Med Hypotheses. 2017 (Jan); 98: 2–4 ~ FULL TEXT
Federica Bressi, Manuele Casale, Rocco Papalia, Antonio Moffa,
Alberto Di Martino, Sandra Miccinilli, Fabrizio Salvinelli,
Vincenzo Denaro, Silvia Sterzi
Department of Physical and Rehabilitation Medicine,
Campus Bio-Medico University,
Subjective tinnitus and cervical spine disorders (CSD) are among the most common complaints encountered by physicians. Although the relationship between tinnitus and CSD has attracted great interest during the past several years, the pathogenesis of tinnitus induced by CSD remains unclear.
Conceivably, cervical spine disorders could trigger a somatosensory pathway-induced disinhibition of dorsal cochlear nucleus (DCN) activity in the auditory pathway; furthermore, CSD can cause inner ear blood impairment induced by vertebral arteries hemodynamic alterations and trigeminal irritation.
In genetically -predisposed CSD patients with reduced serotoninergic tone, signals from chronically stimulated DCNs could activate specific cortical neuronal networks and plastic neural changes resulting in tinnitus. Therefore, an early specific tailored CSD treatments and/or boosting serotoninergic activity may be required to prevent the creation of 'tinnitus memory circuits' in CSD patients.
From the Full-Text Article:
Tinnitus is an auditory percept – often described as a ‘ringing in the ears’– in absence of a corresponding auditory stimulus and is experienced by approximately 10–20 % of the population. 
Tinnitus can result from many different aetiologies, it is usually caused by a disorder of the auditory system or somatosensory system, but it can also result for a combination of both of them.  A major challenge in tinnitus research is to identify the different causes of tinnitus in order to develop specific therapies for each tinnitus subtype.  Tinnitus could be associated with upper cervical spine disorders (CSD) such as prolapsed intervertebral disks or instability of the craniocervical junction, and neck withplash.  In the 1920s the Neri -Barre -Lieou  syndrome was described and it is characterized by a broad spectrum of osteoarticular (neck pain with or without root signs) and neurovascular symptoms (headache, auricular signs with vertigo, nystagmus, hypoacusia, retro-orbital pain, and photophobic diplopia).
Some patients with tinnitus could be evoked or modulated by input from the somatic system, for instance by forceful muscle contractions of the head, neck, and limbs, and pressure on myofascial trigger points; two-thirds of the individuals with tinnitus can modulate the loudness or pitch of their tinnitus by voluntary or external manipulations of the jaw, movements of the eyes, or pressure applied to head and neck regions. [7, 8]
CSD could cause subjective tinnitus evoking plastic changes in central nervous system (CNS) auditory pathways, moreover if concomitant with reduced serotoninergic (5-HT) filtering of incoming signals, yielding tinnitus chronicization in predisposed subjects.
Generation of tinnitus
Connections between the dorsal column of the spinal cord and the cochlear nuclei (CN) have been found in several animal studies. [9, 10] Such axons of the dorsal column originate from the C1–C8 dorsal roots of the spinal cord. In particular, CSD stimulation of the C2 dorsal root ganglion and fasciculus cuneatus converge to a common region of the lower medulla, the medullary somatosensory nuclei (MSN). The MSN fibers project to the ipsilateral dorsal CN and the modulation of MSN on DCN results in disinhibition of DCN; form which it generates responses from cells in the CN. Increased DCN activity should then be relayed to higher auditory centers, resulting in tinnitus. 
Blood to the inner ear is supplied by the internal auditory artery, which usually originates from the AICA, branch of the basilar artery (BA), which provides the brainstem and cerebellum, arising from the intersection of two vertebral arteries (VAs) at the ponto-medullary junction. Based on this close anatomical relationship between the vertebral arteries and the cervical spine, CSD may also affect vertebral artery hemodynamics which can cause inner ear blood impairment. It is known that the inner ear is an ‘‘end organ’’, since it is supplied only by one or two cochlear arteries, which stem from branches of the internal auditory artery.  The consequent cochlear damage reduces cochlear nerve activity, and such reduced activity within the affected peripheral auditory region downregulates inhibitory cortical processes. Down-regulation leads to hyperexcitability within central auditory structures, including primary auditory cortex.  Chronic CSD not rarely can cause trigeminal irritation which may reduce cochlear blood supply with subsequent Corti’s organ cells damage. 
Elaboration of tinnitus and “tinnitus memory circuits”
In the sensory system, Serotonin (5-HT) transmission represents one of the most important modulatory network and plays a pivotal role in the perception and processing of painful stimuli.  Since 1948, when 5-HT was first isolated, to this date, researchers have identified 15 distinct 5-HT receptors.  As shown by Thompson et al.  serotonergic fibres and terminal endings are present in most of auditory nuclei in CNS, particularly in the cochlear nucleus (CN), inferior colliculus (IC), the nuclei of the lateral lemniscus and superior olivary complex, . Therefore, a reduction of serotoninergic tone could lead to an increased neural activity resulting in the consolidation of plastic changes in higher auditory centers.
Studies with positron emission tomographic (PET) pointed out an increased activation of auditory cortical areas involving in the pathological subjective tinnitus. 
Some genetic factors causing serotoninergic dysfunction, may contribute to tinnitus susceptibility. Polymorphisms in genes expressing proteins relevant to 5-HT neurotransmission can lead to important consequences in the 5HT pattern. A common polymorphism at the promoter region of serotonin transporter gene influences the reuptake of serotonin, thereby regulating its concentration in the synaptic cleft., Serotonin reuptake is attenuated, resulting in increased availability of serotonin in the synapse and down-regulation of post-synaptic binding sites among individuals with one or more copies of the short allele at this location. 
Some studies stressed that the short/short and short/long genotypes provide approximately 50% reduction in 5-HTT expression and 5-HT uptake, as compared the long/long genotype, both in vitro  and in vivo.  It will be interesting to evaluate whether tinnitus predisposition may be conferred by the “long” allele, whose enhanced transcriptional efficiency can be expected to result in increased 5-HT uptake and decreased extracellular serotonergic activity.
The pathogenesis of subjective tinnitus in individuals with CSD may include two components:
1. the signal generation
A. The generation of a neural signal by CSD-induced stimulation of the dorsal roots of the spinal cord, transferred from somatosensory to auditory information coding at the level of the DCN,
B. The cochlear damage induced by inner ear blood impairment.
2. A reduction of 5-HT filtering of incoming sensory signals allowing aberrant neural activity from the periphery to induce and consolidate memory circuits in higher auditory centers (Fig. 1).
If proven correct in animal and human models, this hypothesis would be consistent with early and specific multidisciplinary treatments to prevent the “tinnitus memory circuits”. These treatments will likely have to focus on amelioration of the CSD and/or on pharmacologically potentiating 5-HT neurotransmission. Most importantly, therapeutic interventions should be undertaken prior to the establishment of irreversible plastic changes in the CNS.
The pathogenesis of subjective tinnitus
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