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Scientifically formulated and clinically tested nutritional supplements

James Kaltenbach, Ph.D.
May 22, 2002

When I was an undergraduate, I majored in the field of geology, studying rocks. Now here I am, thirty years later, studying the effects of rock music.

So we've heard a lot about tinnitus tonight, and the stage is set to look at some of the basic research issues. Tinnitus is a very prevalent problem: two to four million people in the United States experience it in a severe enough form that they are debilitated by it. That's a lot of people.

Despite the prevalence of tinnitus, there still remains relatively little research at the basic science level. In fact, it wasn't until the late 1990s that we started seeing a serious interest taken by the scientific community to develop animal models where mechanisms of tinnitus could be systematically studied. The American Tinnitus Association has been key in stimulating this research. The purpose of this presentation is to give you an overview of some of the results of these research efforts. And I'll focus particularly on the period of the last five to seven years, when these developments have been most dramatic.

All of us in the tinnitus community operate under the hope that improvements in the treatment of tinnitus will be facilitated by an understanding of its underlying pathologies and mechanisms of generation. And there's a good reason for believing this. It's not just an assumption. If you look at the ability to treat deafness with the cochlear implant, the ability to develop that implant followed an understanding of how the inner ear worked. Studies went back to the 1930s the 1940s. The basic science of the inner ear physiology was worked out, and once that understanding was established, it paved the way for the later treatment of hearing loss through the development of the cochlear implant. So by analogy, we expect the knowledge base we gain from basic tinnitus research will lead to hopefully similar treatment abilities.

The goals of basic tinnitus research are three-fold. First, we seek to define the underlying pathology of tinnitus—that is, what goes wrong in the system that results in the perception of tinnitus? Second, we want to identify the sites of generation—where are the disturbances located in the body, where in the brain, where in the central nervous system? Third, to develop strategies for new therapeutic approaches, having laid the foundation through an understanding of the pathology and the sites of generation, hopefully we'll be able to generate new therapeutic approaches.

So let's start with the first issue: the nature of the pathology, and specifically, the disturbance in neural function that leads to tinnitus. One type of change, which has been implicated in the last five to seven years as an underlying cause of at least some types of tinnitus, is something called neural hyperactivity. Hyperactivity is defined as an increase in the level of spontaneous or arresting activity of neurons. Neurons are normally buzzing away at a certain, fairly low base level. And then they become hyperactive. Their fire rates go up. What does that look like? [Points to overhead presentation.] This frame shows normal spontaneous activity. And you can see these discharges, what are called spikes; they're voltage events. Put an electrode on the appropriate part of the brain, you will record activity that looks like this in a normal subject. This particular subject happened to be a hamster; the animal models make very good models for studies of tinnitus. However, if you expose the hamster to intense noise and put the electrode in the exact same place, you get what we see in the lower frame here, increases in the magnitude of these voltage events and much more of them—this is what we call hyperactivity.

Now, why do we think this hyperactivity has anything to do with tinnitus? The reason is quite simple. First, if you look at the pattern of the hyperactivity, which is represented by this upper curve here, it shows a peak above the baseline level, which is represented by this lower curve down here. This is the normal activity that we get. It's normally very low, but following noise exposure the activity level goes way up and gives you a nice peak. Likewise, if you take a normal animal and stimulate it with a low level sound, you can convert this activity to what you see by this curve here. So in other words, the pattern of activity that you see here—this was recorded a month after the noise exposure—is very similar to what you get immediately when you stimulate with a sound. In other words, the brain is acting like it's responding to a sound even though there's no longer any sound there.

The second reason we believe that this hyperactivity is related to tinnitus is that, indeed, we've seen in the literature that the same sound that causes this hyperactivity actually causes the animals to develop tinnitus. And the two phenomena, the tinnitus and the hyperactivity, now appear to be reasonably well correlated.

Now what causes neurons to become hyperactive? The most likely explanation of this hyperactivity: it's a change that results from alteration in the balance of excitatory and inhibitory inputs to neurons. Put another way, neurons are like people. Neurons are receiving inputs from all over the world of the nervous system. Some of these inputs come from other neurons. Some of these inputs are excitatory; they have high levels of activation. They might be responding to a stimulus, or they might be responding to a thought or a state of mind. There are all kinds of signals in the brain. Things you may want to ignore might result in an inhibitory signal. The neurons that have become hyperactive lose some of this inhibition, but they don't necessarily lose much excitation; in fact, the pendulum swings over to the excitatory side when inhibition is lost, so the neurons, in other words, become disinhibited. And that results in a higher level of activation.

