For me, one simple fact offers opposition. When the brain is damaged, why are there times a "LTC" sufferer feels good, or does not notice something would be damaged. Why should we function absolutely right from time to time?
The assumption is that various brain functions are encoded and transmitted to their end organs by specific neuronal circuits. For example, if I want to wiggle my right thumb, the encoding of that action propogates through a specific "circuit". My prefrontal cortex initiates the will and a plan to wiggle my thumb, which is then propagated to my premotor cortex, which then sends signals to my basal ganglia, which then coordinates the sequence of movements to wiggle my thumb, which then sends signals to my primary left motor cortex. Signals from my left primary motor cortex then descends down through my left corona radiata fibers through my left internal capsule to my brainstem. From here, motor fibers carrying those signals cross the midline, at the bottom my brainstem (caudal medulla) to descend down through the right corticospinal tract of my spinal cord. These fibers then synapse with alpha-motor neurons of my peripheral nerves, which exit from my spinal cord, travel through my right brachial plexus in my shoulder and down to the neuromuscular junctions of the muscles of my right thumb, to convey those signals to my thumb, causing it to wiggle. This completes that "circuit" of neuronal connections to perform that function. If one segment of that "circuit" is broken, then theoretically, the ability to perform that function is lost.
So then why do many of us who are experiencing symptoms that are attributed to serotonin deficiency experience a fluctuation in our symptoms and an improvement after medication, if we have truly destroyed serotonin neurons and effectively broken the "circuit" involved in those functions? Why did my memory improve after tianeptine? Why does my dizziness still come and go? If I have destroyed, certain serotonin neurons involved in the circuits for memory storage and retreival and those that control dizziness, shouldn't those functions be persistently impaired without fluctation or improvement after medications that may increase serotonin?
We know that serotonin neurons derive from the dorsal and median raphe nuclei in the brainstem, and then ascend through the subcortical white matter, to innervate various cortical and subcortical structures. However, what if these ascending neurons from the brainstem are not intrinscially involved in the circuit designated for a specific function, but serve to modulate that circuit and control its functioning extrinsically? This led ScaredFirstTimer and I to come up with the following postulates:
1. The ascending serotonin neurons from the brainstem seem to extrinsically modulate various circuits embedded in cortical/subcortical tissue, rather than intrinsically be a part of those circuits.
2. The ability of population of serotonin fibers assigned to a specific circuit to modulate that circuit is based not necessarily on the number of fibers, but on the net serotonin outflow from those fibers to their assigned circuit.
3. This system is highly redundant, so that the loss of some fibers assigned to a circuit does not necessarily mean the loss of the ability to modulate their respective circuit because the remaining fibers still produce enough serotonin outflow to control the circuit.
These postulates led to the following model that may explain why we experience these transient fluctuations:
Suppose we have a circuit in our brain that is assigned to a specific neurologic function (for example, memory retrieval to our consciousness). Now suppose we have 100 serotonin fibers ascending from the brainstem assigned to specifically modulate this circuit. Lets say due to environmental and biologic factors, there is an 80% chance that each of these fibers are functioning at normal capacity at any given time. So on average, 80 of these 100 fibers are working normally.
Then lets say you need at least the equilavent serotonin outflow of 35 working fibers to properly modulate that circuit. Suppose then, after an MDMA neurotoxic event, you only have 40 remaining fibers left assigned to that circuit. If each of these remaining fibers have an 80% chance of functioning at normal capacity as we defined above, then on average 32 out of those 40 fibers are working normally, which is less than the requisite 35 fibers. So on an average day, that circuit is not modulated properly and the respective function is impaired.
However, lets say on a on a good day at least 35 of those fibers are firing normally. The chance of a "good day" in this scenario is 658008*(0.8^35 * 0.2^5) + 91390*(0.8^36 * 0.2^4) + 9880*(0.8^37 * 0.2^3) + 780*(0.8^38 * 0.2^2) + 40*(0.8^39 * 0.2) + (0.8^40) = approximately 16%. Conversely, the chance of a bad day would be 84%.
Now based on postulates 2 and 3, if we can increase the serotonin outflow from the remaining fibers so that outflow is greater than the equivalent outflow of 35 fibers firing normally, then the ability of the remaning fibers to modulate their assigned circuit would be retained. This would explain why agents that can increase serotonin outflow such as SSRIs can cause an improvement of the modulation of that circuit, resulting in an improved neurologic function corresponding to that circuit.
This model would also explain why some people are resistant to SSRI's, etc. If the loss of serotonin fibers due to MDMA is too high, then no matter how much you boost the serotonin outflow of the remaining fibers, it is not enough to meet the requisite outflow of the equivalent of 35 normally functioning fibers. Hence, you may find yourself in a situation like some LTC sufferers such as bben where any and all medications do not seem to work, whereas in others, such as Ro4eva, they do seem to work.
Finally, if we prescribe to the basic principle of traumatic brain injury, that the potential for recovery is based on age, extent of damage, and one's biologic predisposition to neuroplasticity and neurogenesis, then the greater the extent of damage (greater loss of serotonin fibers assigned to a specific circuit), the less likely it would be to have a functional recovery over one's lifetime. This would explain the relatively expeditious recovery of people likely Dawglaw, and persisent deficits seen in people like bben or Shambha.
Again, this is just a theoretical model. But it is a model that could explain fluctuations in symptoms, response to medications, and the ability for some to recover but not others, in the setting of serotonin fiber neurotoxicity and cell loss.
