Trigeminal Nerve Stimulation: an Overview

Trigeminal Nerve Stimulation (TNS) is a novel medical therapy being developed by NeuroSigma for the treatment of neurologic and psychiatric conditions including epilepsy, depression, attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), Lennox Gastaut Syndrome (LGS), and Traumatic Brain Injury (TBI). TNS uses mild electrical signals to stimulate branches of the trigeminal nerve and achieve its therapeutic effect. TNS is unique among neurostimulation therapies because it can be delivered via a non-invasive external trigeminal nerve stimulation (eTNS™) system or a minimally-invasive subcutaneous trigeminal nerve stimulation (sTNS™) system, which is currently under development.

This unique feature of TNS creates an integrated neuromodulation platform where patients can try the therapy with the non-invasive eTNS device. Patients that respond and are seeking continuous stimulation may opt for implantation of sTNS, secure in the knowledge that they will benefit from the treatment prior to undergoing surgery.

NeuroSigma's lead product, the Monarch™ eTNS™ system is now approved for the treatment of epilepsy in the European Union, Canada and Australia, and for the treatment of depression the European Union and Canada. For more information on the Monarch, please visit our specialty site at www.Monarch-eTNS.com.

CAUTION: We have not received approval from the FDA to market our eTNS™ system or proposed sTNS™ system in the United States. Our eTNS™ system and proposed sTNS™ system are classified as investigational devices and are limited by Federal (or United States) law to investigational use only.

TNS

Anatomy of the Trigeminal Nerve

TNS Targets

The trigeminal nerve is the largest cranial nerve and provides sensation to the face via three separate divisions (V1 – V3). NeuroSigma's TNS technology targets the V1 division of the trigeminal nerve. The V1 division covers the forehead and scalp and sits just beneath the surface of the skin. Because the nerve is so close to the skin's surface, it creates a unique anatomical situation where TNS can be delivered via both a non-invasive, external system (eTNS), or a minimally-invasive subcutaneous system (sTNS), which is currently under development.

TNS Signals

Once signals from the trigeminal nerve enter the brain, they are routed through a complex network of structures in the brainstem, thalamus, and cortex. Important connections in the brainstem include the nucleus tractus solitarius (NTS) and locus coeruleus (LC). The NTS is a key regulator of the parasympathetic, or “rest and digest” nervous system, and provides a direct connection between the trigeminal and vagus nerve systems. The LC is an important component of the sympathetic, or “fight and flight” nervous system, and has been implicated in neurologic and psychiatric conditions such as Parkinson's, Alzheimer's and major depressive disorder (MDD). The LC produces much of the brain's supply of norepinephrine (NE), a brain chemical involved in mood and anxiety disorders, and in concentration and attention, as well as having an anti-epileptic effect.

Once signals from the trigeminal nerve pass through the brainstem, they travel to higher brain regions via the thalamus, and then onto the primary sensory cortex. Research has demonstrated that the trigeminal nerve also has direct connections to a part of the brain known as the anterior cingulate gyrus, an area thought to be involved in the regulation of attention and mood. Other signals may be passed from NTS to the thalamus and to the amygdala, an area involved in anxiety.

TNS: Mechanism of Action

A series of neurophysiology studies in animals and brain imaging work in humans provide insight into this unique therapy. In the year 2000, researchers at Duke University used a rat model of epilepsy to investigate the effects of TNS on the frequency and severity of seizures. Importantly, these studies demonstrated that TNS exerted a significant anti-seizure effect and that the anti-seizure effect of TNS improves when the stimulation is delivered bilaterally (i.e. on both sides) and at high frequencies (>100Hz). More recently, studies of local field potentials (LFPs) in the cortex of rats have demonstrated that TNS exerts a direct inhibitory effect on neurons in the cortex, a brain region involved in the initiation and propagation of seizures.

TNS Seizure

Studies of TNS in rats have shown that the anti-seizure effect increases when stimulation is delivered at high frequencies (>100 Hz) and bilaterally (*p < 0.05).
Fanselow et al., Journal of Neuroscience, 2000.

Neuroimaging work in patients receiving eTNS supports findings from the animal studies shown above, and provides additional insight into how eTNS may work in epilepsy and neuropsychiatric disorders. A team of scientists at UCLA, including Dr. Ian Cook, a Professor-in-Residence of Psychiatry and Biobehavioral Sciences and currently our Senior Vice President and Chief Medical Officer, used Positron Emission Tomography (PET) to measure changes in brain blood flow among patients receiving eTNS. They found that use of eTNS is associated with decreased blood flow to specific regions of the cortex. They found that use of eTNS is associated with decreased blood flow to specific large regions of the cortex. This finding is consistent with results obtained from the rat studies, and suggests that TNS may decrease seizure activity by inhibiting overactive neurons. The team at UCLA also found that eTNS simultaneously increased blood flow in other brain regions, including those associated with mood, attention, and executive function. These findings may explain clinical studies showing that use of eTNS can improve symptoms of depression, attention deficit hyperactivity disorder (ADHD), and post-traumatic stress disorder (PTSD)

TNS Blood Flow

Taken as a whole, results from the anatomic, animal, and neuroimaging studies provide a framework for understanding TNS. The trigeminal nerve provides a direct pathway to key regions of the brainstem, thalamus and cortex. Once signals from the trigeminal enter the brain, they change neuronal activity in these key regions, potentially decreasing activity in regions that can prevent the spread of seizure activity in patients with epilepsy, and increasing activity in regions that are frequently underactive in people with depression and anxiety disorders.

TNS: A Neuromodulation Platform for the 21st Century

Traditional approaches to treating epilepsy and neuropsychiatric disorders have focused on the use of pharmaceutical products. While these treatments have been successful for many individuals, significant numbers of patients continue to suffer despite trying multiple medications, and the medications often carry side effects that limit their use. In recent years neuromodulation has emerged as an alternative treatment for these disorders, but current generation systems are invasive, expensive, and lack a way to predict whether a patient will respond to that treatment prior to implantation.

TNS offers an entirely new paradigm in neuromodulation for the 21st century. NeuroSigma's unique eTNS/sTNS approach provides an integrated platform that uses the brain's existing circuitry to achieve a therapeutic effect. Patients can quickly and simply initiate treatment with the non-invasive eTNS system. Therapy is simple to deliver, and can be done in the comfort and privacy of one's own home. Those patients who have responded to eTNS and are seeking continuous stimulation can eventually choose to have implantation of the sTNS system, secure in the knowledge that it will be effective prior to exposing themselves to the risks of surgery.

For more information about NeuroSigma and TNS, please fill-out a contact form and a NeuroSigma representative will contact you shortly.

NeuroSigma's lead product, the Monarch™ eTNS™ system is now approved for the treatment of epilepsy in the European Union, Canada and Australia, and for the treatment of depression the European Union and Canada. For more information on the Monarch, please visit our specialty site here www.monarch-etns.com.

CAUTION: We have not received approval from the FDA to market our eTNS™ system or proposed sTNS™ system in the United States. Our eTNS™ system and proposed sTNS™ system are classified as investigational devices and are limited by Federal (or United States) law to investigational use only.

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