If you wish to discuss the below document by Perseverance, please visit the original discussion thread:
http://www.benzobuddies.org/forum/index.php?topic=106121.0
While there can be many causes of tinnitus (5), this paper will be focusing on ways benzodiazepines might be involved and potential treatment.
Tinnitus has been associated with benzodiazepine usage and protracted tinnitus has been reported after discontinuation of benzodiazepines. (5, 6) Ironically, benzodiazepines have also been shown to reduce tinnitus symptoms. (4, 5) Many researchers believe the explanation for tinnitus lies in the Neural Synchrony Hypothesis. In this model, the neurons in the Auditory Cortex become overactive. I will explain this hypothesis in simple terms as we go along. First we will begin by looking at how sound travels from the outer ear to the brain.
Referring to the picture above, sound vibrations (or sound waves) travel into the External Auditory Canal (aka the ear canal), where they hit the Tympanic Membrane (aka the eardrum). The Tympanic Membrane vibrates in sympathy with these sound waves. As it vibrates, it moves a series of tiny bones in the middle ear (Malleus and Incus), which carry the vibrations to a fluid-filled tube called the cochlea in the inner ear. The fluid inside the cochlea vibrates a series of tiny hairs called cilia, which are attached to Cochlear nerves (aka auditory nerves). The movement of these cilia stimulates the nerves, and they send signals to the brain, which, in turn, processes these signals into the sounds we hear. (7)
Then there are a lot of stages between the ear and the brain (shown below (8 )), that we will not go into, but it is important that you are aware of this.
Problems in any of the stages (shown above) along the auditory pathway between the ear and the Auditory Cortex (the auditory section of the brain) can cause tinnitus. This is because the absence of an auditory signal can make the neurons in the Auditory Cortex misbehave (this will be discussed shortly). Therefore, any condition that prevents auditory signals from reaching the Auditory Cortex in the brain can cause tinnitus.
For example, if damage were to occur to the tiny hair cells inside the cochlea, say either by loud sounds or ototoxic medications, they would be unable to transmit signals to the Cochlear nerve. That would disrupt the signal path to the Auditory Cortex and cause tinnitus.
The Auditory Cortex is the part of the brain where you actually ‘hear’ sounds. Neurons in the Auditory Cortex are organized according to the frequency of sound to which they respond best. Neurons at one end of the Auditory Cortex respond best to low frequencies; neurons at the other respond best to high frequencies, as shown below. (9, 14) This type of arrangement is known as tonotopy. (13) Since each of these sections of neurons within the Auditory Cortex responds to a different frequency of sound, when a particular section is activated by an incoming auditory signal, you will ‘hear’ the sound frequency represented by that section.
The Auditory Cortex does not like disruption in the auditory signal pathway. When any section of the Auditory Cortex does not receive the signals it is supposed to the neurons in that section can become over-active. According to the Neural Synchrony Hypothesis, tinnitus is generated when synchronous activity develops among neurons in frequency regions of the Primary Auditory Cortex that have been partially deafferented (meaning the incoming auditory signals are lower than normal). (3)
In other words, when the auditory input is lower than it should be, which could be due to things like damage to the inner ear, the neurons in the Auditory Cortex can become over-active. The firing rates of the neurons start to increase, then an abnormal synchronous firing pattern of the neurons develops where the neurons begin to fire off electrical signals at the same time. Scientists call this synchronous activity ‘neural synchrony.’ It is the neural synchrony which generates the sounds of tinnitus that you hear. This hypothesis may explain why hearing loss can cause tinnitus. (3, 12) Here is a link to an animation that shows what neural synchrony looks like:
http://www.mind.ilstu.edu/curriculum/neural_synchrony/neural_synchrony.php?modGUI=233&compGUI=1824&itemGUI=3153
The section or sections of the Auditory Cortex where the over-activity of the neurons is occurring will determine the frequency of the sound of the tinnitus you hear. This cause of tinnitus is known as the ‘Neural Synchrony Hypothesis.’
Increased activity in neurons is known as excitation. On the opposite end of the spectrum, a decrease in neuron activity is called inhibition. GABA is the main neurotransmitter used by the brain for inhibition. When GABA binds to receptors on the neurons it decreases the neurons activity. Therefore, GABA is classified as an inhibitory neurotransmitter.
An imbalance between stimulating and inhibiting signal information in the affected areas of the nerve cell network can result in hyperactivity and synchronisation. In other words, when the ear stops talking to the nerve cells in the auditory cortex they will start to talk to themselves and create tinnitus. (12)
Some researchers believe that innate deficiencies in GABAergic mechanisms might be involved in the pathophysiology of tinnitus. SPECT imaging studies have shown diminished benzodiazepine binding sites in the Medial Temporal Cortex in some tinnitus patients. It has also been suggested that a ‘benzodiazepine deficiency syndrome’ might even exist. (4)
Loss of inhibition can leave neurons in a hyper-excitable state. Benzodiazepines can increase inhibition by enhancing the action of GABA, and therefore have been shown to be an effective treatment for tinnitus. However, benzodiazepine discontinuation has been shown to be associated with protracted tinnitus. (5, 6) So how could a medication used to treat tinnitus also be a possible cause of tinnitus?
