by Barry Keate
In the latest issue of Quiet Times (March 20011) I answered a question regarding Vagus Nerve Stimulation (VNS) for the reduction of tinnitus. Researchers at the University of Texas induced tinnitus in laboratory rats then treated them with a combination of VNS and sound therapy. Rats that experienced both the VNS stimulation and the sound therapy appeared to overcome their tinnitus while rats that only had one or the other, but not both, did not recover.
This elicited an astonished response from a reader who asked, “How can one tell that the tinnitus is improved in rats? There is not an audiological device in the world that can measure and quantify tinnitus without the subject being able to communicate with the doctor, and rats can’t speak! So fundamentally, this entire experiment is impossible. There simply is no way to know that a rat has tinnitus.”
This was a great question and pretty much stopped me in my tracks. It is very easy for someone like me, who regularly reviews clinical studies and attends meetings of the International Tinnitus Forum, to accept a concept as a given and completely blow by the fundamental question of why a particular precept is true and workable.
Here, then, is the story of the development of an animal model of tinnitus and a way to determine if a rat has it.
The need for an animal model has been obvious for decades. Without it, experimentation took place only in humans, resulting in investigations that were on a superficial level due to restrictions by the nature and ethics of human experimentation. A way of investigating central auditory cortex responses without the practical and ethical constraints imposed on humans was needed for fundamental science to progress.
Pawel Jastreboff, PhD, famed for developing Tinnitus Retraining Therapy, and his colleagues in 1988, developed the earliest animal model.1 They verified the model by two separate means, electrophysiological and behavioral.
1 – In electrophysiological verification, guinea pigs were injected with sodium salicylate, the active ingredient in aspirin. This is known, in high doses, to reliably cause subjective, high frequency tinnitus in humans. Electrodes were inserted into the auditory cortex before injection to measure neuronal activity. Neuronal activity was analyzed both before and after injection.
Comparisons of spontaneous neuronal activity after injection revealed the same elevated responses as were seen by external sound stimulation. This indicated that changes induced by salicylate were interpreted by the guinea pig nervous system as sound and since the sound was not externally generated, it was, by definition, tinnitus.
2 – During behavioral verification, adult male laboratory rats were trained to drink water when a sound was present but to stop drinking whenever the sound was turned off. They were deprived of some water so they would lick water in the test chamber as long as a sound was present. They were then conditioned by the delivery of mild shock to stop licking when the sound stopped.
After conditioning, rats put into a test cage without sound drank very little water. When sound was turned on, they started drinking. They also started drinking after they had been injected with a high dose of salicylate but not after injection with placebo. The salicylate caused tinnitus, leading the rats to think the external sound was still turned on and they continued drinking.
Once researchers establish which rats or other laboratory animals have tinnitus, they can then conduct studies on various treatment therapies. They are much less constrained with ethical considerations than when working on humans so they can conduct experiments that would not be allowed on human subjects.
Animal models have become increasingly sophisticated and allow for a number of different research approaches and treatment therapies. Some researchers train laboratory rats to drink during quiet periods but to stop drinking when sound is turned on. Others are trained to press a lever for food in the presence of continuous noise.
In 1999, Carol Bauer and colleagues developed a new paradigm for an animal model.2 Novel features included oral dosing of salicylate and assessment of tinnitus over several months rather than several days, as before.
In 2004, Richard Salvi, Ph.D., Director of the Center for Hearing and Deafness at the University of Buffalo, and his colleagues, developed an animal model of tinnitus that allowed them to monitor the activity of individual neurons in animal brains where the phantom sounds are thought to occur.3 The researchers monitored changes in the auditory cortex before, during and after inducing tinnitus.
As animal models have developed with greater complexity and sophistication, many studies have been conducted on treatment therapies for tinnitus. While it is beyond the scope of this paper to examine all of these in detail, the one that inspired this is Vagus Nerve Stimulation (VNS) for the treatment of tinnitus.4]
The vagus nerve extends from the brain to the chest and abdomen. It conveys sensory information from the body’s organs to the central nervous system. Currently, VNS has been used successfully to treat more than 50,000 patients for epilepsy and depression.
Study authors Dr. Navzer Engineer and Dr. Michael Kilgard, at the University of Texas in Dallas, induced tinnitus in laboratory rats using loud noise. After verifying which rats had tinnitus, they treated them with sound tones combined with brief pulses of VNS. At the end of the study, rats that experienced both the electrical stimulation and the sound tones appeared to overcome their tinnitus while rats that only had the electrical stimulation or the sound tones, but not both, did not recover.
The successful group had eliminated the physiological and behavioral symptoms of tinnitus. Three weeks after the therapy, investigators studied the brains of sacrificed rats and determined that the technique produced long-range changes in cortical organization. This means it reversed the abnormal brain changes that trigger tinnitus.
This was a very preliminary and limited study. It was also conducted on animals with extremely early-onset tinnitus. The authors are working on a design for a full clinical study for treating tinnitus. While this is very exciting, it must be remembered that there are many successful experiments in animal models that simply don’t pan out when they are applied to humans. Also this treatment is invasive, accomplished by means of an implantable electronic device, much like a heart pacemaker, that powers electrodes connected to the vagus nerve.
Whatever the results may be for this particular therapy, the development of an animal model of tinnitus has been crucial for the understanding of the basic science behind its development. I’m certain there will be many more breakthroughs in tinnitus treatment due to animal models.
1. Jastreboff, PJ. Brennan, JF. Sasaki, CT. An Animal Model for Tinnitus, Laryngoscope 98: March 1988.
2. Bauer, CA et. al. Behavioral Model of Chronic Tinnitus in Rats. Otolaryngol Head Neck Surg. 1999 Oct;121(4):457-62.
4. Vagus Nerve Stimulation Helps resolve Tinnitus in Rats – Clinical Trials to Follow. Neurology Today. 17 February 2011; Volume 11(4); Pp 1,12-14.