Comment on use of transcutaneous trigeminal nerve stimulation for PTSD

Exploring non-pharmacologic means to treat PTSD will always  get a thumbs up from me.  The results of a recent Clinical Trial exploring the use of transcutaneous trigeminal nerve stimulation was just published in the journal Neuromodulation: Technology at the Neural Interface. Study results were modest but what is most intriguing is how stimulating the trigeminal nerve would have a positive effect on PTSD and also, from previous studies, positive effects on reducing the frequency of epileptic seizures.

Monarch™ eTNS™

Looking at the Neurosigma website, the company who's product the Monarch™ eTNS™ is behind this research, they point out that the trigeminal nerve is the largest cranial nerve.  Yes it is considered by some
criteria to be "the largest" but the vagus nerve is the longest cranial nerve and by far the most complex.  The vagus nerve supplies vital organs, is the primary parasympathetic nerve, plays a vital role in our immune system, and helps to control systemic inflammation.

Also, they do not call the superficial stimulation of the trigeminal nerve with the Monarch transcutaneous stimulation but refer to it as external stimulation.  I'm wondering if that is for marketing purposes.  Why purchase a Monarch if a similar function can be served by a transcutaneous nerve stimulator?

As to how the trigeminal nerve, a nerve whose primary function is for sensory and motor functions in the face and mouth regions, can have such systemic effects on complex disorders such as PTSD and epilepsy, the answer may come from tracing the path of the trigeminal nerve. The nucleus tractus solitarius, located in the dorsomedial medulla, does receive a few projections from the trigeminal nerve.  The Neurosigma website points this out.  They also state the involvement of the locus coeruleus in the proposed mechanism for the effects of trigeminal nerve stimulation. Again, there are some connections. The vagus nerve supplies dense connections to the these structures, not just a few fibers.

Regarding the proposed involvement of the locus coeruleus in the etiology of trigeminal nerve stimulation, therapy, recent research has shown that the antidepressant effects of vagus nerve stimulation (VNS) is via the locus coeruleus (LC).  Here are some highlights of that study (Journal of Psychiatric Research Sep 2015):

• VNS has an antidepressant-like effect in the forced swim test.
• Lesioning the LC abolishes this antidepressant-like effect of VNS.
• Our results support a key role for the LC in the antidepressant mechanism of VNS.
• The results of this study demonstrate that the noradrenergic neurons from the LC play an important role in the antidepressant-like effect of VNS. 

Just last week (Feb 16, 2016) a new study has added a key piece to the Alzheimer's puzzle by demonstrating the locus coeruleus to be 'ground zero' in the etiology of Alzheimer's:

Researchers highlight brain region as 'ground zero' of Alzheimer's disease
The locus coeruleus is a small, bluish part of the brainstem that releases norepinephrine, the neurotransmitter responsible for regulating heart rate, attention, memory, and cognition. Its cells, or neurons, send branch-like axons throughout much of the brain and help regulate blood vessel activity. Its high interconnectedness may make it more susceptible to the effects of toxins and infections compared to other brain regions, said lead author Mara Mather.

Mather, Professor of Gerontology and Psychology at the University of Southern California Leonard Davis School of Gerontology, added that the locus coeruleus is the first brain region to show tau pathology—the slow-spreading tangles of protein that can later become telltale signs of Alzheimer's disease. Though not everyone will get Alzheimer's, autopsy results indicate that most people have some initial indications of tau pathology in the locus coeruleus by early adulthood, she added. Trends in Cognitive Sciences March 2016

It appears to me to be quite clear that transcutaneous vagus nerve stimulation (see previous post) could play a key role in protection from Alzheimer's disease and there is a new Clinical Trial starting very soon to test that hypothesis. Details from the Clinical Trial:
There are three aims in this project:

1. To investigate how the functional interaction between the locus coeruleus and other brain areas, in particular the medial temporal lobe areas, during memory processes (encoding, consolidation and retrieval) change with development of Alzheimer's disease.
2. To investigate associations between noradrenaline, memory performance and brain functioning. The investigators aim to investigate how acute noradrenalin levels change during the different memory processes and whether or not this is beneficial for performance. Furthermore, the investigators will investigate whether this interaction between noradrenalin, memory performance and brain functioning is different healthy older individuals (n =35) or patients with prodromal Alzheimer's disease (n =35).
3. To investigate the underlying neural network changes during transcutaneous vagus nerve stimulation. The investigators will focus on differences in functional connectivity between the locus coeruleus and the medial temporal lobe areas in healthy older individuals and prodromal Alzheimer's disease patients. An experimental condition will be compared with a sham condition in a pseudo-randomized cross-over design.

After some initial excitement regarding the potential of trigeminal nerve stimulation, it appears as though stimulating the trigeminal nerve is just acting as a middleman to achieve the same or better effects that can be achieved using vagus nerve stimulation.  Neurosigma does state "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." So lets just cut out the BS and go for the gold.

This is not a technology I would invest in.  Best bet, in my opinion, cut out the middleman and go right to the source - stimulate the vagus nerve to treat PTSD.  DARPA, the Defense Advanced Research Project Agency has been funding research on vagus nerve stimulation to treat PTSD. DARPA's research appears to focus on the vagus nerve with no mention of the trigeminal nerve. As for a potential new Clinical Trial, perhaps stimulating the auricular branch of the vagus nerve and the trigeminal nerve simultaneously would provide some sort of synergist effect as opposed to just stimulating the vagus nerve.

Bindi and Third Eye

Another possible explanation for the positive effects of transcutaneous trigeminal nerve stimulation is it's effect on the "third eye" as the locations on the forehead are the same..  The "third eye" is a mystical concept that turns out to have real evolutionary significance. There are some 'primitive' extant reptiles such as the Tuatara which has a parietal eye that in 'higher' vertebrates became the pineal gland. The FDA approved Cefaly for migraines appears to be capitalizing on this concept by its design. Dimethyltryptamine (DMT) has been shown to be produced by the mammalian pineal gland. Interesting!

The Cefaly trigeminal nerve stimulator for migraines - Third Eye?