Tinnitus, a phantom auditory perception that can seriously affect quality of life, is generally triggered by cochlear trauma and associated with aberrant activity throughout the auditory pathways, often referred to as hyperactivity. Studies suggest that non-auditory structures, such as prefrontal cortex (PFC), may be involved in tinnitus generation, by affecting sensory gating in auditory thalamus, allowing hyperactivity to reach the cortex and lead to perception. Indeed, human studies have shown that repetitive transcranial magnetic stimulation (rTMS) of PFC can alleviate tinnitus. The current study investigated whether this therapeutic effect is achieved through inhibition of thalamic hyperactivity, comparing effects of two common clinical rTMS protocols with sham treatment, in a guinea pig tinnitus model. Animals underwent acoustic trauma and once tinnitus developed were treated with either intermittent theta burst stimulation (iTBS), 20 Hz rTMS, or sham rTMS (10 days, 10 min/day; weekdays only). Tinnitus was reassessed and extracellular recordings of spontaneous tonic and burst firing rates in auditory thalamus made. To verify effects in PFC, densities of neurons positive for calcium-binding proteins, calbindin and parvalbumin, were investigated using immunohistochemistry. Both rTMS protocols significantly reduced tinnitus compared to sham. However, spontaneous tonic firing decreased following 20 Hz stimulation and increased following iTBS in auditory thalamus. Burst rate was significantly different between 20 Hz and iTBS stimulation, and burst duration was increased only after 20 Hz treatment. Density of calbindin, but not parvalbumin positive neurons, was significantly increased in the most dorsal region of PFC indicating that rTMS directly affected PFC. Our results support the involvement of PFC in tinnitus modulation, and the therapeutic benefit of rTMS on PFC in treating tinnitus, but indicate this is not achieved solely by suppression of thalamic hyperactivity.
Mild traumatic brain injury (mTBI) causes structural, cellular and biochemical alterations which are difficult to detect in the brain and may persist chronically following single or repeated injury. Lipids are abundant in the brain and readily cross the blood-brain barrier, suggesting that lipidomic analysis of blood samples may provide valuable insight into the neuropathological state. This study used liquid chromatography-mass spectrometry (LC-MS) to examine plasma lipid concentrations at 11 days following sham (no injury), one (1×) or two (2×) mTBI in rats. Eighteen lipid species were identified that distinguished between sham, 1× and 2× mTBI. Three distinct patterns were found: (1) lipids that were altered significantly in concentration after either 1× or 2× F mTBI: cholesterol ester CE (14:0) (increased), phosphoserine PS (14:0/18:2) and hexosylceramide HCER (d18:0/26:0) (decreased), phosphoinositol PI(16:0/18:2) (increased with 1×, decreased with 2× mTBI); (2) lipids that were altered in response to 1× mTBI only: free fatty acid FFA (18:3 and 20:3) (increased); (3) lipids that were altered in response to 2× mTBI only: HCER (22:0), phosphoethanolamine PE (P-18:1/20:4 and P-18:0/20:1) (increased), lysophosphatidylethanolamine LPE (20:1), phosphocholine PC (20:0/22:4), PI (18:1/18:2 and 20:0/18:2) (decreased). These findings suggest that increasing numbers of mTBI induce a range of changes dependent upon the lipid species, which likely reflect a balance of damage and reparative responses.
Animal models of tinnitus rely on interpretation of behavioural or reflexive tests to determine the presence of this phantom perception. A commonly used test is the gap prepulse inhibition of acoustic startle (GPIAS), which is often combined with prepulse inhibition (PPI) to ensure that reduced GPIAS suppression is not due to hearing loss caused by the acoustic trauma commonly used to trigger tinnitus development. In our laboratory GPIAS and PPI are routinely used on two colonies of outbred tri-colour guinea pigs. However, our results show that these colonies show divergent results even before any tinnitus-inducing treatment, which impacts their suitability in tinnitus models. Although colony 1 and 2 show similar results in PPI (~95% of animals showing significant suppression), only ~30% of colony 2 also shows significant suppression in GPIAS compared to ~75% of colony 1. Cochlear sensitivity measured using compound action potentials showed no significant differences between colonies. Therefore, peripheral threshold loss was excluded as a possible factor. Our results show that similar strains of laboratory animals can show highly divergent results and GPIAS testing for tinnitus will not work for every animal strain. In addition, our data support the notion that PPI and GPIAS responses may rely on different neural circuitry.
Background: Major depressive disorder is one of the most prevalent and costly medical conditions, with approximately 280 million people affected worldwide. It is estimated that 30-60% of individuals suffering from this disorder are treatment-resistant, not responding to psychotherapy or antidepressants. Non-invasive brain stimulation in the form of repetitive transcranial magnetic stimulation (rTMS) is often considered an alternative treatment with response rates of up to 60% in this population. However, outcomes are variable suggesting that treatment protocols remain suboptimal. Current clinical guidelines are poorly defined due to a lack of systematic evaluation when techniques were first developed. Our lab has compared a range of brain stimulation protocols in a preclinical model of treatment-resistant depression and has shown that rTMS delivered at a low intensity matches the behavioural effects obtained from the much higher intensities that are currently approved for the treatment of depression in the clinic. Structural brain changes were also observed at the lower intensity, which may lead to longer lasting beneficial effects as in seen in previous animal studies. It is hypothesised that the same outcomes will translate to patients in a clinical setting. Methods: Participants will be recruited from patients diagnosed with Major Depressive Disorder. The study will consist of 4 to 6 weeks of treatment comprising 20-30 sessions (weekdays-only) of rTMS to the left dorsolateral prefrontal cortex. A “head-to-head trial” has been established due to ethical considerations and the need to retain the current clinical protocol. Patients will be randomly assigned to the FDA-approved standard protocol or standard protocol plus an additional low intensity stimulation group. In addition, patients will undergo psychological testing and a blood test at baseline, post-treatment and again at a 6-month follow up appointment Discussion: This study will prospectively evaluate the antidepressant efficacy of a new rTMS parameter. Specifically, we will translate a novel low intensity rTMS protocol and compare its long-term effects to the current FDA-accredited standard protocol. We will also test the validity of blood biomarkers, including those identified in our previous animal studies, to objectively monitor individual’s response to rTMS treatment. Trial registration: Registered with Australian New Zealand Clinical Trials Registry, prospectively registered 20/11/2018, Registration ACTRN12618001889246.
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