond to specific, previously unrecognized small molecules. DREADDs achieve comparable effects versus optogenetics but last longer (40).

Special neuromodulation concepts

Closed- versus open-loop stimulation. In open-loop stimulation, stimulation is delivered at a fixed or scheduled interval, regardless of input from the patient. Implantable open loop devices may stimulate based on a duty cycle or a ratio between a devices on and off time. With closed-loop stimulation, activation of a neuromodulatory device occurs in response to stimuli sensed from the body of the wearer. For example, hemiplegic patients with walking impairment might improve their ambulation using a closed-loop functional electrical stimulation device that senses the position of the foot to time stimulation of the quadriceps or hamstring muscles. Common commercial functional electrical stimulation devices include Bioness® and WalkAide® models (06). Responsive neurostimulation can treat epilepsy by stimulating the brain in response to the detection of pre-defined electrocorticography patterns that may lead to a seizure (39).

Sensory prosthetics. Implantable neuromodulation devices can help restore various sensory impairments. The cochlear implant is one such device. A retinal prosthetic may use electric or light-based photodiode stimulation to improve vision, eg, in retinitis pigmentosa and age-related macular degeneration (15). Direct electric stimulation of the optic nerve, lateral geniculate nucleus, or cortex may also serve as targets for visual prosthetics (15).

Sensory substitution. Neuromodulation applications have been developed to substitute a lost sensory modality using alternative, unimpaired senses. Tactile sensory substitution devices may allow individuals to see by translating visual input through a camera into a two-dimensional spatial representation of the visual input onto the skin or even the tongue (15). Other devices can help convert visual stimuli into auditory stimuli (37).

A note about brain-computer interfaces. Interest in brain-computer interfaces has increased in recent years. Although both brain-computer interfaces and neuromodulation are neural engineering applications, they represent two distinct but overlapping concepts. Motor brain-computer interfaces skip traditional neuromuscular pathways and output directly to a digital interface (42) rather than stimulating part of the nervous system. A sensory brain-computer interface may qualify as neuromodulation. However, current sensory prosthetics, such as cochlear implants, are not brain-computer interfaces because the stimulation occurs at the level of the peripheral nerve and not directly onto the brain.