Researchers are still trying to sort it all out, however, possible Benzodiazepine related causes of tinnitus might include things such as: 1) ototoxic effects; 2) Down-regulation of GABAA receptors; 3) increased Glutamate activity; 4) Benzodiazepine induced changes to the Serotonin neurotransmitter system; 5) Benzodiazepine induced uncoupling of GABAA receptors - which could involve a permanent conformational change in existing receptors, production of an endogenous regulatory GABA-A receptor ligand, a change in phosphorylation, or a displacement of GABA-A receptor subunits. (4, 5, 10)
Regardless of how benzodiazepines may be involved in tinnitus, many scientists believe that the sounds of tinnitus stem from the over-excited neurons in the Auditory Cortex and that treatment should focus on inhibiting this neuronal over-activity. (5)
Researchers studying tinnitus discovered that when a patient with tinnitus listened to tones that matched the frequencies of their tinnitus, the tinnitus would diminish for a period of time after the tone was turned off. They refer to the sounds that match the tone of the tinnitus as ‘masking sounds.’ (3)
The period of diminished tinnitus following the cessation of the masking sounds is referred to as ‘residual inhibition’ or ‘RI.’ Researchers theorized that the masking sounds provoke an inhibition response that calms the over-activity. They discovered that For RI to be experienced, masking sounds must be presented at levels exceeding the loudness of tinnitus and for at least 10 seconds. (3)
These studies lead to the development of a relatively new therapy that is based on the Neural Synchrony Hypothesis, called acoustic coordinated reset (CR®) neuromodulation therapy. Acoustic CR neuromodulation therapy was developed by researchers at ANM Medical in Germany. I found out that this device has been approved in the UK, but could not locate the approval status in other countries- so I sent them an email requesting this information. I will post their reply on this thread when I hear back from them.
The acoustic coordinated reset (CR®) neuromodulation therapy device works by using tones that cause the brain to ‘unlearn’ the tinnitus sound. Special tones are used that target the hyperactive, synchronous nerve cells in the auditory cortex. The goal is to disrupt the pathological neuronal synchrony to achieve a state of desynchronisation. Repeating the desynchronisation process continuously causes the nerve cells to ‘unlearn’ step by step how to engage in hyperactivity and synchrony. (1, 11)
Here is a video that explains how acoustic coordinated reset (CR®) neuromodulation therapy works:
https://www.youtube.com/watch?v=fIAjJogJ0cs
I hope that the mods do not deactivate this link as it is a great audio visual explanation that really puts this complex concept into layman’s terms- it is definitely worth your time to watch it. You could also find it by doing a search for ‘Tinnitus Treatment - Causes and treatment of tinnitus’ on youtube.
If you have noticed in the past that your tinnitus has diminished after listening to certain tones, you might want to ask your doctor if you could be a candidate for this type of therapy. The American Tinnitus Association has a list of the sounds of tinnitus at this link- after listening to these tones for a minimum of 10 seconds you may notice your tinnitus diminishing:
http://www.ata.org/sounds-of-tinnitus
There are also web sites such as HushTinnitus dot com that offer free tests to see if you experience RI after listening to certain tones. HushTinnitus was developed by Clyde Witchard who did extensive research into using tones to induce RI. (15) Be sure to check with your doctor before engaging in such activities as certain disorders- such as Meniere’s Disease, can be made worse by this type of therapy.
Whether acoustic coordinated reset (CR®) neuromodulation therapy will work for benzodiazepine induced tinnitus remains to be seen. If any of the members here have access to this therapy in their country and decide to give it a whirl, your feedback would be appreciated.
Further Reading
Ringing Ears: The Neuroscience of Tinnitus
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073522/
Cross-Modal Plasticity Results in Increased Inhibition in Primary Auditory Cortical Areas
http://www.hindawi.com/journals/np/2013/530651/
Effects of ( -1 -baclofen, clonazepam, and diazepam on tone
exposure-induced hyperexcitability of the inferior colliculus in the rat:
possible therapeutic implications for pharmacological management of
tinnitus and hyperacusis
https://www.utdallas.edu/~amoller/publications/332.pdf
Tinnitus, Unipolar Brush Cells, and Cerebellar Glutamatergic Function in an Animal Model
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681784/
References
1) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710266/
2) http://www.ata.org/sounds-of-tinnitus
3) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2580805/
4) http://www.tinnitusjournal.com/detalhe_artigo.asp?id=231
5) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832848/
6) http://www.benzo.org.uk/busto.htm
7) http://www.fi.edu/fellows/fellow2/apr99/auditorypath.html
8 ) http://www.dana.org/Publications/GuideDetails.aspx?id=50018
9) https://en.wikipedia.org/wiki/Auditory_cortex
10) http://www.medscape.com/viewarticle/767520_1
11) http://anm-medical.com/index.php?option=com_content&view=article&id=75&Itemid=99&lang=en
12) http://anm-medical.com/index.php/en/crr-technology/scientific-principles
13) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830355/
14) http://www.d.umn.edu/~jfitzake/Lectures/UndergradPharmacy/SensoryPhysiology/Audition/TonotopicMaps.html
15) http://www.residualinhibition.com/residual-inhibition.pdf