What causes the shift of the balance between excitation and inhibition? First, neuronal plasticity. If you injure the system in any way—too much sound, a toxic drug—you can trigger the nervous system actually to rewire. It will start reconnecting to other neurons. Sometimes, this is a physical change where the neurons actually make new connections. Other times, it retrains the neuron to seek inputs from other neurons that are normally a source of significant input. So the nervous system is very delicate and it doesn't take much to get it rewired. Some of the rewiring is a good thing. Rewiring in everyday life is how we learn from our experiences. This is also neuronal plasticity. But when rewiring results from an injury, an over-stimulation or some other kind of insult, that's a bad thing. It can result in shifting this balance of normal excitation and inhibition. That can result in the hyperactivity I'm talking about.

A second triggering mechanism of this swing from a normal state to a hyperactive state is called cochlear outer hair cell damage. The cochlea is a structure inside the inner ear that normally converts the mechanical energy of sound to an electrical signal. It's the energy converter. It preserves the signal of sound in the form of electrical signals and then relays that input to the brain. The outer hair cells are located in the cochlea. The hair cells are lined up in rows along the stretch of this coiled cochlea. There are three rows of outer hair cells and three rows of inner hair cells. These are the cells we hear with. You damage these you lose your hearing. But you also can induce tinnitus.

Typically, intense noise and certain kinds of drugs will cause damage to the outer hair cells. We've finished a study that took us about four years, and we now have unequivocal data to support the view that this kind of injury results in hyperactivity. And we now know that hyperactivity is related to tinnitus, so it looks like the outer hair cell loss is what triggers the tinnitus.

So where in the brain does this hyperactivity actually occur? First of all tinnitus is primarily a disorder of the auditory system, the sense of hearing. However, tinnitus can be associated with disorders of other sensory systems. An example of that is tempero-mandibular joint pain. Frequently, TMJ pain is associated with tinnitus.

Another example is a center motor disorder. Certain oro-facial movements, that is, of the mouth or the face, can induce tinnitus or make it worse. A study by Dr. Levine showed that 30 percent of his patients with tinnitus developed louder tinnitus when pressure was applied to their necks, faces, or shoulder regions. Other labs have shown that a large percentage of patients can worsen their tinnitus by clenching their jaws. These are what are called somatic forms of tinnitus, or somatic tinnitus.

Tinnitus is also associated with disorders of attention like hyperattentiveness, meaning too much attention to detail. Dr. Jacobson pointed out earlier that tinnitus is actually a very low level sound in your head, that it is matched to a very quiet sound that is even quieter than a whisper. How is it that it could be so bothersome? Well, one disorder that could lead to that is hyperattentiveness. We tune in to the signal a little bit more than we should and that leads to the disturbance, the emotional reaction associated with tinnitus. And, of course, the emotions themselves could be a source of worsening of tinnitus or even a trigger of tinnitus. We know that stress and depression, for example, will sometimes bring on tinnitus or make it worse.

In more than half of subjects with tinnitus, the condition persisted even after the connection between the brain and the ear was severed. The first time I heard that, which was about 20 years ago, I was quite surprised because I was used to thinking that tinnitus was an ear problem. In 1981, a study was published again on the basis of hundreds of patients that had tinnitus and had undergone surgery on their auditory nerves. Sixty percent of them or so continued to experience the tinnitus after the nerve was cut, and in many of them the tinnitus actually got worse after the surgery. So that suggests that tinnitus originates at the central level of the auditory system rather than the ear. It's a disorder where we should be looking at the brain, perhaps, rather than the ear. Even though the disorder may be triggered by damage to the outer hair cells of the cochlea, the actual hyperactivity may be located centrally.

I'm going to go back to the diagram of the central auditory pathways as it relates to the input from the ear. This is the ear here, the outer hairs cells shown here, the inner hairs cells there, the auditory nerve takes it origin from these hair cells, conveys the signals to the brain, and then once it reaches the brain, you can see these projections getting rather complicated. It projects all over the place. But the main point is that there are several stations within the brain that receive these projections. And they project up the brain to the highest level, up here in the cerebral hemispheres. This region is called the auditory cortex. Down here in the brain stem, you see a few nuclei. These are receivers of the input from the ear. The cochlear nucleus is here, a very significant structure in relation to tinnitus.

