Dr. Michael L. Oshinsky is the Program Director for Pain and Migraine at the National Institute of Neurological Disorders and Stroke. As a Program Director at NINDS, Dr. Oshinsky is responsible for research and administrative issues related to migraine, other headache disorders, neuropathic pain, peripheral and central mechanisms that mediate pain, central processing of pain perception, disease-related pain disorders, and pain management.
What neuromodulation strategies are currently being investigated?
DR. OSHINSKY:At National Institute of Neurological Disorders and Stroke (NINDS) we fund lots of different studies of neuromodulation devices to treat headache.
Currently the field of neuromodulation is really exciting. NINDS and NIH in general is funding many different types of neuromodulation devices and strategies to treat trigeminal pain, headache, and other pain disorders—everything from stimulating peripheral nerves to implanted devices, to even implanting polymers next to nerves that can then be stimulated noninvasively through the skin.
For headache, there have been studies of the vagus nerve and its mechanism of action. Researchers have looked at what cellular and circuit level changes are associated with stimulating the vagus nerve and how that can then lead to an alleviation of the symptoms of migraine, be it the frequency of migraine or the intensity of the headaches themselves.
There are also investigations of deep brain stimulation. That means implanting electrodes in the cortex and other areas of the brain involved in processing pain signals from the body or trigeminal region. Researchers have examined whether or not modulating those electrical signals can lead to the alleviation of headache, or even in the decrease in frequency of headaches themselves.
How does neuromodulation alleviate migraine pain?
DR. OSHINSKY:There are many different strategies that neuromodulation devices can use to treat trigeminal pain and headache, and even migraine.
One strategy is stimulating a cranial nerve, such as the trigeminal nerve and its various branches, or treating a combination of nerves, such as the occipital nerve and the trigeminal nerve. Both of these strategies are used to treat headache.
So, the mechanistic question is, how does stimulating these areas lead to a lessening or alleviating migraine symptoms or decrease pain and headache?
Initially, Wall’s Gate theory was used to explain this phenomenon. In Pat Wall’s Gate theory of pain, when there was a stimulation or an activation of large beta fibers there was a corresponding suppression of C fibers. But that has not panned out in our circuit understanding of all levels of the spinal cord, or even the dorsal horn portion of the brain stem.
From experimental evidence we do know that stimulating the vagus nerve, or the occipital nerve, does modulate levels of inhibitory neurotransmitters at the level of the dorsal horn, such as GABA, and that can lead to a decrease in excitatory neurotransmitters, such as glutamate, which would enhance pain.
So, either increase GABA or decrease glutamate, and that can lead to alleviating the symptoms of migraine and headache disorders.
They looked at a group of people in the Danish Headache Registry and assessed various factors of impact, disability, comorbidities, and so forth. They determined that 8 days of migraine is, in terms of impact, equivalent to the full ICDH-3 criteria. That essentially doubled the number of people that could be identified as having chronic migraine.
What have we found out about human neuromodulation using animal models?
DR. OSHINSKY:In the context of understanding how neuromodulation can affect the perception of pain, or even the frequency of recurrent headache disorders, animal models can be very helpful.
In these model systems—be they small animal systems, such as the mouse or the rat, or in large animals, such as the goat, the dog, etc.—we can do pathophysiology studies in a very controlled environment that we can't do in humans.
In the case of the rodents, we can do controlled studies to look at neurochemistry—changes in extracellular levels of neurotransmitters. We can also look at changes of electrophysiology at multiple levels of the nervous system, which is not easily attainable from a larger animal system, or maybe even from humans.
But there are shortcomings in using those small animal systems and that is scaling down these electrical devices, these neuromodulation devices, to work in these small animals. That reduction in scale changes the physics of the interaction of the neuromodulation device with the target tissue, in this case either peripheral nerve or the central nervous system.
And that is why we also use large animal systems to test and validate the pathophysiological mechanisms that we've discovered in the small animal systems to better understand how they could potentially work in humans.
That is the goal of using the larger animal systems—scaling up the size. We want to make sure that the interaction of the electrical stimulation device in the tissue is maintained in a similar way. We want to be assured that what we understand theoretically from the small animal can be applied to the large animal systems.
Of course, the gold standard is to eventually do the appropriate clinical trials. In all these types of work, we are very enthusiastic at the NIH in supporting and contributing to the development of new neuromodulation devices for the treatment of migraine and other headache disorders.
The views expressed here are those of Dr. Oshinsky and not the official policy of NINDS and NIH, the federal agency.