The central thesis of this paper is that low levels of dopamine and serotonin interfere with limbic system inhibitory circuits for controlling central noise, while high levels of free bivalent copper contribute to over-excitation of both the limbic system and the auditory cortex. All of these factors create a chronic state of hypervigilance and stress arousal, which complicates the tinnitus clinical picture. When this is the case, psychological therapies such as cognitive behavioral therapy, self-regulation therapy and neural feedback are more effective once the basic underlying biochemical imbalance has been corrected with individualized nutrient therapies.
Tinnitus is the experience of hearing a sound when there is no evidence of an external sound stimulus. In that sense, it is very much like phantom limb pain, where an individual experiences pain in a body part that has been amputated. Estimates of the prevalence of tinnitus in the American population range from 10 to 15 % (Crayton & Walsh, 2007). Many people have a mild experience of tinnitus that is not particularly disturbing or disabling. However, others describe the effect of tinnitus as severely impairing the quality of their lives or even disabling. In this paper, I shall present an integrative model of tinnitus and a nonpharmacological treatment protocol.
To date, there are no effective general pharmacological treatments for tinnitus (G. B. Parker et al., 2006). Recent guidelines recommend against the use of anxiolytics and antidepressants (Crayton & Walsh, 2007). Auditory masking and retraining strategies, however, have shown effectiveness for some but not all tinnitus patients (Oz et al., 2013) (Tyler, Noble, Coelho, & Ji, 2012).
Tinnitus is often comorbid with anxiety, depression, insomnia, irritability and/or stress intolerance. Psychological treatment including cognitive behavioral therapy, self-regulation therapy and neural feedback have all been used with some efficacy for decades (Hesser, Weise, Westin, & Andersson, 2011; McKenna, Handscomb, Hoare, & Hall, 2014; Milner et al., 2016). The treatment effect, however, may be more an acceptance of the tinnitus experience than actual reduction of tinnitus sensation (Moschen et al., 2015).
Until recently, it has been thought that tinnitus is caused by peripheral noise-induced hearing loss followed by changes in the central auditory pathways (Jastreboff, 1990). Some support for this explanation has been provided by animal studies (Irvine, Rajan, & Brown, 2001). Hyperactivity of certain auditory pathways has also been visualized by functional imaging studies in tinnitus patients (Arnold, Bartenstein, Oestreicher, Romer, & Schwaiger, 1996; Lanting, de Kleine, & van Dijk, 2009).
Limbic involvement in tinnitus has been explained as a reaction to the unpleasant experience of tinnitus (Jastreboff & Jastreboff, 2000). More recently, a complex feedback system has been identified between the limbic system and the auditory cortex (Rauschecker, Leaver, & Muhlau, 2010). Rauschecker proposes that it is the failure of limbic and para-limbic structures to inhibit or cancel signals at the thalamic level that causes tinnitus to become chronic.
Tinnitus has also been associated with hypozincemia (Ochi, Kinoshita, Kenmochi, Nishino, & Ohashi, 2003; G. B. Parker et al., 2008). However, a recent large population study did not find significant correlation between low levels of zinc and tinnitus experience (G. Parker et al., 2011). This is likely due to the heterogeneity of the tinnitus population, making statistical significance of low zinc levels unlikely. Multiple causes are likely to be involved. Just as the diagnosis of mental health problems is often based upon symptoms rather than the multiplicity of underlying biochemical causal factors (Crayton & Walsh, 2007), tinnitus is likely to present as a constellation of causal factors with overlapping symptom presentation.
The comorbidities of tinnitus (anxiety, depression, insomnia, irritability and stress intolerance) are also symptoms associated with Kryptopyrrole disorder. Kryptopyrrole disorder is objectively identified through urinalysis. Elevations of urinary pyrrole molecules in excess of 10 mcg/dc is pathognomonic for a syndrome of mental health problems including anxiety, obsessive worry, insomnia, depressed mood, stress intolerance and irritability. Interestingly, tinnitus is frequently seen in this constellation of symptoms with Kryptopyrrole disorder.
The mechanism by which excessive pyrrole molecules cause this constellation of symptoms is very interesting. Pyrrole molecules are a byproduct of hemoglobin synthesis. Typically, pyrroles circulate through the bloodstream and are filtered out in the kidneys and excreted in the urine. While circulating in the bloodstream, pyrrole molecules have a high affinity for zinc and vitamin B6. Therefore, excessive pyrrole production causes the excretion of zinc and B6 in urine, creating functional deficiencies in zinc and B6.