Okay, so the question to be asked: where in the brain does the disorder called tinnitus originate? After noise exposure, hyperactivity is observed in the lower auditory brain stem in a structure called the dorsal cochlear nucleus. The hyperactivity is not eliminated by surgically removing input to the brain from the ear. That matches the clinical finding that severing the auditory nerve does not get rid of tinnitus. And studies are now under way to determine whether the hyperactivity seen at this dorsal cochlear nucleus level reaches the higher levels of the auditory system, i.e. the cortex. Now that's a significant question because the cortex is usually thought to be where conscious perception resides. Most people studying the brain believe that consciousness is rooted in the cortex. The consciousness of auditory or acoustic stimuli is therefore rooted in the auditory cortex.

Brain images of human patients with various forms of tinnitus reveal the involvement of auditory cortex as well as the midbrain area called the inferior calculus. This is the lateral view of the brain and the checkerboard pattern corresponds to regions in a tinnitus patient. This is a study of a tinnitus subject in silence and the image was obtained using Postitron Emission Tomography or PET imaging. And it's superimposed on another type of image called a Magnetic Resonance Imaging or MRI. And you can see the region that was activated in the tinnitus subject is right up here in what's called the temporal region of the brain, the temporal lobe. This is what is meant by the auditory cortex.

Interestingly, if you take someone without tinnitus and stimulate that person with a tone, this same region lights up. In other words, it looks like tinnitus involves an increase in activity of the auditory cortex. What pathologies could underly the form of tinnitus associated with temporal mandibular joint syndrome, TMJ? The pain associated with TMJ is carried along the fifth cranial nerve, called the trigeminal nerve, and in very recent years it's been found, by Dr. Susan Shore at the Kresge Hearing Research Institute, that the trigeminal ganglion provides input to the dorsal cochlear nucleus. I mentioned in an earlier slide that the dorsal cochlear nucleus becomes hyperactive after noise exposure. Very likely the trigeminal nerve input or the ganglion input to the dorsal cochlear nucleus is modulating the level of activity in this structure and depending on the condition of the temporal mandibular joint, may or may not result in a trigeminal input to the dorsal cochlear nuclei. So this is very likely to be a good experimental model for teasing out the mechanisms of a common form of tinnitus that occurs with another sensory disorder.

Let's talk about therapeutic approaches. What are some of the possibilities raised by these research findings in recent years? Well, you've got the possibility of some pharmacological approaches; therapeutic drugs are now being tested on specific targets of the brain, and the top candidates are drugs with known inhibitory effects on spontaneous activity. Agents have been identified that do in fact reverse the effect of hyperactivity in the auditory system. In fact, a large number of agents seem to have the ability to stimulate inhibitory input. The trouble is that none of these agents are yet specific to the auditory system. The reason that's a problem is that these agents will act on other regions of the brain and thereby cause undesirable side effects. We need to develop analogs of these inhibitory compounds that are specific to the auditory system and specifically to the structure I've talked about, the dorsal cochlear nucleus or auditory cortex and we need to find drugs that are more potent so that we don't need to use high concentrations to get an effect. I think the research we've seen in recent years really opens up this possibility and brings it within reach, hopefully within the next few years.

Another option opened up by these research findings is the possibility of electrical stimulation. Can we stimulate circuits that are inhibitory in function? Does, for example, electrical stimulation of the inhibitory circuits of the dorsal cochlear nucleus alleviate tinnitus? Interestingly, in 1994, a paper did in fact come out from the House Ear Institute in Los Angeles that reported that tinnitus was alleviated in six out of seven patients who used an implant on the dorsal cochlear nucleus. They turned it on daily, every day for about a month, and they experienced major improvement in their tinnitus. So indeed the dorsal cochlear nucleus may be a great target for the treatment of tinnitus. And as technology develops, it should become more reasonable and realistic to foresee a day when the dorsal cochlear implant will be done in the same way a cochlear implant is done today.

All right, I'll summarize what I've said up to this point: in the past five years there's been an increase in research efforts concerned with the neural basis of tinnitus. That these efforts suggest that hyperactivity is an important pathology that underlies some forms of tinnitus and this hyperactivity has been identified at various levels of the brain. Efforts are now underway to identify agents that will alleviate the condition of hyperactivity. And the research needs to be expanded. I can't overemphasize this point. It needs to be expanded further to accelerate the progress in the understanding of tinnitus and tinnitus treatments so that we can see these treatments develop not just in our own lifetime but hopefully in the next five to ten years. We don't have any treatment yet that works for most people. The treatments that are out there are very useful for many individuals. The trouble is they don't work for most individuals. At least they're not the aspirin for the headache. We don't have a headache killer like aspirin to get rid of tinnitus and that's really, I think, what we can hope for and within reason anticipate seeing develop sometime within the next decade.

Thanks a lot for your attention.
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