Here is an interesting question, but first the background info:
1. According to the available literature, panic attacks are accompanied by increased levels of orexin.
2. In my understanding the onset period of narcolepsy, during which time the orexin neurons are destroyed by the presumed autoimmune reaction, is about six months.
3. There is much anecdotal evidence (apparently unknown to any researchers) gained from speaking with narcoleptics that panic attacks are common in narcoleptics prior to "finalizing" (my term) of the disorder between the ages (approx.) of 25 and 35, even though symptom onset may have begun as early as infancy.
The question: How is this possible? If narcolepsy is a condition characterized by low or undetectable CSF levels of orexin, how can narcoleptics be having panic attacks, which are characterized by high orexin levels?
My surmise is that this phenomena is caused by the last dying orexin neurons working overtime to try to keep up the orexin supply, sometimes inadvertently oversupplying the peptide in the process. It is worth noting, however, that these panic attacks can go on for years before going away and the narcolepsy becoming symptomatically more pronounced.
Your opinions, corrections and suggestions are eagerly anticipated.
Note: Although I can provide a few citations, most of this is based on anecdotal information, including that provided by myself.
Moshe, I am interested in cataplexy and its relationship with laughter.
I believe the problem arises due to the fact that orexin is involved with more than one response.
" For example, as discussed by (Donadio et al., 2008), the defense reaction or the ‘fight-or-flight’ response is associated with stimulation of the medial hypothalamus and periaqueductal gray and changes in cardiorespiratory function related to potential motor activity, e.g., increased cardiac output, blood pressure, and ventilation. In contrast, the vigilance reaction is associated with stimulation of the lateral hypothalamus and the ventrolateral periaqueductal gray and changes in cardiorespiratory and motor function related to vigilance and preparation for action, e.g., inhibition of movement, increased attention, increased blood pressure, apnea and bradycardia. These workers argue that the cataplexy of orexin deficiency has considerable overlap with the vigilance reaction. An additional category of stress response is that of panic-anxiety attacks (Johnson et al., 2010). Here in rodent models an anxiety-like state can be induced by systemic infusion of sodium lactate along with chronic inhibition of GABA synthesis in the hypothalamus (Johnson et al., 2010). Silencing of hypothalamic orexin neurons by focal injection of an siRNA for prepro-orexin blocks the panic-anxiety response in this rodent model. The vigilance, fight-or-flight, and panic-anxiety stress responses are similar in many respects and all are linked to orexin. (See below)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405125/
Basil, Thanks for answering. I think I sort of understand the connection between maintenance of vigilance and cataplexy, although I don't understand how that connects to my question. And I'm fairly certain that I understand fairly well the connection between orexin and anxiety. Therefore my question. Working backwards from point #3 in my question, it makes no sense for people with N to have panic attacks some years after onset of N.
I presume you are aware that the cataplexy associated with N is caused by down dysregulation of norepinephrine, which itself is caused by missing or severely impaired orexinergic signaling? That's why SNRI's can be somewhat or even very effective at controlling C. It's been suggested that the point at which destruction of orexin neurons begets C is 95%.
If laughing is a vestigial response to relief from fear (which is why we laugh more at jokes that build some tension on the way to the relief of the punchline) that relief probably causes a dive in brain orexin levels. So if a type 1 narcoleptic has some remaining orexin such that his normal brain orexin levels are between 7 and 10 percent of normal (these number just for discussion purposes) and someone tells him a joke, the drop in orexin levels, and therefore the resulting down dysregulation of norepinephrine, due to the removal of the suspense of the telling of the joke should provoke an episode of C. Makes perfect sense to me.
If you have the time you might like to read my essay on humour and laughter. I am trying to work in the connection between laughter and cataplexy.
https://sites.google.com/site/basilhughhall/anewtheoryoflaughterandhumor
Basil:
As you know if you read my profile, I am not a scientist. I am a narcoleptic. While your writing is very accessible, there is simply far too much of it for my poor broken brain to handle. I did try.
I searched the document and found no mention of either orexin/hypocretin or norepinephrine. With all due respect I have made a great effort to understand orexin's role in the brain and in my view any neuropsychological examination of the "fight of flight" response would be incomplete without including that neuroprotein. And as I mentioned, now that the cause of cataplexy has been determined any attempt to understand the connection between laughter (or other emotion that triggers C) and C without considering the actions of orexin and norepinephrine is very much lacking, scientifically.
Thanks so much for enlightening me.
Moshe
Moshe, I am slowly building a picture of the nature of laughter. I still have to write up how the balance of serotonin and dopamine is important in both laughing and crying. I have long wondered why laughter causes cataplexy in certain individuals and I am only now looking at orexin. The whole thing, like anything connected with brain function, is extremely complex
On further research I find that there are two distinct orexins OR1 and OR2 which attach to two different receptors. Which complicates things as a loss of receptor cells can influence which orexin is not being, or not being, expressed.
"In normal REM sleep, several groups of monoaminergic cells become silent. Norepinephrine-, serotonin-, and histamine-containing neurons are inhibited."
It is low orexin input that lowers Norepinephrine levels which then gives rise to loss of muscle tone.
The inhibition of serotonin producing cells when orexin is low is interesting as low serotonin can give rise to anxiety attacks. I suffered from anxiety attacks, which stopped when I was given serotonin reuptake inhibitors. It could be that the lowering of serotonin, due to low orexin levels, is the cause of some anxiety attacks.
Basil, it's important to remember that orexin has been called the "conductor of the neural orchestra". Orexin acts as a sensor and reporter of external (environmental) and internal (biological) conditions and also acts to tweak the body's response to each. Orexin regulates food seeking, homeostasis, sex drive, thermogenesis, respiration, executive function and cognition, motivation, mood, circulatory and cardiac function, intestinal motility, olfactory perception and a host of other processes. Also, because orexin directly regulates other neurotransmitters, when orexin is not available the result is a series of cascading failures of those other systems that can cause a multitude of other symptoms that appear to be unrelated. This does not help in getting a dx.
Now, it appears you might be on to an answer to my question when you point out that low serotonin levels can give rise to panic attacks. I will look into that.
Regarding C, there it is also important to keep in mind that for many PWN (people with narcolepsy) laughter is only one of many possible triggers. Anger and frustration are common triggers. Happiness and sex are common triggers. I know many PWN +C (type 1 N) who have trained themselves to not experience any great range of emotion in order to forestall episodes of C. Think about that..... there is one of the greatest tragedies of this silent, invisible (mostly), heinous, horrific illness: Can you imagine training yourself not to love, not to laugh?
I'm glad to see your research is leading you in the right direction, and I hope you find out what you want to know. You may like to visit the Facebook group "Narcolepsy/Cataplexy Education Focused Group"; it's an open grop and you'll be able to chat with many PWN of both kinds. You might also be interested to read the attachment.
Best regards,
Moshe
https://docs.google.com/document/d/1erq61j-qoRvjgUSK5FlR8Hi874wdi3c88KaIJQ56RXU/edit?usp=sharing
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