Both zinc and B6 are critical for the synthesis of the calming catecholamines such as serotonin, dopamine and GABA. This suggests that pyrrole over-activity could interfere with the inhibitory capacity of the limbic system in controlling central auditory noise stimulation by reducing catecholamine production. In addition, low levels of zinc are often a cause of high levels of bivalent free copper. This is due to the fact that copper levels are regulated by a protein called ceruloplasmin, which is zinc dependent. Biochemically, these factors create a homeostatic balance between zinc and copper. Ideally, the ratio of copper to zinc is around 0.8 to 1.0, and free copper is below 25. Free copper is calculated as 100 x (serum copper – (3 x ceruloplasmin))/serum copper.
Free copper is neuro-excitatory, and at very high levels it is neurotoxic. In addition, free copper is a critical cofactor in the conversion of dopamine to norepinephrine. Low levels of zinc in combination with high levels of free copper can convert sufficient dopamine to norepinephrine to produce the symptom constellation described above. Low levels of dopamine will cause anhedonia, amotivation and a failure of the reward system. High levels of norepinephrine, which is a primary stress neurotransmitter, can cause hypervigilance, anxiety, obsessive rumination and insomnia. Patients often describe this syndrome as “tired body/racing mind.”
The Proposed Protocol
Identifying patients who are appropriate for this integrative treatment approach is relatively easy. First, they are likely to be tinnitus patients who describe their symptoms as “intolerable” and “emotionally disabling.” They will have a high incidence of comorbid symptoms such as anxiety, obsessive worry, reduced motivation, depression, anhedonia, and insomnia. They are likely to describe their quality of life as severely impacted by tinnitus, and they may be partially or totally disabled by the experience.
Second, laboratory testing confirms a diagnosis of Kryptopyrrole disorder. Laboratory tests to confirm Kryptopyrrole disorder would include blood test for whole blood histamine, plasma zinc, serum copper, and ceruloplasmin. These tests allow for the calculation of copper to zinc ratios and percent free copper. Urinalysis revealing excessive Kryptopyrrole concludes the laboratory testing.
Following a definitive diagnosis, treatment consists of patient education and nutritional supplementation to compensate for the loss of zinc and B6. Additional nutrients are needed for antioxidant support such as vitamin C and E, selenium and biotin. Dosing strategies are determined individually by body weight and symptomatology.
Improvement is often seen within 3 to 5 weeks with significant improvement after three months of compliance with the nutritional program. Concurrent with nutritional therapy, cognitive behavioral therapy, self-regulation therapy and stress management are often appropriate. In my experience, these psychotherapies are much more effective after the basic biochemical imbalances have been addressed.
Follow-up sessions are scheduled for six months and one year. At this time, fine-tuning of the nutritional protocol and a discussion of dietary or lifestyle changes to support continued recovery is appropriate. In one case, a patient who had successfully eliminated tinnitus as well as the comorbid emotional symptoms was found to have relapsed. An analysis of diet revealed high levels of consumption of high copper foods such as kale, shellfish and cashews. Continuing on the supplement protocol but eliminating high copper foods allowed this patient to return to a near symptom-free state. In another case, chronic caregiver stress caused periodic relapses requiring additional zinc and B6 as well as stress management and supportive psychotherapy.
This approach is not recommended for all tinnitus patients. For example, tinnitus patients who do not have some of the emotional comorbid features seen in Kryptopyrrole disorder are less likely to benefit. It is actually the patient who is suffering the most who is more likely to benefit. In my experience, the integration of biological and psychological intervention relieves patients of the stigma associated with addressing the psychological comorbidities of tinnitus alone. Once properly educated, patients often feel relief and hope, which helps motivate compliance with the treatment protocol. After initial symptom resolution they typically respond to psychotherapy quickly and effectively.
This paper presents the rationale for integrative treatment of a certain subset of tinnitus patients. It is my goal to evaluate this approach with a large enough sample size to allow statistical analysis. To date, I have had success with three of three initial patients. A sample size of 20 to 30 appropriate patients should be sufficient to draw conclusions about the efficacy of this approach.
Dr. Richard A. Wyckoff, PhD
Adult and Geriatric Behavioral Medicine
Diplomate, American Academy of Pain Management
Diplomate, American Board of Disability Analysts
Founder, The Alliance for Nutrition & Mental Health
Appletree Executive Suites
13606 NE. 20th St., Suite 205
Bellevue, WA 98005
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