OptiNAD+ and tinnitus

We got one email regarding tinnitus and OptiNAD+, and our support team responded right away. The person was speculating that it might be from depletion of methyl groups, and Rachael from our support team told him that is what the trimethylglycine was in there for. She also said that often times reactions can be very complex, and it is difficult or impossible for us to speculate as to why one person might react one way to something. She also explained that we are limited in our capacity to respond by the FDA as well, as we are not doctors. We cannot attempt to fulfill the role of a physician by diagnosing, preventing, treating, or curing a disease. The person who emailed us said he was going to go see his doctor about it. That's where it was left.

To start, tinnitus is a poorly understood issue, and likely a very complex mechanism. I have bad tinnitus from not protecting my ears from sound systems in clubs that were running them too high, and a firework that went off next to my head. It's constant for me, and something I will just have to live with the rest of my life. My father told me when I was young to protect my ears, but we are all idiots when we are young, so I didn't really listen. I wish I had. Anyone here reading this: PROTECT YOUR EARS! If you are going to be in a place with loud music, have a set of high fidelity ear plugs with you. Literally one night in a club running their systems too high can change your ears for the rest of your life. I actually completely lost hearing in one of my ears for weeks. It took over a year for it to get back to normal, and that new normal was not like before. Being extra cautious with your ears around loud noises is always a good idea.

Tinnitus is estimated to affect 20% of the people in the US and Europe. Many people have mild tinnitus and don't realize it at first. In fact, people just saying the word tinnitus makes me focus on it and make it worse. That's a very common thing in people that have tinnitus. Hearing someone talk about it, or reading someone discussing it, can bring it back to the forefront in your mind. Tinnitus is one of the most commonly reported side effects of many drugs, and even some drugs that show promise in helping with tinnitus can cause it/set it off in other people. Other factors like stress, fatigue, smoking, poor sleep, and diet are commonly associated with it as well. Many things cause issues with studying tinnitus, too. Dropouts and noncompliance is a big issue in studies trying to assess it. Then you have the variable nature of the factors and treatment from person to person. Some people get relief from using benzodiazepines. Other people have their tinnitus set off by benzos. Some people have it set off by antihistamines. Aspirin is another one that commonly sets it off in some people. There has been speculation that insufficient GABA-mediated currents are to blame. Others have speculated that it is GABA-B specifically. Then yet others point towards the metabotropic glutamate receptors, which are co-expressed postsynaptically with GABA-B. Others have speculated that it is histamine related, and reduction in brain histamine is to blame. However, some people treat their tinnitus with the histamine receptor agonist beta-histine. That's more common in tinnitus arising from Ménière’s disease, but the contradiction in lower/higher histamine still confounds things. Tinnitus is not a simple thing, and I don't think we are going to solve it here today. I wish we could, as I would prefer to not deal with tinnitus myself. However, tons of people have spent decades trying to just understand the mechanisms, much less figure out a way to treat it. Just for reference, my tinnitus is not affected by OptiNAD+, positively or negatively.

So where does that leave us? Well we can speculate all we want. A recent study does potentially shine some light on things.

Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition

Here, we developed an in vitro paradigm for imaging nucleus-level activity of auditory brainstem circuits in tinnitus mice. FA imaging revealed that DCN responses are increased in amplitude and their ability to spatially spread, a finding that is consistent with previously identified neural correlates of tinnitus. Moreover, we show pharmacological dissection of the contribution of excitation and inhibition in the generation of enhanced and more spatially spread FA response. Decreased GABAergic inhibition mediates, at least in part, these changes.

FA imaging has the advantage of homogeneous intrinsic labeling that leads to robust signals with low animal to animal variability. In addition, FA imaging can be used with older animals. These are important advantages over other in vitro imaging techniques that depend on the loading of exogenous dyes. The ability of FA imaging to reveal hyperactive auditory brainstem circuits in vitro is an important advancement in the field of tinnitus. Although hyperactivity may or may not be the cause of tinnitus (29, 30), hyperactivity provides a reliable marker of tinnitus that has also been seen in the inferior colliculus and the auditory cortex (13,23, 31–33). Given that FA imaging allows for measurement of circuit activity levels at different auditory nuclei within the same animal, FA imaging experiments in vitro are expected to provide information about the development of tinnitus. Determining the path (bottom up or top down) and the exact time course of the development of hyperactivity may allow for manipulations that can delay or stop the progression of tinnitus.

Similar autofluorescent intrinsic signals have also been recorded from activity-dependent changes in the redox state of nicotinamide adenine dinucleotide molecules NADH and NADPH [together as NAD(P)H] (34, 35). Despite the advantages offered by intrinsic signals, FA and NAD(P)H responses are slow and therefore, not ideal for cellular and microcircuit resolution. Previous studies have revealed that FA signal is primarily related to postsynaptic activity, although a late part of the response may be related to glial activity (16, 18, 20). FA responses were only partially inhibited by CNQX and AP5 in the DCN (Fig. 5), indicating that antidromic/presynaptic activity as well as postsynaptic activity contribute to the FA autofluorescence responses. Additionally, activation of metabotropic glutamate receptors may contribute to the remaining FA signal. Our results are consistent with FA cortical slice responses (16). Although FA signals are not suitable for cellular resolution, they can reveal specific hypotheses about altered microcircuit and neurotransmitter properties associated with tinnitus that can be assessed with whole-cell recording and more sensitive circuit mapping techniques.

Our results provide information about the tinnitus-associated changes in the balance of excitation and inhibition in the DCN. Previous studies have suggested that tinnitus-related hyperactivity is mediated by the lack of glycinergic inhibition, which is evidenced by altered in vivo response of DCN principal neurons to increasing levels of sound and changes in the expression of specific glycine receptor subunits (11, 12, 28). However, no antagonists in animals with behavioral evidence of tinnitus were used in these studies. Here, we used specific antagonists to dissect the role of glycine and GABARs in the spread of FA signal. Application of these antagonists revealed that a reduction in GABAergic inhibition is the main cause for increased DCN surround signals in tinnitus mice. We used electrical stimulation for all of our experiments, and therefore, we hypothesize that changes in electrically evoked activation of synaptic GABARs enhance the spread of FA signals in tinnitus mice. However, our results cannot exclude the role of changes in tonic GABA inhibition in mediating the enhanced FA signal in tinnitus mice. Our proposed mechanism is consistent with the effect of several GABA-enhancing drugs that reduce the perceptual loudness of tinnitus in some patients (36). Our results do not exclude the contribution of the previously observed changes in the expression of glycine receptor subunits (28) in determining the expression of other neural correlates of tinnitus such as increased synchrony or altered tonotopy. Additionally, our results cannot exclude changes in intrinsic properties of principal neurons or changes in the excitability of axons. Finally, our studies indicate that no changes in excitatory neurotransmission mediate enhanced signals in tinnitus mice. Although previous studies have suggested that an increase in excitatory inputs in the DCN after noise damage could lead to hyperactivity (15), our study provides an experimental test of the role of excitation and inhibition in the same animals with behavioral evidence of tinnitus.