Neuromodulation for Migraine: an Overview of Treatment Modalities
Neuromodulation is the use of technologies with chemical, electrical, electromagnetic and other functions to either stimulate or inhibit nervous system activity.
Nervous system regulation via neuromodulation, which directly targets the nerves, is used to treat chronic pain and the symptoms of neurological disorders. One familiar and commonly prescribed form of neuromodulation is the TENS (transcutaneous electrical nerve stimulator) unit, which uses a mild electrical frequency to treat pain symptoms from chronic conditions such as arthritis and fibromyalgia.
Notably, neuromodulation is a safe and effective way to treat chronic and episodic migraine. For migraineurs, neuromodulation may reduce migraine episodes, pain and duration with regular use. Various types of neuromodulation devices, available with or without a prescription, leverage a wide range of modalities to treat migraine and act on different parts of the nervous system. Each approach has the overall goal of quieting central nervous system hyperactivity.
The neurophysiological complexity of migraine accounts for the variability of effective approaches within neuromodulation. Initially, migraine was believed to be primarily a vascular disorder caused by meningeal vasodilation; the increase of blood flow in the protective outer layers of the brain, due to temporarily widened blood vessels in this area.
However, research in the last two decades has found that migraine involves “multiple cortical, subcortical, and brain stem areas that regulate autonomic, affective, cognitive, and sensory functions,” according to a review published in Headache, The Journal of Head and Face Pain.
What are the types of neuromodulation used to treat migraine?
External Trigeminal Nerve Stimulation (eTNS)
The nervous systems of people with migraine are hypersensitive to stimuli sensed by afferent nerves, causing hyperactivity within the central nervous system. Hyperactivation of the trigeminal nerve, the largest cranial nerve, is often the genesis of migraine attacks.
The trigeminal nerve controls sensory and motor function in parts of the head, mouth, jaw and face. In response to external stimuli, the trigeminal nerve sends signals to the somatosensory cortex that enable sensory and motor control. When hypersensitive afferent trigeminal nerve endings are stimulated by external triggers, pain signals travel to the trigeminal spinal nucleus caudalis in the brainstem.
In response, the entire nucleus caudalis becomes overstimulated, which can affect the whole brain — a process called central sensitization. In people with migraine, pain signals also set off a wave of synaptic activity called cortical spreading depression (CSD); a period in which cortical neurons are hyperactive, then suddenly quiet.
Central sensitization and the neuronal hyperactivity stage of CSD cause a range of migraine symptoms. Central sensitization can contribute to a migraine being prolonged, and light and sound sensitivity during a migraine attack. Central nervous system connections to the gastrointestinal system are also impacted by central sensitization and CSD, which causes nausea.
CSD causes inflammation and swelling in the cortex and vasoconstriction, which are contributors to head pain. Synaptic misfiring related to CSD impacts the ocular nerve, which leads to the unusual visual sensations experienced during migraine with aura.
eTNS devices deliver low frequency electrical pulses to the trigeminal nerve to regulate nervous system hyperactivity connected to trigeminal nerve overstimulation. eTNS devices send current through electrodes placed on the forehead to the supraorbital branch of the trigeminal nerve. From the supraorbital branch, nerve fibers carry information to a region of the brain stem, the trigeminal nuclei, which processes sensory information from the trigeminal nerve.
eTNS is shown to act positively on brain stem regions linked to arousal and the release of neurotransmitters, particularly serotonin, noradrenaline and dopamine. eTNS may lessen migraine occurrence, length and pain partly because of an enhanced release of noradrenaline and serotonin, modulating neurotransmission. eTNS also inhibits synaptic misfiring of neurons in the cortex due to CSD and is known to decrease brain inflammation — all actions that reduce migraine symptoms and duration.
CEFALY and Relivion are two leading, FDA-cleared eTNS devices. CEFALY is available without a prescription, while Relivion requires a prescription. CEFALY targets the trigeminal nerve, while Relivion targets the trigeminal and occipital nerves.
Transcutaneous Vagus Nerve Stimulation (tVNS)
tVNS devices use low frequency electrical pulses to stimulate the vagus nerve non-invasively. Electrodes are placed on the ear (auricular vagus nerve stimulation) or the neck (cervical vagus nerve stimulation) to send pulses to sensory receptors in the vagus nerve.
The vagus nerve may be an effective neuromodulation target because of its function as the main nerve of the parasympathetic system, and its relation to the trigeminal nerve.
The vagus nerve controls autonomic functions such as heart rate, breathing and digestion, and is activated when the body is in a resting state. Within the sensory nucleus of the brain stem, the vagus nerve has connections to the trigeminal nerve, which has a main role in the opposing sympathetic nerve system.
Studies show vagus nerve stimulation may dull pain signals and quiet neuronal hyperactivity associated with the trigeminal system and CSD.
gammaCore is an FDA-cleared tVNS device prescribed for at-home treatment of migraine and cluster headache.
Transcranial Magnetic Stimulation (TMS)
TMS is a non-invasive brain stimulation technique that alters the firing in synaptic connections between the cortex and deeper regions of the brain connected to pain. TMS is often used to stimulate the left motor cortex for the treatment of migraine and other chronic pain disorders, and scientists are investigating other central nervous system targets for TMS.
TMS technology operates on well-known principles of electromagnetism. A coil is placed on the head over the targeted area, and an electrical current is sent from the TMS machine to the coil, where it circulates. All electrical currents produce a magnetic field, and it is the magnetic field generated within the TMS coil that stimulates the brain.
A magnetic field generated by a current can also act on other currents. In the case of TMS, magnetic fields affect neurophysiological connections in the brain, altering the firing of synapses that carry pain messages. TMS short circuits synaptic communication to inhibit hyperactivity in targeted areas. TMS may also act positively on the hyperactivity associated with CSD.
TMS has been extensively studied and has also been used as a treatment for intractable depression, obsessive compulsive disorder, schizophrenia and conditions that cause chronic pain. eNeura’s SAVI Dual device allows patients to self-administer single pulse transcranial magnetic stimulation at home.
Transcranial Direct Current Stimulation (tDCS)
Unlike other forms of neuromodulation that generate electrical currents, tDCS does not send electrical pulses to a targeted region. Instead, an electrical current travels between two electrodes — an anode and cathode. The area of the brain stimulated depends on the placement of the electrodes.
tDCS can either inhibit or increase the action potential of neurons within a cortical region. The increase or decrease in action potential is determined by whether a targeted area is affected by an anode, which is negatively charged, or a positively charged cathode.
During stimulation, the action potential of neurons within the cortical area under the anode is increased by the electrode’s positive current. Inversely, the action potential of neurons in the cortical area under the cathode is decreased by a negative current.
Studies show that both cathodal and anodal tDCS are effective treatments for migraine. Cathodal tDCS has been applied to the primary motor and sensory cortexes. Anodal tDCS has been applied to the occipital cortex. These regions of the cerebral cortex are impacted by migraine. The cerebral cortex contributes to how the brain senses and perceives pain and migraine aura is connected to visual changes in occipital lobe.
Both anodal and cathodal tDCS act positively on the neuronal hyperactivity associated with CSD in the cerebral cortex and impact how the brain processes pain signals. Repeat treatment sessions with tDCS can correct maladaptive plasticity — nervous system disruptions that lead to disease symptoms.
Scientists are still measuring the efficacy of tDCS, determining why the technology is effective and whether cathodal or anodal stimulation is superior. tDCS is not self-administered and requires multiple treatments to correct maladaptive plasticity.
